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Haloperidol Oral Solution BP 10 mg/5 ml | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Increased mortality in elderly people with dementia
Rare cases of sudden death have been reported in psychiatric patients receiving antipsychotics, including haloperidol (see section 4.8).
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled study, the rate of death in patients treated with antipsychotics was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that treatment of elderly patients with haloperidol is also associated with increased mortality. This association may be stronger for haloperidol than for atypical antipsychotic medicinal products, is most pronounced in the first 30 days after the start of treatment, and persists for at least 6 months. 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.
Cardiovascular effects
QTc prolongation and/or ventricular arrhythmias, in addition to sudden death, have been reported with haloperidol (see sections 4.3 and 4.8). The risk of these events appears to increase with high doses, high plasma concentrations, in predisposed patients or with parenteral use, particularly intravenous administration.
Caution is advised in patients with bradycardia, cardiac disease, family history of QTc prolongation or history of heavy alcohol exposure. Caution is also required in patients with potentially high plasma concentrations (see section 4.4, Poor metabolisers of CYP2D6).
A baseline ECG is recommended before treatment. During therapy, the need for ECG monitoring for QTc interval prolongation and for ventricular arrhythmias must be assessed in all patients. Whilst on therapy, it is recommended to reduce the dose if QTc is prolonged, but haloperidol must be discontinued if the QTc exceeds 500 ms.
Electrolyte disturbances such as hypokalaemia and hypomagnesaemia increase the risk for ventricular arrhythmias and must be corrected before treatment with haloperidol is started. Therefore, baseline and periodic electrolyte monitoring is recommended.
Tachycardia and hypotension (including orthostatic hypotension) have also been reported (see section 4.8). Caution is recommended when haloperidol is administered to patients manifesting hypotension or orthostatic hypotension.
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. Observational studies comparing the stroke rate in elderly patients exposed to any antipsychotic to the stroke rate in those not exposed to such medicinal products found an increased stroke rate among exposed patients. This increase may be higher with all butyrophenones, including haloperidol. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other patient populations. Haloperidol must be used with caution in patients with risk factors for stroke.
Neuroleptic malignant syndrome
Haloperidol has been associated with neuroleptic malignant syndrome: a rare idiosyncratic response characterized by hyperthermia, generalised muscle rigidity, autonomic instability, altered consciousness and increased serum creatine phosphokinase levels. Hyperthermia is often an early sign of this syndrome. Antipsychotic treatment must be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.
Tardive dyskinesia
Tardive dyskinesia may appear in some patients on long-term therapy or after discontinuation of the medicinal product.
The syndrome is mainly characterized by rhythmic involuntary movements of the tongue, face, mouth or jaw. The manifestations may be permanent in some patients. The syndrome may be masked when treatment is reinstituted, when the dose is increased or when a switch is made to a different antipsychotic. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including haloperidol, must be considered.
Extrapyramidal symptoms
Extrapyramidal symptoms may occur (e.g. tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia). The use of haloperidol has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Acute dystonia may occur during the first few days of treatment with haloperidol, but later onset as well as onset after dose increases has been reported. Dystonic symptoms can include, but are not limited to, torticollis, facial grimacing, trismus, tongue protrusion, and abnormal eye movements, including oculogyric crisis. Males and younger age groups are at higher risk of experiencing such reactions. Acute dystonia may necessitate stopping the medicinal product.
Antiparkinson medicinal products of the anticholinergic type may be prescribed as required to manage extrapyramidal symptoms, but it is recommended that they are not prescribed routinely as a preventive measure. If concomitant treatment with an antiparkinson medicinal product is required, it may have to be continued after stopping haloperidol if its excretion is faster than that of haloperidol in order to avoid the development or aggravation of extrapyramidal symptoms. The possible increase in intraocular pressure must be considered when anticholinergic medicinal products, including antiparkinson medicinal products, are administered concomitantly with haloperidol.
Seizures/Convulsions
It has been reported that seizures can be triggered by haloperidol. Caution is advised in patients suffering from epilepsy and in conditions predisposing to seizures (e.g., alcohol withdrawal and brain damage).
Hepatobiliary concerns
As Haloperidol is metabolised by the liver, dose adjustment and caution is advised in patients with hepatic impairment (see sections 4.2 and 5.2). Isolated cases of liver function abnormalities or hepatitis, most often cholestatic, have been reported (see section 4.8).
Endocrine system concerns
Thyroxin may facilitate haloperidol toxicity. Antipsychotic therapy in patients with hyperthyroidism must be used only with caution and must always be accompanied by therapy to achieve a euthyroid state.
Hormonal effects of antipsychotics include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligomenorrhoea or amenorrhoea (see section 4.8). Tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Although no clear association with the administration of antipsychotics and human breast tumours has been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history. Haloperidol must be used with caution in patients with pre-existing hyperprolactinaemia and in patients with possible prolactin-dependent tumours (see section 5.3).
Hypoglycaemia and syndrome of inappropriate antidiuretic hormone secretion have been reported with haloperidol (see section 4.8).
Venous thromboembolism
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Haloperidol 10mg/5ml Oral Solution and preventive measures undertaken.
Treatment response and withdrawal
In schizophrenia, the response to antipsychotic treatment may be delayed.
If antipsychotics are withdrawn, recurrence of symptoms related to the underlying condition may not become apparent for several weeks or months.
There have been very rare reports of acute withdrawal symptoms (including nausea, vomiting and insomnia) after abrupt withdrawal of high doses of antipsychotics. Gradual withdrawal is advisable as a precautionary measure.
Patients with depression
It is recommended that haloperidol is not used alone in patients in whom depression is predominant. It may be combined with antidepressants to treat those conditions in which depression and psychosis coexist (see section 4.5).
Switch from mania to depression
There is a risk in the treatment of manic episodes of bipolar disorder for patients to switch from mania to depression.
Monitoring of patients for the switch to a depressive episode with the accompanying risks such as suicidal behaviour is important in order to intervene when such switches occur.
Poor metabolisers of CYP2D6
Haloperidol should be used with caution in patients who are known poor metabolisers of cytochrome P450 (CYP) 2D6 and who are coadministered a CYP3A4 inhibitor.
Paediatric population
Available safety data in the paediatric population indicate a risk of developing extrapyramidal symptoms, including tardive dyskinesia, and sedation. Limited long-term safety data are available.
4.5 |
Haloperidol Oral Solution BP 10 mg/5 ml | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
Cardiovascular effects
Haloperidol is contraindicated in combination with medicinal products known to prolong the QTc interval (see section 4.3).
Examples include:
• Class IA antiarrhythmics (e.g. disopyramide, quinidine).
• Class III antiarrhythmics (e.g. amiodarone, dofetilide, dronedarone, ibutilide, sotalol).
• Certain antidepressants (e.g. citalopram, escitalopram).
• Certain antibiotics (e.g. azithromycin, clarithromycin, erythromycin, levofloxacin, moxifloxacin, telithromycin).
• Other antipsychotics (e.g. phenothiazine derivatives, sertindole, pimozide, ziprasidone)
• Certain antifungals (e.g. pentamidine).
• Certain antimalarials (e.g. halofantrine).
• Certain gastrointestinal medicinal products (e.g. dolasetron).
• Certain medicinal products used in cancer (e.g. toremifene, vandetanib).
• Certain other medicinal products (e.g. bepridil, methadone).
This list is not exhaustive.
Caution is advised when haloperidol is used in combination with medicinal products known to cause electrolyte imbalance (see section 4.4).
Medicinal products that may increase haloperidol plasma concentrations
Haloperidol is metabolised by several routes (see section 5.2). The major pathways are glucuronidation and ketone reduction. The cytochrome P450 enzyme system is also involved, particularly CYP3A4 and, to a lesser extent, CYP2D6. Inhibition of these routes of metabolism by another medicinal product or a decrease in CYP2D6 enzyme activity may result in increased haloperidol concentrations. The effect of CYP3A4 inhibition and of decreased CYP2D6 enzyme activity may be additive (see section 5.2). Based on limited and sometimes conflicting information, the potential increase in haloperidol plasma concentrations when a CYP3A4 and/or CYP2D6 inhibitor is coadministered may range between 20 to 40%, although in some cases, increases of up to 100% have been reported. Examples of medicinal products that may increase haloperidol plasma concentrations (based on clinical experience or drug interaction mechanism) include:
• CYP3A4 inhibitors – alprazolam, fluvoxamine, indinavir, itraconazole, ketoconazole, nefazodone, posaconazole, saquinavir, verapamil, voriconazole.
• CYP2D6 inhibitors – bupropion, chlorpromazine, duloxetine, paroxetine, promethazine, sertraline, venlafaxine.
• Combined CYP3A4 and CYP2D6 inhibitors: fluoxetine, ritonavir.
• Uncertain mechanism – buspirone.
This list is not exhaustive.
Increased haloperidol plasma concentrations may result in an increased risk of adverse events, including QTcprolongation (see section 4.4). Increases in QTc have been observed when haloperidol was given with a combination of the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day).
It is recommended that patients who take haloperidol concomitantly with such medicinal products be monitored for signs or symptoms of increased or prolonged pharmacologic effects of haloperidol, and the haloperidol dose be decreased as deemed necessary.
Medicinal products that may decrease haloperidol plasma concentrations
Coadministration of haloperidol with potent enzyme inducers of CYP3A4 may gradually decrease the plasma concentrations of haloperidol to such an extent that efficacy may be reduced. Examples include:
• Carbamazepine, phenobarbital, phenytoin, rifampicin, St John's Wort (Hypericum perforatum).
This list is not exhaustive.
Enzyme induction may be observed after a few days of treatment. Maximal enzyme induction is generally seen in about 2 weeks and may then be sustained for the same period of time after the cessation of therapy with the medicinal product.
During combination treatment with inducers of CYP3A4, it is recommended that patients be monitored and the haloperidol dose increased as deemed necessary. After withdrawal of the CYP3A4 inducer, the concentration of haloperidol may gradually increase and therefore it may be necessary to reduce the haloperidol dose.
Sodium valproate is known to inhibit glucuronidation, but does not affect haloperidol plasma concentrations.
Effect of haloperidol on other medicinal products
Haloperidol can increase the CNS depression produced by alcohol or CNS-depressant medicinal products, including hypnotics, sedatives or strong analgesics. An enhanced CNS effect, when combined with methyldopa, has also been reported.
Haloperidol may antagonise the action of adrenaline and other sympathomimetic medicinal products (e.g. stimulants like amphetamines) and reverse the blood pressure-lowering effects of adrenergic-blocking medicinal products such as guanethidine.
Haloperidol may antagonise the effect of levodopa and other dopamine agonists.
Haloperidol is an inhibitor of CYP2D6. Haloperidol inhibits the metabolism of tricyclic antidepressants (e.g. imipramine, desipramine), thereby increasing plasma concentrations of these medicinal products.
Other forms of interaction
In rare cases the following symptoms were reported during the concomitant use of lithium and haloperidol: encephalopathy, extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome, acute brain syndrome and coma. Most of these symptoms were reversible. It remains unclear whether this represents a distinct clinical entity.
Nonetheless, it is advised that in patients who are treated concomitantly with lithium and haloperidol, therapy must be stopped immediately if such symptoms occur.
Antagonism of the effect of the anticoagulant phenindione has been reported.
4.6 |
Haloperidol Oral Solution BP 10 mg/5 ml | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
A moderate amount of data on pregnant women (more than 400 pregnancy outcomes) indicate no malformative or foeto/neonatal toxicity of haloperidol. However, there have been isolated case reports of birth defects following foetal exposure to haloperidol, mostly in combination with other medicinal products. Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of haloperidol during pregnancy.
Newborn infants exposed to antipsychotics (including haloperidol) 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, it is recommended that newborn infants be monitored carefully.
Breastfeeding
Haloperidol is excreted in human milk. Small amounts of haloperidol have been detected in plasma and urine of breastfed newborns of mothers treated with haloperidol. There is insufficient information on the effects of haloperidol in breastfed infants. A decision must be made whether to discontinue breastfeeding or to discontinue haloperidoltherapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility
Haloperidol elevates prolactin level. Hyperprolactinaemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients (see section 4.4).
4.7 |
Haloperidol Oral Solution BP 10 mg/5 ml | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Haloperidol has a moderate influence on the ability to drive and use machines. Some degree of sedation or impairment of alertness may occur, particularly with higher doses and at the start of treatment and may be potentiated by alcohol. It is recommended that patients be advised not to drive or operate machines during treatment, until their susceptibility is known.
4.8 |
Haloperidol Oral Solution BP 10 mg/5 ml | Clinical particulars - Undesirable effects | Undesirable effects
The safety of Haloperidol was evaluated in 284 haloperidol-treated subjects who participated in 3 placebo-controlled clinical studies and in 1295 haloperidol-treated patients who participated in sixteen double blind active comparator-controlled clinical studies.
Based on pooled safety data from these clinical studies, the most commonly reported adverse reactions were: Extrapyramidal disorder (34%), Insomnia (19%), Agitation (15%), Hyperkinesia (13%), Headache (12%), Psychotic disorder (9%), Depression (8%), Weight increased (8%), Tremor (8%), Hypertonia (7%), Orthostatic hypotension (7%), dystonia (6%) and Somnolence (5).
In addition, the safety of haloperidol decanoate was evaluated in 410 patients who participated in 3 comparator studies (1 comparing haloperidol decanoate versus fluphenazine and 2 comparing the decanoate formula to oral haloperidol), 9 open label studies and 1 dose response study.
Table 5 lists adverse reactions as follows:
• Reported in clinical studies with haloperidol.
• Reported in clinical studies with haloperidol decanoate and relate to the active moiety.
• From postmarketing experience with haloperidol and haloperidol decanoate.
Adverse reaction frequencies are based on (or estimated from) clinical trials or epidemiology studies with haloperidol, and classified using 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
Very rare:
<1/10,000
Not known:
cannot be estimated from the available data.
The adverse reactions are presented by System Organ Class and in order of decreasing seriousness within each frequency category.
Table 5: Adverse reactions
System Organ Class
Adverse Drug Reaction
Frequency
Very Common
Common
Uncommon
Rare
Not Known
Blood and lymphatic System disorders
Leukopenia
Pancytopenia
Agranulocytosis
Thrombocytopenia
Neutropenia
Immune System disorders
Hypersensitivity
Anaphylactic reaction
Endocrine disorders
Hyperprolactinaemia
Inappropriate antidiuretic hormone secretion
Metabolism and Nutritional disorders
Hypoglycaemia
Psychiatric disorders
Agitation
Insomnia
Psychotic disorder
Depression
Confusional state
Loss of libido
Libido decreased
Restlessness
Nervous System disorders
Extrapyramidal disorder
Hyperkinesia
Headache
Tardive dyskinesia
Akathisia
Bradykinesia
Dyskinesia
Dystonia
Hypokinesia
Hypertonia
Dizziness
Somnolence
Tremor
Convulsion
Parkinsonism
Sedation
Muscle contractions involuntary
Neuroleptic malignant syndrome
Motor dysfunction
Nystagmus
Akinesia
Cogwheel rigidity
Masked facies
Eye disorders
Oculogyric crisis
Visual disturbance
Vision blurred
Cardiac disorders
Tachycardia
Ventricular fibrillation
Torsade de pointes
Ventricular tachycardia
Extrasystoles
Vascular Disorders
Hypotension
Orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Dyspnoea
Bronchospasm
Laryngeal oedema
Laryngospasm
Gastrointestinal disorders
Vomiting
Nausea
Constipation
Dry mouth
Salivary hypersectretion
Hepatobiliary disorders
Liver function test abnormal
Hepatitis
Jaundice
Acute hepatic failure
Cholestasis
Skin and subcutaneous tissue disorders
Rash
Photosensitivity reaction
Urticaria
Pruritis
Hyperhidrosis
Angioedema
Dermatitis exfoliative
Leukocytoclastic vasculitis
Musculoskeletal and Connective Tissue disorders
Torticollis
Muscle rigidity
Muscle Spasms
Musculoskeletal stiffness
Trismus
Muscle twitching
Rhabdomyolysis
Renal and Urinary disorders
Urinary retention
Pregnancy, Puerperium and Perinatal conditions
Drug withdrawal syndrome neonatal (see section 4.6)
Reproductive System and Breast disorders
Erectile dysfunction
Amenorrhoea
Galactorrhoea
Dysmenorrhoea
Breast pain
Breast discomfort
Menorrhagia
Menstrual disorder
Sexual Dysfunction
Priapism
Gynaecomastiaa
General disorders and administration site conditions
Hyperthermia
Oedema
Gait disturbance
Sudden death
Face oedema
Hypothermia
Investigations
Weight increased
Weight decreased
Electrocardiogram QT prolonged
Electrocardiogram QT prolonged, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), torsade de pointes and sudden death have been reported with haloperidol.
Class effects of antipsychotics
Cardiac arrest has been reported with antipsychotics.
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotics. The frequency is unknown.
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.
4.9 |
Haloperidol Oral Solution BP 10 mg/5 ml | Clinical particulars - Overdose | Overdose
Symptoms and signs
The manifestations of haloperidol overdose are an exaggeration of the known pharmacological effects and adverse reactions. The most prominent symptoms are severe extrapyramidal reactions, hypotension and sedation. An extrapyramidal reaction is manifest by muscular rigidity and a generalised or localised tremor. Hypertension rather than hypotension is also possible.
In extreme cases, the patient would appear comatose with respiratory depression and hypotension that could be severe enough to produce a shock-like state. The risk of ventricular arrhythmias, possibly associated with QTc prolongation, must be considered.
Treatment
There is no specific antidote. Treatment is supportive. The efficacy of activated charcoal has not been established. Dialysis is not recommended in the treatment of overdose because it removes only very small amounts of haloperidol (see section 5.2).
For comatose patients, a patent airway must be established by use of an oropharyngeal airway or endotracheal tube. Respiratory depression may necessitate artificial respiration.
It is recommended that ECG and vital signs be monitored, and that monitoring continues until the ECG is normal. Treatment of severe arrhythmias with appropriate anti-arrhythmic measures is recommended.
Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma or concentrated albumin and vasopressor agents, such as dopamine or noradrenaline. Adrenaline must not be used because it might cause profound hypotension in the presence of haloperidol.
In cases of severe extrapyramidal reactions, parenteral administration of an antiparkinson medicinal product is recommended.
5. Pharmacological properties
5.1 |
Haloperidol Oral Solution BP 10 mg/5 ml | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
The average bioavailability of haloperidol after administration of the tablet or oral solution is 60 to 70%. Peak plasma levels of haloperidol are generally attained within 2 to 6 hours of oral dosing. A high inter-subject variability in plasma concentrations was observed. Steady state is reached within 1 week of treatment initiation.
Distribution
Mean haloperidol plasma protein binding in adults is approximately 88 to 92%. There is a high inter-subject variability for plasma protein binding. Haloperidol is rapidly distributed to various tissues and organs, as indicated by the large volume of distribution (mean values 8 to 21 l/kg after intravenous dosing). Haloperidol crosses the blood-brain barrier easily. It also crosses the placenta and is excreted in breast milk.
Biotransformation
Haloperidol is extensively metabolised in the liver. The main metabolic pathways of haloperidol in humans include glucuronidation, ketone reduction, oxidative N-dealkylation and formation of pyridinium metabolites. The metabolites of haloperidol are not considered to make a significant contribution to its activity; however, the reduction pathway accounts approximately for 23% of the biotransformation, and back-conversion of the reduced metabolite of haloperidol to haloperidol cannot be fully ruled out. The cytochrome P450 enzymes CYP3A4 and CYP2D6 are involved in haloperidol metabolism. Inhibition or induction of CYP3A4, or inhibition of CYP2D6, may affect haloperidol metabolism. A decrease in CYP2D6 enzyme activity may result in increased haloperidol concentrations.
Elimination
The terminal elimination half-life of haloperidol is on average 24 hours (range of means 15 to 37 hours) after oral administration. Haloperidol apparent clearance after extravascular administration ranges from 0.9 to 1.5 l/h/kg and is reduced in poor metabolisers of CYP2D6. Reduced CYP2D6 enzyme activity may result in increased concentrations of haloperidol. The inter-subject variability (coefficient of variation, %) in haloperidol clearance was estimated to be 44% in a population pharmacokinetic analysis in patients with schizophrenia. After intravenous haloperidol administration, 21% of the dose was eliminated in the faeces and 33% in the urine. Less than 3% of the dose is excreted unchanged in the urine.
Linearity/non-linearity
A linear relationship exists between haloperidol dose and plasma concentrations in adults.
Special populations
Elderly
Haloperidol plasma concentrations in elderly patients were higher than in younger adults administered the same dose. Results from small clinical studies suggest a lower clearance and a longer elimination half-life of haloperidol in elderly patients. The results are within the observed variability in haloperidol pharmacokinetics. Dose adjustment is recommended in elderly patients (see section 4.2).
Renal impairment
The influence of renal impairment on the pharmacokinetics of haloperidol has not been evaluated. About one-third of a haloperidol dose is excreted in urine, mostly as metabolites. Less than 3% of administered haloperidol is eliminated unchanged in the urine. Haloperidol metabolites are not considered to make a significant contribution to its activity, although for the reduced metabolite of haloperidol, back-conversion to haloperidol cannot be fully ruled out. Even though impairment of renal function is not expected to affect haloperidol elimination to a clinically relevant extent, caution is advised in patients with renal impairment, and especially those with severe impairment, due to the long half-life of haloperidol and its reduced metabolite, and the possibility of accumulation (see section 4.2).
Because of the high haloperidol distribution volume and its high protein binding, only very small amounts are removed by dialysis.
Hepatic impairment
The influence of hepatic impairment on the pharmacokinetics of haloperidol has not been evaluated. However, hepatic impairment may have significant effects on the pharmacokinetics of haloperidol because it is extensively metabolised in the liver. Therefore, dose adjustment and caution is advised in patients with hepatic impairment (see sections 4.2 and 4.4).
Paediatric population
Limited plasma concentration data were established in paediatric studies including 78 patients with various disorders (schizophrenia, psychotic disorder, Tourette's syndrome, autism) who received oral haloperidol doses up to a maximum of 30 mg/day. These studies included mainly children and adolescents aged between 2 and 17 years. Plasma concentrations measured at various time points and after various durations of treatment, were either undetectable or ranged up to a maximum of 44.3 ng/ml. As in adults, high inter-subject variability in plasma concentrations was observed. There was a trend toward shorter half-lives in children compared to adults.
In 2 studies in children receiving haloperidol treatment for tics and Tourette's syndrome, a positive response was associated with plasma concentrations of 1 to 4 ng/ml
Pharmacokinetic/pharmacodynamics relationships
Therapeutic concentrations
Based on published data from multiple clinical studies, therapeutic response is obtained in most patients with acute or chronic schizophrenia at plasma concentrations of 1 to 10 ng/ml. A subset of patients may require higher concentrations as a consequence of a high inter-subject variability in haloperidol pharmacokinetics.
In patients with first-episode schizophrenia, therapeutic response may be obtained at concentrations as low as 0.6 to 3.2ng/ml, as estimated based on measurements of D2 receptor occupancy and assuming that a D2 receptor occupancy level of 60 to 80% is most appropriate for obtaining therapeutic response and limiting extrapyramidal symptoms. On average, concentrations in this range would be obtained with doses of 1 to 4 mg daily.
Due to the high inter-subject variability in haloperidol pharmacokinetics and the concentration-effect relationship, it is recommended to adjust the individual haloperidol dose based on the patient's response, taking into account data suggesting a lag time of 5 days to reach half of the maximal therapeutic response. Measurement of haloperidol blood concentrations may be considered in individual cases.
Cardiovascular effects
The risk of QTc prolongation increases with haloperidol dose and with haloperidol plasma concentrations.
Extrapyramidal symptoms
Extrapyramidal symptoms can occur within the therapeutic range, although the frequency is usually higher with doses producing higher than therapeutic concentrations.
5.3 |
Haloperidol Oral Solution BP 10 mg/5 ml | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Non-clinical data reveal no special hazards for humans based on conventional studies of repeat dose toxicity and genotoxicity. In rodents, haloperidol administration showed a decrease in fertility, limited teratogenicity as well as embryo-toxic effects.
In a carcinogenicity study of haloperidol, dose-dependent increases in pituitary gland adenomas and mammary gland carcinomas were seen in female mice. These tumours may be caused by prolonged dopamine D2 antagonism and hyperprolactinaemia. The relevance of these tumour findings in rodents in terms of human risk is unknown.
Haloperidol has been shown to block the cardiac hERG channel in several published studies in vitro. In a number of in vivo studies, intravenous administration of haloperidol in some animal models has caused significant QTc prolongation at doses around 0.3 mg/kg, producing Cmax plasma levels at least 7 to 14 times higher than the therapeutic plasma concentrations of 1 to 10 ng/ml that were effective in the majority of patients in clinical studies. These intravenous doses, which prolonged QTc, did not cause arrhythmias. In some animal studies, higher intravenous haloperidol doses of 1 mg/kg or greater caused QTc prolongation and/or ventricular arrhythmias at Cmax plasma levels at least 38 to 137 times higher than the therapeutic plasma concentrations that were effective in the majority of patients in clinical studies.
6. |
Haloperidol Oral Solution BP 10 mg/5 ml | Pharmaceutical particulars - List of excipients | List of excipients
Lactic acid
Methylhydroxybenzoate
Propylhydroxybenzoate
Propylene Glycol
Purified Water
6.2 |
Haloperidol Oral Solution BP 10 mg/5 ml | Pharmaceutical particulars - Incompatibilities | Incompatibilities
None known
6.3 |
Haloperidol Oral Solution BP 10 mg/5 ml | Pharmaceutical particulars - Shelf life | Shelf life
3 years
6.4 |
Haloperidol Oral Solution BP 10 mg/5 ml | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25°C. Store in the original container.
6.5 |
Haloperidol Oral Solution BP 10 mg/5 ml | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
100 ml, 200 ml and 500 ml type III amber glass bottle with 28 x 18 ROPP LDPE plain white or aluminium cap with EPE (expanded polyethylene) wads and epoxy phenolic lacquer or child resistant closures with expanded polyethylene liners.
100 ml, 200 ml and 500 ml high density polyethylene bottle with 28 mm white polypropylene closure.
Not all pack sizes may be marketed.
6.6 |
Haloperidol Oral Solution BP 10 mg/5 ml | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Not applicable.
7. |
Haloperidol Oral Solution BP 10 mg/5 ml | Marketing authorisation holder | Pinewood Laboratories Limited, Ballymacarbry, Clonmel, Co. Tipperary, Ireland
8. Marketing authorisation number(s)
PL 04917/0024
9. |
Haloperidol Oral Solution BP 10 mg/5 ml | Date of first authorisation/renewal of the authorisation | 27/02/2007
10. |
Haloperidol Oral Solution BP 10 mg/5 ml | Date of revision of the text | 23/10/2017 |
Haloperidol Oral Solution BP 5 mg/5 ml | Name of the medicinal product | Haloperidol Oral Solution BP 5 mg/5 ml
2. |
Haloperidol Oral Solution BP 5 mg/5 ml | Qualitative and quantitative composition | Each 5 ml contains 5 mg of Haloperidol
For the full list of excipients, see section 6.1.
3. |
Haloperidol Oral Solution BP 5 mg/5 ml | Pharmaceutical form | Oral Solution
4. |
Haloperidol Oral Solution BP 5 mg/5 ml | Clinical particulars - Therapeutic indications | Therapeutic indications
Adult patients aged 18 years and above
• Treatment of schizophrenia and schizoaffective disorder.
• Acute treatment of delirium when non-pharmacological treatments have failed.
• Treatment of moderate to severe manic episodes associated with bipolar I disorder.
• Treatment of acute psychomotor agitation associated with psychotic disorder or manic episodes of bipolar I disorder.
• Treatment of persistent aggression and psychotic symptoms in patients with moderate to severe Alzheimer's dementia and vascular dementia when non-pharmacological treatments have failed and when there is a risk of harm to self or others.
• Treatment of tic disorders, including Tourette's syndrome, in patients with severe impairment after educational, psychological and other pharmacological treatments have failed.
• Treatment of mild to moderate chorea in Huntington's disease, when other medicinal products are ineffective or not tolerated.
Paediatric patients
Treatment of:
• Schizophrenia in adolescents aged 13 to 17 years when other pharmacological treatments have failed or are not tolerated.
• Persistent, severe aggression in children and adolescents aged 6 to 17 years with autism or pervasive developmental disorders, when other treatments have failed or are not tolerated.
• Tic disorders, including Tourette's syndrome, in children and adolescents aged 10 to 17 years with severe impairment after educational, psychological and other pharmacological treatments have failed.
4.2 |
Haloperidol Oral Solution BP 5 mg/5 ml | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Adults
A low initial dose is recommended, which subsequently may be adjusted according to the patient's response. Patients must always be maintained on the minimal effective dose (see section 5.2).
Oral solution:
The dose recommendations for Haloperidol Oral Solution BP 5 mg/5 ml are presented in Table 1.
Table 1: Haloperidol dose recommendations for adults aged 18 years and above
Treatment of schizophrenia and schizoaffective disorder
• 2 to 10 mg/day orally, as a single dose or in 2 divided doses. Patients with first-episode schizophrenia generally respond to 2 to 4 mg/day, whereas patients with multiple-episode schizophrenia may need doses up to 10 mg/day.
• Adjustments to the dose may be made every 1 to 7 days.
•Doses above 10 mg/day have not demonstrated superior efficacy to lower doses in the majority of patients and may cause an increased incidence of extrapyramidal symptoms. The individual benefit-risk should be assessed when considering doses above 10 mg/day.
•The maximum dose is 20 mg/day because safety concerns outweigh the clinical benefits of treatment at higher doses.
Acute treatment of delirium when non-pharmacological treatments have failed
• 1 to 10 mg/day orally, as a single dose or in 2 to 3 divided doses.
• Treatment should be started at the lowest possible dose, and the dose should be adjusted in increments at 2- to 4- hour intervals if agitation continues, up to a maximum of 10 mg/day.
Treatment of moderate to severe manic episodes associated with bipolar I disorder
• 2 to 10 mg/day orally, as a single dose or in 2 divided doses.
• Adjustments to the dose may be made every 1 to 3 days.
• Doses above 10 mg/day have not demonstrated superior efficacy to lower doses in the majority of patients and may cause an increased incidence of extrapyramidal symptoms. The individual benefit-risk should be assessed when considering doses above 10 mg/day.
• The maximum dose is 15 mg/day because safety concerns outweigh the clinical benefits of treatment at higher doses.
• The continued use of Haloperidol should be evaluated early in treatment (see section 4.4).
Treatment of acute psychomotor agitation associated with psychotic disorder or manic episodes of bipolar I disorder
• 5 to 10 mg orally, repeated after 12 hours if necessary to a maximum of 20 mg/day.
• The continued use of Haloperidol should be evaluated early in treatment (see section 4.4).
• When switching from haloperidol intramuscular injection, Haloperidol orally should be initiated at a 1:1 dose conversion rate followed by dose adjustment according to clinical response.
Treatment of persistent aggression and psychotic symptoms in patients with moderate to severe Alzheimer's dementia and vascular dementia when non-pharmacological treatments have failed and when there is a risk of harm to self or others
• 0.5 to 5 mg/day orally, as a single dose or in 2 divided doses.
• Adjustments to the dose may be made every 1 to 3 days.
• The need for continued treatment must be reassessed after no more than 6 weeks.
Treatment of tic disorders, including Tourette's syndrome, in patients with severe impairment after educational, psychological and other pharmacological treatments have failed
• 0.5 to 5 mg/day orally, as a single dose or in 2 divided doses.
• Adjustments to the dose may be made every 1 to 7 days.
• The need for continued treatment must be reassessed every 6 to 12 months.
Treatment of mild to moderate chorea in Huntington's disease, when other medicinal products are ineffective or not tolerated
• 2 to 10 mg/day orally, as a single dose or in 2 divided doses.
• Adjustments to the dose may be made every 1 to 3 days.
5mg/5ml oral solution:
The quantity (ml) required to achieve a given single dose using Haloperidol Oral Solution BP 5 mg/5 ml is presented in Table 2.
Table 2: Conversion table for Haloperidol Oral Solution BP 5 mg/5 ml
mg haloperidol
ml Haloperidol Oral Solution BP 5 mg/5 ml
0.5mg
0.5 ml
1 mg
1 ml
2 mg
2 ml
5 mg
5 ml
10 mg
10 ml
15 mg
15 ml
20 mg
20 ml
Treatment withdrawal
Gradual withdrawal of haloperidol is advisable (see section 4.4).
Missed dose
If patients miss a dose, it is recommended that they take the next dose as usual, and do not take a double dose.
Special populations
Elderly
The following initial haloperidol doses are recommended in elderly patients:
• Treatment of persistent aggression and psychotic symptoms in patients with moderate to severe Alzheimer's dementia and vascular dementia when non-pharmacological treatments have failed and when there is a risk of harm to self or others – 0.5 mg/day.
• All other indications – half the lowest adult dose.
The haloperidol dose may be adjusted according to the patient's response. Careful and gradual dose up-titration in elderly patients is recommended.
The maximum dose in elderly patients is 5 mg/day.
Doses above 5 mg/day should only be considered in patients who have tolerated higher doses and after reassessment of the patient's individual benefit-risk profile.
Renal impairment
The influence of renal impairment on the pharmacokinetics of haloperidol has not been evaluated. No dose adjustment is recommended, but caution is advised when treating patients with renal impairment. However, patients with severe renal impairment may require a lower initial dose, with subsequent adjustments at smaller increments and at longer intervals than in patients without renal impairment (see section 5.2).
Hepatic impairment
The influence of hepatic impairment on the pharmacokinetics of haloperidol has not been evaluated. Since haloperidol is extensively metabolised in the liver, it is recommended to halve the initial dose, and adjust the dose with smaller increments and at longer intervals than in patients without hepatic impairment (see sections 4.4 and 5.2).
Paediatric population
The dose recommendations for Haloperidol Oral Solution BP 5 mg/5 ml are presented in Table 4.
Table 4: Haloperidol dose recommendations for paediatric populations
Treatment of schizophrenia in adolescents aged 13 to 17 years when other pharmacological treatments have failed or are not tolerated
• The recommended dose is 0.5 to 3 mg/day, administered orally in divided doses (2 to 3 times a day).
• It is recommended to assess the individual benefit-risk when considering doses above 3 mg/day.
• The maximum recommended dose is 5 mg/day.
• The treatment duration must be individually evaluated.
Treatment of persistent, severe aggression in children and adolescents aged 6 to 17 years with autism or pervasive developmental disorders, when other treatments have failed or are not tolerated
• The recommended doses are 0.5 to 3 mg/day in children aged 6 to 11 years and 0.5 to 5 mg/day in adolescents aged 12 to 17 years, administered orally in divided doses (2 to 3 times a day).
• The need for continued treatment must be reassessed after 6 weeks.
Treatment of tic disorders, including Tourette's syndrome, in children and adolescents aged 10 to 17 years with severe impairment after educational, psychological and other pharmacological treatments have failed
• The recommended doses are 0.5 to 3 mg/day in children and adolescents aged 10 to 17 years, administered orally in divided doses (2 to 3 times a day).
• The need for continued treatment must be reassessed every 6 to 12 months.
The safety and efficacy of Haloperidol Oral Solution BP 5 mg/5 ml in children below the ages defined in the indications have not been established. Data are not available for children aged less than 3 years.
Method of administration
Haloperidol Oral Solution BP 5 mg/5 ml is for oral use.
4.3 |
Haloperidol Oral Solution BP 5 mg/5 ml | Clinical particulars - Contraindications | Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Comatose state.
• Central nervous system (CNS) depression.
• Parkinson's disease.
• Dementia with Lewy bodies.
• Progressive supranuclear palsy.
• Known QTc interval prolongation or congenital long QT syndrome.
• Recent acute myocardial infarction.
• Uncompensated heart failure.
• History of ventricular arrhythmia or torsades de pointes.
• Uncorrected hypokalaemia.
• Concomitant treatment with medicinal products that prolong the QT interval (see section 4.5).
4.4 |
Haloperidol Oral Solution BP 5 mg/5 ml | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Increased mortality in elderly people with dementia
Rare cases of sudden death have been reported in psychiatric patients receiving antipsychotics, including haloperidol (see section 4.8).
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled study, the rate of death in patients treated with antipsychotics was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that treatment of elderly patients with haloperidol is also associated with increased mortality. This association may be stronger for haloperidol than for atypical antipsychotic medicinal products, is most pronounced in the first 30 days after the start of treatment, and persists for at least 6 months. 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.
Cardiovascular effects
QTc prolongation and/or ventricular arrhythmias, in addition to sudden death, have been reported with haloperidol (see sections 4.3 and 4.8). The risk of these events appears to increase with high doses, high plasma concentrations, in predisposed patients or with parenteral use, particularly intravenous administration.
Caution is advised in patients with bradycardia, cardiac disease, family history of QTc prolongation or history of heavy alcohol exposure. Caution is also required in patients with potentially high plasma concentrations (see section 4.4, Poor metabolisers of CYP2D6).
A baseline ECG is recommended before treatment. During therapy, the need for ECG monitoring for QTc interval prolongation and for ventricular arrhythmias must be assessed in all patients. Whilst on therapy, it is recommended to reduce the dose if QTc is prolonged, but haloperidol must be discontinued if the QTc exceeds 500 ms.
Electrolyte disturbances such as hypokalaemia and hypomagnesaemia increase the risk for ventricular arrhythmias and must be corrected before treatment with haloperidol is started. Therefore, baseline and periodic electrolyte monitoring is recommended.
Tachycardia and hypotension (including orthostatic hypotension) have also been reported (see section 4.8). Caution is recommended when haloperidol is administered to patients manifesting hypotension or orthostatic hypotension.
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. Observational studies comparing the stroke rate in elderly patients exposed to any antipsychotic to the stroke rate in those not exposed to such medicinal products found an increased stroke rate among exposed patients. This increase may be higher with all butyrophenones, including haloperidol. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other patient populations. Haloperidol must be used with caution in patients with risk factors for stroke.
Neuroleptic malignant syndrome
Haloperidol has been associated with neuroleptic malignant syndrome: a rare idiosyncratic response characterized by hyperthermia, generalised muscle rigidity, autonomic instability, altered consciousness and increased serum creatine phosphokinase levels. Hyperthermia is often an early sign of this syndrome. Antipsychotic treatment must be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.
Tardive dyskinesia
Tardive dyskinesia may appear in some patients on long-term therapy or after discontinuation of the medicinal product.
The syndrome is mainly characterized by rhythmic involuntary movements of the tongue, face, mouth or jaw. The manifestations may be permanent in some patients. The syndrome may be masked when treatment is reinstituted, when the dose is increased or when a switch is made to a different antipsychotic. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including haloperidol, must be considered.
Extrapyramidal symptoms
Extrapyramidal symptoms may occur (e.g. tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia). The use of haloperidol has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Acute dystonia may occur during the first few days of treatment with haloperidol, but later onset as well as onset after dose increases has been reported. Dystonic symptoms can include, but are not limited to, torticollis, facial grimacing, trismus, tongue protrusion, and abnormal eye movements, including oculogyric crisis. Males and younger age groups are at higher risk of experiencing such reactions. Acute dystonia may necessitate stopping the medicinal product.
Antiparkinson medicinal products of the anticholinergic type may be prescribed as required to manage extrapyramidal symptoms, but it is recommended that they are not prescribed routinely as a preventive measure. If concomitant treatment with an antiparkinson medicinal product is required, it may have to be continued after stopping haloperidol if its excretion is faster than that of haloperidol in order to avoid the development or aggravation of extrapyramidal symptoms. The possible increase in intraocular pressure must be considered when anticholinergic medicinal products, including antiparkinson medicinal products, are administered concomitantly with haloperidol.
Seizures/Convulsions
It has been reported that seizures can be triggered by haloperidol. Caution is advised in patients suffering from epilepsy and in conditions predisposing to seizures (e.g., alcohol withdrawal and brain damage).
Hepatobiliary concerns
As Haloperidol is metabolised by the liver, dose adjustment and caution is advised in patients with hepatic impairment (see sections 4.2 and 5.2). Isolated cases of liver function abnormalities or hepatitis, most often cholestatic, have been reported (see section 4.8).
Endocrine system concerns
Thyroxin may facilitate haloperidol toxicity. Antipsychotic therapy in patients with hyperthyroidism must be used only with caution and must always be accompanied by therapy to achieve a euthyroid state.
Hormonal effects of antipsychotics include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligomenorrhoea or amenorrhoea (see section 4.8). Tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Although no clear association with the administration of antipsychotics and human breast tumours has been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history. Haloperidol must be used with caution in patients with pre-existing hyperprolactinaemia and in patients with possible prolactin-dependent tumours (see section 5.3).
Hypoglycaemia and syndrome of inappropriate antidiuretic hormone secretion have been reported with haloperidol (see section 4.8).
Venous thromboembolism
Cases of venous thromboembolism (VTE) have been reported with antipsychotics. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Haloperidol and preventive measures undertaken.
Treatment response and withdrawal
In schizophrenia, the response to antipsychotic treatment may be delayed.
If antipsychotics are withdrawn, recurrence of symptoms related to the underlying condition may not become apparent for several weeks or months.
There have been very rare reports of acute withdrawal symptoms (including nausea, vomiting and insomnia) after abrupt withdrawal of high doses of antipsychotics. Gradual withdrawal is advisable as a precautionary measure.
Patients with depression
It is recommended that haloperidol is not used alone in patients in whom depression is predominant. It may be combined with antidepressants to treat those conditions in which depression and psychosis coexist (see section 4.5).
Switch from mania to depression
There is a risk in the treatment of manic episodes of bipolar disorder for patients to switch from mania to depression.
Monitoring of patients for the switch to a depressive episode with the accompanying risks such as suicidal behaviour is important in order to intervene when such switches occur.
Poor metabolisers of CYP2D6
Haloperidol should be used with caution in patients who are known poor metabolisers of cytochrome P450 (CYP) 2D6 and who are coadministered a CYP3A4 inhibitor.
Paediatric population
Available safety data in the paediatric population indicate a risk of developing extrapyramidal symptoms, including tardive dyskinesia, and sedation. Limited long-term safety data are available.
4.5 |
Haloperidol Oral Solution BP 5 mg/5 ml | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
Cardiovascular effects
Haloperidol is contraindicated in combination with medicinal products known to prolong the QTc interval (see section 4.3).
Examples include:
• Class IA antiarrhythmics (e.g. disopyramide, quinidine).
• Class III antiarrhythmics (e.g. amiodarone, dofetilide, dronedarone, ibutilide, sotalol).
• Certain antidepressants (e.g. citalopram, escitalopram).
• Certain antibiotics (e.g. azithromycin, clarithromycin, erythromycin, levofloxacin, moxifloxacin, telithromycin).
• Other antipsychotics (e.g. phenothiazine derivatives, sertindole, pimozide, ziprasidone)
• Certain antifungals (e.g. pentamidine).
• Certain antimalarials (e.g. halofantrine).
• Certain gastrointestinal medicinal products (e.g. dolasetron).
• Certain medicinal products used in cancer (e.g. toremifene, vandetanib).
• Certain other medicinal products (e.g. bepridil, methadone).
This list is not exhaustive.
Caution is advised when haloperidol is used in combination with medicinal products known to cause electrolyte imbalance (see section 4.4).
Medicinal products that may increase haloperidol plasma concentrations
Haloperidol is metabolised by several routes (see section 5.2). The major pathways are glucuronidation and ketone reduction. The cytochrome P450 enzyme system is also involved, particularly CYP3A4 and, to a lesser extent, CYP2D6. Inhibition of these routes of metabolism by another medicinal product or a decrease in CYP2D6 enzyme activity may result in increased haloperidol concentrations. The effect of CYP3A4 inhibition and of decreased CYP2D6 enzyme activity may be additive (see section 5.2). Based on limited and sometimes conflicting information, the potential increase in haloperidol plasma concentrations when a CYP3A4 and/or CYP2D6 inhibitor is coadministered may range between 20 to 40%, although in some cases, increases of up to 100% have been reported. Examples of medicinal products that may increase haloperidol plasma concentrations (based on clinical experience or drug interaction mechanism) include:
• CYP3A4 inhibitors – alprazolam, fluvoxamine, indinavir, itraconazole, ketoconazole, nefazodone, posaconazole, saquinavir, verapamil, voriconazole.
• CYP2D6 inhibitors – bupropion, chlorpromazine, duloxetine, paroxetine, promethazine, sertraline, venlafaxine.
• Combined CYP3A4 and CYP2D6 inhibitors: fluoxetine, ritonavir.
• Uncertain mechanism – buspirone.
This list is not exhaustive.
Increased haloperidol plasma concentrations may result in an increased risk of adverse events, including QTc prolongation (see section 4.4). Increases in QTc have been observed when haloperidol was given with a combination of the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day).
It is recommended that patients who take haloperidol concomitantly with such medicinal products be monitored for signs or symptoms of increased or prolonged pharmacologic effects of haloperidol, and the haloperidol dose be decreased as deemed necessary.
Medicinal products that may decrease haloperidol plasma concentrations
Coadministration of haloperidol with potent enzyme inducers of CYP3A4 may gradually decrease the plasma concentrations of haloperidol to such an extent that efficacy may be reduced. Examples include:
• Carbamazepine, phenobarbital, phenytoin, rifampicin, St John's Wort (Hypericum perforatum).
This list is not exhaustive.
Enzyme induction may be observed after a few days of treatment. Maximal enzyme induction is generally seen in about 2 weeks and may then be sustained for the same period of time after the cessation of therapy with the medicinal product.
During combination treatment with inducers of CYP3A4, it is recommended that patients be monitored and the haloperidol dose increased as deemed necessary. After withdrawal of the CYP3A4 inducer, the concentration of haloperidol may gradually increase and therefore it may be necessary to reduce the haloperidol dose.
Sodium valproate is known to inhibit glucuronidation, but does not affect haloperidol plasma concentrations.
Effect of haloperidol on other medicinal products
Haloperidol can increase the CNS depression produced by alcohol or CNS-depressant medicinal products, including hypnotics, sedatives or strong analgesics. An enhanced CNS effect, when combined with methyldopa, has also been reported.
Haloperidol may antagonise the action of adrenaline and other sympathomimetic medicinal products (e.g. stimulants like amphetamines) and reverse the blood pressure-lowering effects of adrenergic-blocking medicinal products such as guanethidine.
Haloperidol may antagonise the effect of levodopa and other dopamine agonists.
Haloperidol is an inhibitor of CYP2D6. Haloperidol inhibits the metabolism of tricyclic antidepressants (e.g. imipramine, desipramine), thereby increasing plasma concentrations of these medicinal products.
Other forms of interaction
In rare cases the following symptoms were reported during the concomitant use of lithium and haloperidol: encephalopathy, extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome, acute brain syndrome and coma. Most of these symptoms were reversible. It remains unclear whether this represents a distinct clinical entity.
Nonetheless, it is advised that in patients who are treated concomitantly with lithium and haloperidol, therapy must be stopped immediately if such symptoms occur.
Antagonism of the effect of the anticoagulant phenindione has been reported.
4.6 |
Haloperidol Oral Solution BP 5 mg/5 ml | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
A moderate amount of data on pregnant women (more than 400 pregnancy outcomes) indicate no malformative or foeto/neonatal toxicity of haloperidol. However, there have been isolated case reports of birth defects following foetal exposure to haloperidol, mostly in combination with other medicinal products. Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of haloperidol during pregnancy.
Newborn infants exposed to antipsychotics (including haloperidol) 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, it is recommended that newborn infants be monitored carefully.
Breastfeeding
Haloperidol is excreted in human milk. Small amounts of haloperidol have been detected in plasma and urine of breastfed newborns of mothers treated with haloperidol. There is insufficient information on the effects of haloperidol in breastfed infants. A decision must be made whether to discontinue breastfeeding or to discontinue haloperidoltherapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility
Haloperidol elevates prolactin level. Hyperprolactinaemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients (see section 4.4).
4.7 |
Haloperidol Oral Solution BP 5 mg/5 ml | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Haloperidol has a moderate influence on the ability to drive and use machines. Some degree of sedation or impairment of alertness may occur, particularly with higher doses and at the start of treatment and may be potentiated by alcohol. It is recommended that patients be advised not to drive or operate machines during treatment, until their susceptibility is known.
4.8 |
Haloperidol Oral Solution BP 5 mg/5 ml | Clinical particulars - Undesirable effects | Undesirable effects
The safety of Haloperidol was evaluated in 284 haloperidol-treated subjects who participated in 3 placebo-controlled clinical studies and in 1295 haloperidol-treated patients who participated in sixteen double blind active comparator-controlled clinical studies.
Based on pooled safety data from these clinical studies, the most commonly reported adverse reactions were: Extrapyramidal disorder (34%), Insomnia (19%), Agitation (15%), Hyperkinesia (13%), Headache (12%), Psychotic disorder (9%), Depression (8%), Weight increased (8%), Tremor (8%), Hypertonia (7%), Orthostatic hypotension (7%), dystonia (6%) and Somnolence (5).
In addition, the safety of haloperidol decanoate was evaluated in 410 patients who participated in 3 comparator studies (1 comparing haloperidol decanoate versus fluphenazine and 2 comparing the decanoate formula to oral haloperidol), 9 open label studies and 1 dose response study.
Table 5 lists adverse reactions as follows:
• Reported in clinical studies with haloperidol.
• Reported in clinical studies with haloperidol decanoate and relate to the active moiety.
• From postmarketing experience with haloperidol and haloperidol decanoate.
Adverse reaction frequencies are based on (or estimated from) clinical trials or epidemiology studies with haloperidol, and classified using the following convention:
Very common:
Common:
Uncommon:
Rare:
Very rare:
Not known:
≥ 1/10
≥1/100 to <1/10
≥1/1,000 to <1/100
≥1/10,000 to <1/1,000
<1/10,000
cannot be estimated from the available data.
The adverse reactions are presented by System Organ Class and in order of decreasing seriousness within each frequency category.
Table 5: Adverse reactions
System Organ Class
Adverse Drug Reaction
Frequency
Very Common
Common
Uncommon
Rare
Not Known
Blood and lymphatic System disorders
Leukopenia
Pancytopenia
Agranulocytosis
Thrombocytopenia
Neutropenia
Immune System disorders
Hypersensitivity
Anaphylactic reaction
Endocrine disorders
Hyperprolactinaemia
Inappropriate antidiuretic hormone secretion
Metabolism and Nutritional disorders
Hypoglycaemia
Psychiatric disorders
Agitation Insomnia
Psychotic disorder
Depression
Confusional state
Loss of libido
Libido decreased
Restlessness
Nervous System disorders
Extrapyramidal disorder
Hyperkinesia
Headache
Tardive dyskinesia
Akathisia
Bradykinesia
Dyskinesia
Dystonia
Hypokinesia
Hypertonia
Dizziness
Somnolence
Tremor
Convulsion
Parkinsonism
Sedation
Muscle contractions involuntary
Neuroleptic malignant syndrome
Motor dysfunction
Nystagmus
Akinesia
Cogwheel rigidity
Masked facies
Eye disorders
Oculogyric crisis
Visual disturbance
Vision blurred
Cardiac disorders
Tachycardia
Ventricular fibrillation
Torsade de pointes
Ventricular tachycardia
Extrasystoles
Vascular Disorders
Hypotension
Orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Dyspnoea
Bronchospasm
Laryngeal oedema
Laryngospasm
Gastrointestinal disorders
Vomiting
Nausea
Constipation
Dry mouth
Salivary hypersectretion
Hepatobiliary disorders
Liver function test abnormal
Hepatitis
Jaundice
Acute hepatic failure
Cholestasis
Skin and subcutaneous tissue disorders
Rash
Photosensitivity reaction
Urticaria
Pruritis
Hyperhidrosis
Angioedema
Dermatitis exfoliative
Leukocytoclastic vasculitis
Musculoskeletal and Connective Tissue disorders
Torticollis
Muscle rigidity
Muscle Spasms
Musculoskeletal stiffness
Trismus
Muscle twitching
Rhabdomyolysis
Renal and Urinary disorders
Urinary retention
Pregnancy, Puerperium and Perinatal conditions
Drug withdrawal syndrome neonatal
(see section 4.6)
Reproductive System and Breast disorders
Erectile dysfunction
Amenorrhoea
Galactorrhoea
Dysmenorrhoea
Breast pain
Breast discomfort
Menorrhagia
Menstrual disorder
Sexual Dysfunction
Priapism
Gynaecomastiaa
General disorders and administration site conditions
Hyperthermia
Oedema
Gait disturbance
Sudden death
Face oedema
Hypothermia
Investigations
Weight increased
Weight decreased
Electrocardiogram QT prolonged
Electrocardiogram QT prolonged, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), torsade de pointes and sudden death have been reported with haloperidol.
Class effects of antipsychotics
Cardiac arrest has been reported with antipsychotics.
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotics. The frequency is unknown.
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.
4.9 |
Haloperidol Oral Solution BP 5 mg/5 ml | Clinical particulars - Overdose | Overdose
Symptoms and signs
The manifestations of haloperidol overdose are an exaggeration of the known pharmacological effects and adverse reactions. The most prominent symptoms are severe extrapyramidal reactions, hypotension and sedation. An extrapyramidal reaction is manifest by muscular rigidity and a generalised or localised tremor. Hypertension rather than hypotension is also possible.
In extreme cases, the patient would appear comatose with respiratory depression and hypotension that could be severe enough to produce a shock-like state. The risk of ventricular arrhythmias, possibly associated with QTc prolongation, must be considered.
Treatment
There is no specific antidote. Treatment is supportive. The efficacy of activated charcoal has not been established. Dialysis is not recommended in the treatment of overdose because it removes only very small amounts of haloperidol (see section 5.2).
For comatose patients, a patent airway must be established by use of an oropharyngeal airway or endotracheal tube. Respiratory depression may necessitate artificial respiration.
It is recommended that ECG and vital signs be monitored, and that monitoring continues until the ECG is normal. Treatment of severe arrhythmias with appropriate anti-arrhythmic measures is recommended.
Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma or concentrated albumin and vasopressor agents, such as dopamine or noradrenaline. Adrenaline must not be used because it might cause profound hypotension in the presence of haloperidol.
In cases of severe extrapyramidal reactions, parenteral administration of an antiparkinson medicinal product is recommended.
5. Pharmacological properties
5.1 |
Haloperidol Oral Solution BP 5 mg/5 ml | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
The average bioavailability of haloperidol after administration of the tablet or oral solution is 60 to 70%. Peak plasma levels of haloperidol are generally attained within 2 to 6 hours of oral dosing. A high inter-subject variability in plasma concentrations was observed. Steady state is reached within 1 week of treatment initiation.
Distribution
Mean haloperidol plasma protein binding in adults is approximately 88 to 92%. There is a high inter-subject variability for plasma protein binding. Haloperidol is rapidly distributed to various tissues and organs, as indicated by the large volume of distribution (mean values 8 to 21 l/kg after intravenous dosing). Haloperidol crosses the blood-brain barrier easily. It also crosses the placenta and is excreted in breast milk.
Biotransformation
Haloperidol is extensively metabolised in the liver. The main metabolic pathways of haloperidol in humans include glucuronidation, ketone reduction, oxidative N-dealkylation and formation of pyridinium metabolites. The metabolites of haloperidol are not considered to make a significant contribution to its activity; however, the reduction pathway accounts approximately for 23% of the biotransformation, and back-conversion of the reduced metabolite of haloperidol to haloperidol cannot be fully ruled out. The cytochrome P450 enzymes CYP3A4 and CYP2D6 are involved in haloperidol metabolism. Inhibition or induction of CYP3A4, or inhibition of CYP2D6, may affect haloperidol metabolism. A decrease in CYP2D6 enzyme activity may result in increased haloperidol concentrations.
Elimination
The terminal elimination half-life of haloperidol is on average 24 hours (range of means 15 to 37 hours) after oral administration. Haloperidol apparent clearance after extravascular administration ranges from 0.9 to 1.5 l/h/kg and is reduced in poor metabolisers of CYP2D6. Reduced CYP2D6 enzyme activity may result in increased concentrations of haloperidol. The inter-subject variability (coefficient of variation, %) in haloperidol clearance was estimated to be 44% in a population pharmacokinetic analysis in patients with schizophrenia. After intravenous haloperidol administration, 21% of the dose was eliminated in the faeces and 33% in the urine. Less than 3% of the dose is excreted unchanged in the urine.
Linearity/non-linearity
A linear relationship exists between haloperidol dose and plasma concentrations in adults.
Special populations
Elderly
Haloperidol plasma concentrations in elderly patients were higher than in younger adults administered the same dose. Results from small clinical studies suggest a lower clearance and a longer elimination half-life of haloperidol in elderly patients. The results are within the observed variability in haloperidol pharmacokinetics. Dose adjustment is recommended in elderly patients (see section 4.2).
Renal impairment
The influence of renal impairment on the pharmacokinetics of haloperidol has not been evaluated. About one-third of a haloperidol dose is excreted in urine, mostly as metabolites. Less than 3% of administered haloperidol is eliminated unchanged in the urine. Haloperidol metabolites are not considered to make a significant contribution to its activity, although for the reduced metabolite of haloperidol, back-conversion to haloperidol cannot be fully ruled out. Even though impairment of renal function is not expected to affect haloperidol elimination to a clinically relevant extent, caution is advised in patients with renal impairment, and especially those with severe impairment, due to the long half-life of haloperidol and its reduced metabolite, and the possibility of accumulation (see section 4.2).
Because of the high haloperidol distribution volume and its high protein binding, only very small amounts are removed by dialysis.
Hepatic impairment
The influence of hepatic impairment on the pharmacokinetics of haloperidol has not been evaluated. However, hepatic impairment may have significant effects on the pharmacokinetics of haloperidol because it is extensively metabolised in the liver. Therefore, dose adjustment and caution is advised in patients with hepatic impairment (see sections 4.2 and 4.4).
Paediatric population
Limited plasma concentration data were established in paediatric studies including 78 patients with various disorders (schizophrenia, psychotic disorder, Tourette's syndrome, autism) who received oral haloperidol doses up to a maximum of 30 mg/day. These studies included mainly children and adolescents aged between 2 and 17 years. Plasma concentrations measured at various time points and after various durations of treatment, were either undetectable or ranged up to a maximum of 44.3 ng/ml. As in adults, high inter-subject variability in plasma concentrations was observed. There was a trend toward shorter half-lives in children compared to adults.
In 2 studies in children receiving haloperidol treatment for tics and Tourette's syndrome, a positive response was associated with plasma concentrations of 1 to 4 ng/ml
Pharmacokinetic/pharmacodynamics relationships
Therapeutic concentrations
Based on published data from multiple clinical studies, therapeutic response is obtained in most patients with acute or chronic schizophrenia at plasma concentrations of 1 to 10 ng/ml. A subset of patients may require higher concentrations as a consequence of a high inter-subject variability in haloperidol pharmacokinetics.
In patients with first-episode schizophrenia, therapeutic response may be obtained at concentrations as low as 0.6 to 3.2ng/ml, as estimated based on measurements of D2 receptor occupancy and assuming that a D2 receptor occupancy level of 60 to 80% is most appropriate for obtaining therapeutic response and limiting extrapyramidal symptoms. On average, concentrations in this range would be obtained with doses of 1 to 4 mg daily.
Due to the high inter-subject variability in haloperidol pharmacokinetics and the concentration-effect relationship, it is recommended to adjust the individual haloperidol dose based on the patient's response, taking into account data suggesting a lag time of 5 days to reach half of the maximal therapeutic response. Measurement of haloperidol blood concentrations may be considered in individual cases.
Cardiovascular effects
The risk of QTc prolongation increases with haloperidol dose and with haloperidol plasma concentrations.
Extrapyramidal symptoms
Extrapyramidal symptoms can occur within the therapeutic range, although the frequency is usually higher with doses producing higher than therapeutic concentrations.
5.3 |
Haloperidol Oral Solution BP 5 mg/5 ml | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Non-clinical data reveal no special hazards for humans based on conventional studies of repeat dose toxicity and genotoxicity. In rodents, haloperidol administration showed a decrease in fertility, limited teratogenicity as well as embryo-toxic effects.
In a carcinogenicity study of haloperidol, dose-dependent increases in pituitary gland adenomas and mammary gland carcinomas were seen in female mice. These tumours may be caused by prolonged dopamine D2 antagonism and hyperprolactinaemia. The relevance of these tumour findings in rodents in terms of human risk is unknown.
Haloperidol has been shown to block the cardiac hERG channel in several published studies in vitro. In a number of in vivo studies, intravenous administration of haloperidol in some animal models has caused significant QTc prolongation at doses around 0.3 mg/kg, producing Cmax plasma levels at least 7 to 14 times higher than the therapeutic plasma concentrations of 1 to 10 ng/ml that were effective in the majority of patients in clinical studies. These intravenous doses, which prolonged QTc, did not cause arrhythmias. In some animal studies, higher intravenous haloperidol doses of 1 mg/kg or greater caused QTc prolongation and/or ventricular arrhythmias at Cmax plasma levels at least 38 to 137 times higher than the therapeutic plasma concentrations that were effective in the majority of patients in clinical studies.
6. |
Haloperidol Oral Solution BP 5 mg/5 ml | Pharmaceutical particulars - List of excipients | List of excipients
Lactic acid
Methylhydroxybenzoate
Propylhydroxybenzoate
Propylene Glycol
Purified Water
6.2 |
Haloperidol Oral Solution BP 5 mg/5 ml | Pharmaceutical particulars - Incompatibilities | Incompatibilities
None known
6.3 |
Haloperidol Oral Solution BP 5 mg/5 ml | Pharmaceutical particulars - Shelf life | Shelf life
3 years
6.4 |
Haloperidol Oral Solution BP 5 mg/5 ml | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25°C. Store in the original container.
6.5 |
Haloperidol Oral Solution BP 5 mg/5 ml | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
100 ml, 200 ml and 500 ml type III amber glass bottle with 28 x 18 ROPP LDPE plain white or aluminium cap with EPE (expanded polyethylene) wads and epoxy phenolic lacquer or child resistant closures with expanded polyethylene liners.
100 ml, 200 ml and 500 ml high density polyethylene bottle with 28 mm white polypropylene closure.
Not all pack sizes may be marketed.
6.6 |
Haloperidol Oral Solution BP 5 mg/5 ml | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Not applicable.
7. |
Haloperidol Oral Solution BP 5 mg/5 ml | Marketing authorisation holder | Pinewood Laboratories Limited, Ballymacarbry, Clonmel, Co. Tipperary, Ireland
8. Marketing authorisation number(s)
PL 04917/0023
9. |
Haloperidol Oral Solution BP 5 mg/5 ml | Date of first authorisation/renewal of the authorisation | 27/02/2007
10. |
Haloperidol Oral Solution BP 5 mg/5 ml | Date of revision of the text | 23/10/2017 |
Halothane | Name of the medicinal product | Halothane 100% Inhalation Vapour, Liquid.
2. |
Halothane | Qualitative and quantitative composition | Halothane BP 100% v/v.
The finished product is comprised only of the active ingredient, see section 6.1
3. |
Halothane | Pharmaceutical form | Inhalation Liquid.
4. |
Halothane | Clinical particulars - Therapeutic indications | Therapeutic indications
Induction and maintenance of general anaesthesia in adults and children. Use of halothane in paediatric dental anaesthesia should be restricted to hospitals only (see contraindications, section 4.3)
4.2 |
Halothane | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Adults
Induction: Anaesthesia may be induced with 2 to 4% v/v of halothane in oxygen or mixtures of nitrous oxide and oxygen. Induction may also be started at a concentration of 0.5% v/v and increased gradually to the required level.
Maintenance: Anaesthesia is maintained with concentrations of 0.5 to 2% depending on the flow rate used; the lower concentration is usually suitable for the elderly.
Children:
For induction in children a concentration of 1.5 to 2% v/v has been used.
Elderly:
Elderly patients tend to require less halothane than adults but the actual dose is dependent on the patient's physical state.
Method of administration
See section 6.6
4.3 |
Halothane | Clinical particulars - Contraindications | Contraindications
History of unexplained jaundice or pyrexia after a previous exposure to halothane is an absolute contra-indication to its future use in that patient.
Halothane is contraindicated in patients with known, or suspected, genetic predisposition to malignant hyperpyrexia. (see 4.4)
Children under 18 years undergoing dental procedures outside hospital (see 4.4)
4.4 |
Halothane | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Halothane can induce liver damage. Minor changes in serum amino- transferase activity have been reported to occur in up to 30% of patients. The incidence of severe liver damage (jaundice, which may lead to hepatic failure as a consequence of massive hepatic cell necrosis) is much rarer but cases requiring liver transplants and fatalities have been reported. The risk of developing hepatic failure appears to be greatly increased by repeated exposure to halothane. Although short intervals of time between exposures are likely to increase the risk of hepatotoxicity, even long intervals between exposure may not reduce the risks, since some patients have developed severe reactions to halothane given many years after the previous exposure.
Other risk factors for hepatotoxicity include female gender, obesity, middle age and a history of drug allergy. On present available information, the following precautions should be taken:
1. A careful anaesthetic history is to be taken from patients due to undergo anaesthesia in order to determine whether exposure to halothane took place and the nature of any adverse reaction to this agent.
2. History of unexplained jaundice or pyrexia after a previous exposure to halothane is an absolute contraindication to its future use in that patient.
3. Further exposure to halothane within three months is to be avoided unless there are overriding reasons for its re-use.
4. Patients who have exhibited adverse reactions to halothane should be informed and strictly instructed to alert their physician. Details of the reaction should be entered on the patient's medical records.
A rise in CSF and/or intracranial pressure might occur during neurosurgery, the effects of which may be mitigated by the use moderate hyperventilation.
Halothane reduces uterine muscle tone during pregnancy and generally its use is not recommended in obstetrics because of the increased risk of postpartum haemorrhage.
As with other agents of this type, halothane anaesthesia has been shown to trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperpyrexia. This is more common when halothane is co-administered with suxamethonium. The syndrome includes nonspecific features such as hypercapnia, muscle rigidity, tachycardia, tachypnoea, cyanosis, arrhythmias and unstable blood pressure. An increase in overall metabolism may be reflected in an elevated temperature. Treatment includes discontinuation of triggering agents, administration of dantrolene sodium and application of supportive therapy.
During the induction of halothane anaesthesia, a moderate fall in blood pressure commonly occurs. (Halothane lowers arterial blood pressure in a dose-dependent manner). The pressure tends to rise when the vapour concentration is reduced to maintenance levels, but it usually remains steady below the pre-operative level. This hypotensive effect is useful in providing a clear operating field and a reduction in haemorrhage. However, if necessary, intravenous doses of methoxamine (5 mg are usually adequate) can be given to counteract the fall in blood pressure.
Anaesthesia with halothane may be associated with bradycardia, which may augment its hypotensive effect. The intravenous administration of an anticholinergic agent before induction or during maintenance of anaesthesia should be considered, especially in situations where vagal tone is likely to be predominant or when halothane is used in conjunction with other agents likely to cause a bradycardia.
Halothane should be used with caution in patients with:
• Phaeochromocytoma
• Renal failure
• Pre-existing liver disease
• Myasthenia gravis
• Porphyria
Paediatric population
Arrhythmias are very common in children anaesthetised with halothane. Children anaesthetised with halothane should have ECG, blood pressure, oxygen saturation and end tidal CO2 monitoring in a setting where full resuscitative equipment is available and with staff fully trained in the resuscitation of children. The presence of additional arrhythmogenic factors especially hypoxia and carbon dioxide retention, use of sympathomimetics (see 4.5), and other factors which may stimulate the sympathetic nervous system should also be taken into account. Thus, to prevent hypoxia, inhalational anaesthetics are given with concentrations of oxygen greater than 21%.
Use of inhaled anaesthetic agents has been associated with very rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in children during the postoperative period. The condition has been described in patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy. Use of suxamethonium has been associated with most, but not all of these cases. These patients showed evidence of muscle damage with increased serum creatine kinase concentration and myoglobinuria. These patients did NOT have classical signs of malignant hyperthermia such as muscle rigidity, rapid increase in body temperature, or increased oxygen uptake and carbon dioxide production. Prompt and vigorous treatment for hyperkalaemia and arrhythmias is recommended. Subsequent evaluation for latent neuromuscular disease is indicated.
4.5 |
Halothane | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
The incidence of cardiac arrhythmias may be increased when adrenaline, most other sympathomimetics (e.g. methylphenidate), and theophylline are used concurrently with halothane. There is also an increased risk of hypertension when volatile liquid anaesthetics are given with methylphenidate.
The use of beta-adrenoceptor antagonists during halothane anaesthesia is at the discretion of the anaesthetist. The risk of arrhythmias is also increased if halothane is used in patients receiving dopaminergics (e.g. levodopa).
Muscle relaxants: All commonly used muscle relaxants may be used in conjunction with halothane, but, as halothane potentiates the actions of gallamine and D-Tubocurarine, the doses of these muscle relaxant must be reduced. The association of D-Tubocurarine with halothane may lead to a marked fall in blood pressure.
Ganglion blocking agents: Potentiation occurs between halothane and hypotensive agents such as pentolinium and trimetaphan. These drugs must be used in reduced dosage when administered in conjunction with halothane.
Halothane, along with all other general anaesthetics, may interact with aminoglycoside antibiotics resulting in respiratory depression. This effect may be potentiated by the concurrent use of a neuromuscular blocker.
The concurrent use of suxamethonium with halothane is not advisable due to the increased possibility of hyperpyrexia.
Morphine and chlorpromazine increase the depressant effects of halothane on respiration.
The effects of both ergometrine and oxytocin on the parturient uterus are diminished by halothane.
An enhanced hypotensive effect may be seen when general anaesthetics are given with adrenergic neurone blockers, alpha-blockers, antipsychotics or calcium channel blockers.
Monoamine oxidase inhibitors (MAOIs) should normally be stopped 2 weeks before surgery because of hazardous interactions between general anaesthetics and MAOIs.
4.6. |
Halothane | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy:
Studies in animals have shown reproductive toxicity (see section 5.3). Halothane reduces uterine muscle tone during pregnancy and generally its use is not recommended in obstetrics because of the increased risk of postpartum haemorrhage.
Breastfeeding:
Traces of halothane have been detected in breast milk. Breast feeding should be withheld for 24 hours after halothane anaesthesia.
4.7 |
Halothane | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Patients should not drive, or operate machinery, until fully recovered; i.e. for at least 24 hours after receiving halothane.
4.8 |
Halothane | Clinical particulars - Undesirable effects | Undesirable effects
The following undesirable effects have been reported following the use of halothane:
Hepatic necrosis, also known as “Halothane hepatitis” (see section 4.4) occurs rarely but fatalities have been reported. Severe hepatotoxicity occurs more frequently after repeated exposure to halothane.
Eosinophilia has been reported in conjunction with halothane induced hepatotoxicity.
Malignant hyperpyrexia has occasionally been reported with halothane, as with other halogenated anaesthetics. (see 4.4)
Cardiac arrhythmias are very common during halothane anaesthesia. Ventricular arrhythmias occur more frequently than with other volatile anaesthetic agents (see 4.4). There have been instances of cardiac arrest.
As with other halogenated anaesthetics, halothane has a depressant effect on the respiratory and cardiovascular systems and the following undesirable effects have been reported:
Respiratory depression
Hypotension (see 4.4)
Bradycardia (see 4.4)
Skeletal muscle relaxation
Post-operative nausea, vomiting and shivering.
Renal failure, sometimes with concurrent liver failure
Adverse reactions have been spontaneously reported during post-approval use of Halothane. These events are reported voluntarily from a population with an unknown rate of exposure. Therefore it is not possible to estimate the true incidence of adverse events.
Summary of Post-Marketing Adverse Drug Reactions
System Organ
Adverse Reactions
Cardiac disorders
Bradycardia
Intraoperative Cardiac arrest in patient with extraocular cystices
Ventricular extrasystole
Idioventricular rhythm
Hepatobiliary disorders
Fulminant Hepatic Failure
Acute toxic hepatitis
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 below.
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store
4.9 |
Halothane | Clinical particulars - Overdose | Overdose |
Halothane | Clinical particulars - Subsection 10 | Overdose is unlikely under normal circumstances. However, should it occur, halothane administration should cease immediately and the patient ventilated mechanically until blood gases return to an acceptable level.
Signs of overdose are bradycardia and profound hypotension.
5. Pharmacological properties
5.1 |
Halothane | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Halothane is absorbed on inhalation, anaesthesia being induced in about 5 minutes. Recovery is usually rapid but is dependent on the concentration of halothane used and the length of anaesthesia.
Halothane is largely (60-80%) excreted unchanged by the lungs, but variable amounts are metabolised by the liver. Urinary metabolites include trifluoroacetic acid, bromide and chloride ions. Other metabolites may be implicated in halothane hepatoxicity. Halothane also diffuses across the placenta.
5.3 |
Halothane | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Published studies in animals (including primates) at doses resulting in light to moderate anaesthesia demonstrate that the use of anaesthetic agents during the period of rapid brain growth or synaptogenesis results in cell loss in the developing brain that can be associated with prolonged cognitive deficiencies.
The clinical significance of these nonclinical findings in not known.
6. |
Halothane | Pharmaceutical particulars - List of excipients | List of excipients
None.
6.2 |
Halothane | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Vaporiser: Halothane must not be used in the EMO ether vaporiser as it attacks the metal; a vaporiser specially constructed for halothane should be used.
6.3 |
Halothane | Pharmaceutical particulars - Shelf life | Shelf life
60 months (unopened)
6.4 |
Halothane | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store in a dark place below 25°C. Keep well closed.
6.5 |
Halothane | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Amber glass bottle with red collar and an aluminum gold lacquered cap fitted with a polythene wad (contact face polyethylene terephthalate).
Pack size: 250 ml
6.6 |
Halothane | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
None stated.
7. |
Halothane | Marketing authorisation holder | Piramal Critical Care Limited
Suite 4, Ground Floor
Heathrow Boulevard - East Wing,
280 Bath Road,
West Drayton, UB7 0DQ,
United Kingdom
8. Marketing authorisation number(s)
PL 37071/0007
9. |
Halothane | Date of first authorisation/renewal of the authorisation | 01 February 1999/04 February 2009
10. |
Halothane | Date of revision of the text | 03/2019 |
Hana 75 microgram film coated tablets | Name of the medicinal product | Hana 75 microgram film coated tablets
2. |
Hana 75 microgram film coated tablets | Qualitative and quantitative composition | Each tablet contains 75 microgram desogestrel.
Excipient(s) with known effect: each tablet contains approximately 51.5 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
3. |
Hana 75 microgram film coated tablets | Pharmaceutical form | Film coated tablets (tablets).
The tablet is white, round and biconvex without a score line.
4. |
Hana 75 microgram film coated tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Hana is indicated as an oral contraceptive in women of childbearing age.
4.2 |
Hana 75 microgram film coated tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
To prevent pregnancy, Hana must be used as directed (see 'How to take Hana' and 'How to start Hana').
Special populations
Renal impairment
No clinical studies have been performed in patients with renal impairment.
Hepatic impairment
No clinical studies have been performed in patients with hepatic insufficiency. Since the metabolism of steroid hormones might be impaired in patients with severe hepatic disease, the use of Hana in these women is not indicated as long as liver function values have not returned to normal (see section 4.3).
Paediatric population
The safety and efficacy of Hana in adolescents below 18 years has not been established. No data are available.
Method of administration
Oral use.
How to take Hana
Tablets must be taken every day at the same time so that the interval between two tablets is always 24 hours. The first tablet should be taken on the first day of menstrual bleeding. Thereafter one tablet each day is to be taken continuously without taking any notice of possible bleeding. When a pack of pills is finished, a new pack should be started directly the day after the previous one.
How to start Hana
The woman should have none of the contraindications listed in section 4.3 and should be advised to consult with her physician if in doubt.
Any pre-existing bleeding abnormalities such as oligomenorrhoea and amenorrhoea should be investigated by a physician before starting Hana in order that any underlying pathology (see section 4.4) can be managed and followed-up appropriately.
No contraceptive use in the past month
It is preferable to start tablet-taking on day 1 of the woman's natural cycle (day 1 is the first day of menstrual bleeding). However, it can be started on days 2-5, but then a barrier method is recommended for the first 7 days of tablet-taking.
Following miscarriage or abortion
It is recommended to start tablet-taking immediately or within 5 days after miscarriage or abortion. In that case there is no need to use an additional method of contraception.
Following childbirth
The woman should start Hana any day between day 1 and day 21 after childbirth. When starting later, she should use a barrier method for the first 7 days of tablet-taking. However, if unprotected intercourse has already occurred, the woman should take a pregnancy test or talk to her physician before the actual start of Hana.
For additional information for breast-feeding women, see section 4.6.
Starting or resuming Hana after emergency contraception use
If a woman wishes to start taking or continue taking Hana after using emergency hormonal contraception, it is advisable to start tablet-taking on day 1 of the woman's natural cycle.
If she wants to start sooner and she has used emergency contraception containing:
Levonorgestrel
Hana can be started or restarted on the same day as emergency contraception containing levonorgestrel. Additional contraceptive measures (abstinence or barrier methods) are required for the first 7 days of Hana use.
Ulipristal acetate
Hana should be started or restarted no sooner than 5 days (120 hours) after emergency contraception containing ulipristal acetate, because the effectiveness of ulipristal can be reduced (see section 4.5). Additional contraceptive measures (abstinence or barrier methods) are required during the 5 day delay before starting or restarting Hana and for an additional 7 days after starting or restarting Hana (12 days in total).
Ulipristal acetate may conversely reduce the effectiveness of Hana. Concomitant use is therefore not recommended (see section 4.5).
How to start Hana when changing from other contraceptive methods
Changing from a combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring, or transdermal patch).
The woman should start Hana preferably on the day after the last active tablet (the last tablet containing the active substances) of her previous COC or on the day of removal of her vaginal ring or transdermal patch. In these cases, the use of an additional barrier method is not necessary.
The woman may also start at the latest on the day following the usual tablet-free, patch-free, ring-free, or placebo tablet interval of her previous combined hormonal contraceptive, but during the first 7 days of tablet-taking, patch or ring use, an additional barrier method is recommended.
Changing from a progestogen-only-method (minipill, injection, implant or a progestogen-releasing intrauterine system [IUS]).
The woman may switch any day from a minipill, on the day of removal of an implant or an IUS, or on the day the next contraceptive injection is due.
Management of missed tablets
Contraceptive protection may be reduced if more than 36 hours have elapsed between two tablets.
If the user is less than 12 hours late from her usual time of taking any tablet, she should take the missed tablet as soon as she remembers and take the next tablet at the usual time, even if it leads to taking two tablets in one day.
If she is more than 12 hours late from her usual taking time, the woman should immediately take the forgotten tablet and take the next tablet at the usual time, even if it leads to taking two tablets in one day. If more than one tablet has been missed, only one of the missed tablets should be taken immediately. In addition, she should use an additional barrier method of contraception for the next 7 days. Missed tablets at any time in the cycle can reduce the efficacy of Hana and risk pregnancy, but missing a tablet in the first week after initiation of Hana is an especially vulnerable time. The need for emergency contraception must be considered for any missed pills.
Advice in case of gastrointestinal disturbances
If vomiting occurs within 3-4 hours of tablet-taking, then the pill should be considered 'missed' and the advice for a missed tablet should be followed.
In case of severe or persistent gastro-intestinal disturbance (vomiting or diarrhoea), absorption of Hana may not be complete and contraceptive efficacy may be reduced. Additional contraceptive measures will be required for the duration of the illness and for the first 7 days of normal tablet taking.
Regular screening
Women should be advised to continue to have regular smear tests (cervical screening) while taking Hana. Women aged 50 years and above should be advised to attend for regular breast screening while women below 50 years should be advised to report any lump or change in their breast to their physician.
Women should be advised to go for a check-up at a sexual health clinic as soon as they can if they are worried they may have a Sexually Transmitted Infection (STI). Many STIs, including HIV (AIDS), have no symptoms at all. Women can only know for sure that they do not have an STI if they get tested.
4.3 |
Hana 75 microgram film coated tablets | Clinical particulars - Contraindications | Contraindications
Hana must not be used if any of the conditions listed below are present.
• Known or suspected sex-steroid sensitive malignancies.
• Active venous thromboembolic disorder.
• Presence or history of severe hepatic disease as long as liver function values have not returned to normal.
• Undiagnosed vaginal bleeding.
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 |
Hana 75 microgram film coated tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Excluding pregnancy
Excluding pregnancy before starting Hana
Women who have not recently been pregnant
Women who have recently been pregnant
Following childbirth
Following miscarriage, abortion or ectopic pregnancy
Pregnancy can reasonably be excluded if the woman
• has not had unprotected sex since the start of her last menstrual period
or
• has been correctly and consistently using a reliable method of contraception (including condoms where those have been used correctly for every episode of sexual intercourse)
or
• has had unprotected sex but only between day 1 and day 5 of her menstrual cycle.
Pregnancy can reasonably be excluded if the woman
• has not had unprotected sex since childbirth
or
• has had unprotected sex but less than 21 days after childbirth
or
• is fully breastfeeding, amenorrheic and less than 6 months postpartum.
Pregnancy can reasonably be excluded if the woman
• has not had unprotected sex since miscarriage, abortion or ectopic pregnancy
or
• has had unprotected sex but less than 5 days after miscarriage, abortion or ectopic pregnancy.
The woman should use a reliable method of contraception (current contraceptive or a barrier method) until the first day of her next period before starting Hana. She should be advised that if her menstrual period is already late or does not come when she expects it, she may be pregnant and she should do a pregnancy test (at least 3 weeks after the last episode of unprotected sexual intercourse) or see a physician. Provided the pregnancy test is negative she can start Hana on the first day of her next period. If, in the meantime, her menstrual period comes, she can start Hana on the first day of her period.
Excluding pregnancy before starting a new pack of Hana.
Before starting a new pack of Hana, a woman should be reasonably certain that she is not pregnant. If in doubt, particularly if she has not been using Hana correctly and consistently, she should be advised that there is a chance that she may be pregnant and she should do a pregnancy test at least 3 weeks after the last episode of unprotected intercourse. She should continue taking Hana until the result of the pregnancy test is available but if it is positive she should stop immediately and see a physician.
Warnings
If any of the conditions/risk factors mentioned below are present, the woman should be referred to her physician to weigh-up the benefits of progestogen use against the possible risks in her situation before she can start Hana.
In the event of exacerbation, or first appearance of any of these conditions, the woman should be referred to her physician. The physician should then decide on whether the use of Hana should be discontinued.
Breast cancer
Hana is contraindicated in women who have breast cancer because it may increase the risk of recurrence (Section 4.3).
Women with a past history of breast cancer should be referred to a physician before taking Hana.
The risk of breast cancer increases with age. The risk in users of progestogen-only contraceptives (POCs), such as Hana, is possibly of similar magnitude as that associated with combined oral contraceptives (COCs). However, for POCs the evidence is less conclusive.
During use of COCs the risk of having breast cancer diagnosed is slightly increased. This increased risk disappears gradually within 10 years after discontinuation of COC use and is not related to the duration of use, but to the age of the woman when using the COC. The expected number of cases diagnosed per 10,000 women who use COCs (up to 10 years after stopping) relative to never users over the same period has been calculated for the respective age groups and is presented in the table below.
Age group
Expected cases COC-users
Expected cases non-users
16-19 years
4.5
4
20-24 years
17.5
16
25-29 years
48.7
44
30-34 years
110
100
35-39 years
180
160
40-44 years
260
230
Compared to the risk of getting breast cancer ever in life, the increased risk associated with COCs is low. The cases of breast cancer diagnosed in COC users tend to be less advanced than in those who have not used COCs. The increased risk in COC users may be due to an earlier diagnosis, biological effects of the pill or a combination of both.
Hepatic disorders and disturbances of liver function
Hana is contraindicated in women who have, or have had, severe hepatic disease as long as liver function values have not returned to normal (Section 4.3).
When acute or chronic disturbances of liver function occur, the woman should be referred to a specialist for examination and advice.
Since a biological effect of progestogens on liver cancer cannot be excluded, an individual benefit/risk assessment should be made in women with liver cancer.
Hypertension
If sustained hypertension develops during the use of Hana, or if a significant increase in blood pressure does not adequately respond to antihypertensive therapy, a physician should decide whether Hana should be discontinued.
Thromboembolic disorders
Hana is contraindicated in women who have an active venous thromboembolic disorder (Section 4.3).
Epidemiological investigations have associated the use of COCs with an increased incidence of venous thromboembolism (VTE, deep venous thrombosis and pulmonary embolism). Although the clinical relevance of this finding for desogestrel used as a contraceptive in the absence of an oestrogenic component is unknown, Hana should be discontinued in the event of a thrombosis. Discontinuation of Hana should also be considered in case of long-term immobilisation due to surgery or illness.
Women with a history of thromboembolic disorders can take Hana but should be made aware of the possibility of a recurrence.
Changes in bleeding patterns
Hana is contraindicated in women who have undiagnosed vaginal bleeding before they first start taking the tablets (Section 4.3).
Women taking Hana will have bleeding patterns which differ from those associated with their natural cycle. If bleeding is not acceptable to the women (e.g. the frequency of the period is not acceptable), another contraceptive method should be considered. If the bleeding disturbances persist after stopping Hana, the women should be referred to her physician to rule out any pathological cause.
If the bleeding differs from that which would be expected with Hana or is unusually heavy, she should be referred to her physician to rule out any underlying pathology.
Women who repeatedly have post-coital bleeding should be investigated for underlying gynecological pathology, especially cervical cancer. Other causes of post-coital bleeding include benign growths (endometrial and cervical polyps, cervical ectropion); infection (cervicitis, pelvic inflammatory disease, endometritis, vaginitis due to STIs); genital/vulvar lesions (Herpes simplex virus, genital warts); benign conditions usually occurring in postmenopausal women such as vaginal atrophy and uterine prolapse; endometriosis; vaginal and endometrial cancer; and trauma (sexual abuse, foreign bodies).
It is usual that some women may experience amenorrhea because Hana primarily acts by inhibiting ovulation. However, because amenorrhea may indicate pregnancy, if use of Hana has been imperfect, women should be advised to do a pregnancy test. The treatment should be stopped if pregnancy occurs.
Diabetes
Although progestogens may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using progestogen-only pills. However, in the case of any change in insulin requirements during the first months of use, diabetic patients should be referred to their physician.
Psychiatric disorders
Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.
Ectopic pregnancy
Hana consistently inhibits ovulation and so reduces the risk of ectopic pregnancy (see section 5.1). However, as with all women of reproductive age, ectopic pregnancy should be considered in the differential diagnosis if the woman has pelvic pain with either vaginal bleeding/spotting or with amenorrhoea, particularly if Hana has been used inconsistently or incorrectly rendering pregnancy more likely.
Effect on bone mineral density
Treatment with Hana leads to decreased circulating estradiol, to a level corresponding to the early follicular phase. It is as yet unknown whether the decrease has any clinically relevant effect on bone mineral density.
Conditions reported during pregnancy or during sex steroid use
The following conditions have been reported both during pregnancy and during sex steroid use, but an association with the use of progestogens has not been established: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss; (hereditary) angioedema.
Chloasma
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking Hana or consider using another contraceptive.
Reduced efficacy
The efficacy of Hana may be reduced in the event of missed tablets (Section 4.2), gastro-intestinal disturbances (Section 4.2), or concomitant medications that decrease the plasma concentration of etonogestrel, the active metabolite of desogestrel (Section 4.5).
Lactose intolerance
Hana contains lactose and therefore should not be used by women with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption.
Sexually transmitted infections
Hana does not protect against HIV (AIDS) and other sexually transmitted infections.
4.5 |
Hana 75 microgram film coated tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Interactions
Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
Effect of other medicinal products on Hana
Interactions can occur with medicinal products that induce microsomal enzymes, which can result in increased clearance of sex hormones and may lead to breakthrough bleeding and/or contraceptive failure. Enzyme induction can occur after a few days of treatment. Maximum enzyme induction is generally observed within a few weeks. After drug therapy is discontinued, enzyme induction can last for about 4 weeks.
Short-term treatment
Women on treatment with hepatic enzyme-inducing medicinal or herbal products should be advised that the efficacy of Hana may be reduced. A barrier contraceptive method should be used in addition to Hana. The barrier method must be used during the whole time of concomitant drug therapy and for 28 days after discontinuation of the hepatic enzyme-inducing medicinal product.
Chronic and long-term treatment
If enzyme-inducing medicinal products are used chronically or long-term, Hana may not be the most appropriate method of contraception and the woman should be referred to her physician for further advice.
Substances increasing the clearance of contraceptive hormones (diminished contraceptive efficacy by enzyme induction) e.g.:
Barbiturates (e.g. phenobarbital), bosentan, carbamazepine, hydantoins (e.g. phenytoin), primidone, rifampicin, efavirenz and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate, rifabutin and products containing the herbal remedy St. John's Wort (Hypericum perforatum).
Substances with variable effects on the clearance of contraceptive hormones:
When co-administered with hormonal contraceptives, many combinations of HIV protease inhibitors (e.g. ritonavir, nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine) and/or combinations with Hepatitis C virus (HCV) medicinal products (e.g. boceprevir, telaprevir), can increase or decrease plasma concentrations of progestins. The net effect of these changes may be clinically relevant in some cases.
Therefore, the prescribing information of concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations. In case of any doubt, an additional barrier contraceptive method should be used by women on protease inhibitor or non-nucleoside reverse transcriptase inhibitor therapy.
Substances decreasing the clearance of contraceptive hormones (enzyme inhibitors):
Concomitant administration of strong (e.g. ketoconazole, itraconazole, clarithromycin) or moderate (e.g. fluconazole, diltiazem, erythromycin) CYP3A4 inhibitors may increase the serum concentrations of progestins, including etonogestrel, the active metabolite of desogestrel.
The clinical relevance of potential interactions with enzyme inhibitors remains unknown.
Hana and emergency contraception containing ulipristal acetate:
Hana and the emergency contraceptive containing ulipristal acetate both bind to the progesterone receptor. Concomitant use may result in reduced efficacy of both Hana and ulipristal acetate and is therefore not recommended. Hana should be started or restarted no sooner than 5 days (120 hours) after emergency contraception with ulipristal acetate (see section 4.2).
Effects of Hana on other medicinal products
Hormonal contraceptives may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations of other active substances may either increase (e.g. ciclosporine) or decrease (e.g. lamotrigine).
Laboratory tests
Data obtained with COCs have shown that contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, serum levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. The changes generally remain within the normal range. To what extent this also applies to progestogen-only contraceptives is not known.
4.6 |
Hana 75 microgram film coated tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
Hana is not indicated during pregnancy. If pregnancy occurs during treatment with Hana, further intake should be stopped.
Animal studies have shown that very high doses of progestogenic substances may cause masculinisation of female fetuses.
Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during early pregnancy. Pharmacovigilance data collected with various desogestrel-containing COCs also do not indicate an increased risk.
Breastfeeding
Based on clinical study data, Hana does not appear to influence the production or the quality (protein, lactose, or fat concentrations) of breast milk. However, there have been infrequent postmarketing reports of a decrease in breast milk production while using desogestrel. Small amounts of etonogestrel are excreted in the breast milk. As a result, 0.01 - 0.05 microgram etonogestrel per kg body weight per day may be ingested by the child (based on an estimated milk ingestion of 150 ml/kg/day). Like other progestogen-only pills, Hana can be used during breast feeding.
Limited long-term follow-up data are available on children, whose mothers started using desogestrel during the 4th to 8th week post-partum. They were breastfed for 7 months and followed up to 1.5 years (n=32) or to 2.5 years (n=14) of age. Evaluation of growth and physical and psychomotor development did not indicate any differences in comparison to nursing infants, whose mother used a copper-IUD. Based on the available data Hana may be used during lactation. The development and growth of a nursing infant, whose mother uses Hana, should, however, be carefully observed.
Fertility
Hana is indicated for the prevention of pregnancy. For information on return to fertility (ovulation), see section 5.1. There is no evidence suggesting a delay in return of fertility following discontinuation of desogestrel (see section 5.1); therefore if pregnancy is not desired, other contraceptive methods should be used immediately following discontinuation of Hana.
4.7 |
Hana 75 microgram film coated tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Hana has no or negligible influence on the ability to drive and use machines.
4.8 |
Hana 75 microgram film coated tablets | Clinical particulars - Undesirable effects | Undesirable effects
The most commonly reported undesirable effect in the clinical trials is bleeding irregularity. Bleeding irregularity of some kind has been reported in up to 50% of women using desogestrel. Since desogestrel causes ovulation inhibition in close to 100% of cycles, in contrast to other progestogen-only pills, irregular bleeding is more common than with other progestogen-only pills. In 20 - 30% of the women, bleeding may become more frequent, whereas in another 20% bleeding may become less frequent or totally absent.
Vaginal bleeding may also be of longer duration. After a couple of months of treatment, bleeding episodes tend to become less frequent. Information, counselling, and a bleeding diary can improve the woman's acceptance of the bleeding pattern.
The most commonly reported other undesirable effects in the clinical trials with desogestrel (> 2.5%) were acne, mood changes, breast pain, nausea and weight increase. The undesirable effects are listed in the table below by system organ class and frequency.
System Organ Class (MedDRA)*
Frequency of adverse reactions
Common
Uncommon
Rare
Infections and infestations
Vaginal infection
Psychiatric disorders
Mood altered, Depressed mood, Libido decreased
Nervous system disorders
Headache
Eye disorders
Contact lens intolerance
Gastrointestinal disorders
Nausea
Vomiting
Skin and subcutaneous tissue disorders
Acne
Alopecia
Rash, Urticaria, Erythema nodosum
Reproductive system and breast disorders
Breast pain, Menstruation irregular, Amenorrhoea
Dysmenorrhoea, Ovarian cyst
General disorders and administration site condition
Fatigue
Investigations
Weight increase
* MedDRA version 22.0
Breast discharge may occur during use of Hana. On rare occasions, ectopic pregnancies have been reported. Hypersensitivity reactions (including angioedema and anaphylaxis) have also been reported. In addition, aggravation of angioedema and/or aggravation of hereditary angioedema may occur (see section 4.4).
In women using combined oral contraceptives a number of (serious) undesirable effects have been reported. These include venous thromboembolic disorders, arterial thromboembolic disorders, hormone-dependent tumours (e.g. liver tumours, breast cancer), and chloasma, some of which are discussed in more detail in section 4.4. Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with hormonal contraceptives (see section 4.5).
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.
4.9 |
Hana 75 microgram film coated tablets | Clinical particulars - Overdose | Overdose
There have been no reports of serious deleterious effects from overdose. Symptoms that may occur in this case are nausea or vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.
5. Pharmacological properties
5.1 |
Hana 75 microgram film coated tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
After oral dosing of Hana, desogestrel (DSG) is rapidly absorbed and converted into etonogestrel (ENG). Under steady-state conditions, peak serum levels are reached 1.8 hours after tablet-intake and the absolute bioavailability of ENG is approximately 70%.
Distribution
ENG is 95.5-99% bound to serum proteins, predominantly to albumin and to a lesser extent to SHBG.
Biotransformation
DSG is metabolised via hydroxylation and dehydrogenation to the active metabolite ENG. ENG is primarily metabolised by the cytochrome P450 3A (CYP3A) isoenzyme and subsequently conjugated with sulphate and glucuronide.
Elimination
ENG is eliminated with a mean half-life of approximately 30 hours, with no difference between single and multiple dosing. Steady-state levels in plasma are reached after 4-5 days. The serum clearance after i.v. administration of ENG is approximately 10 l per hour. Excretion of ENG and its metabolites either as free steroid or as conjugates, is with urine and faeces (ratio 1.5:1). In lactating women, ENG is excreted in breast milk with a milk/serum ratio of 0.37-0.55. Based on these data and an estimated milk intake of 150 ml/kg/day, 0.01 - 0.05 microgram etonogestrel maybe ingested by the infant.
Special populations
Effect of renal impairment
No studies have been performed to evaluate the effect of renal disease on the pharmacokinetics of DSG.
Effect of hepatic impairment
No studies have been conducted to evaluate the effect of hepatic disease on the pharmacokinetics of DSG. However, steroid hormones may be poorly metabolized in women with impaired liver function.
Ethnic groups
No studies have been performed to assess pharmacokinetics in ethnic groups.
5.3 |
Hana 75 microgram film coated tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Toxicological studies did not reveal any effects other than those, which can be explained from the hormonal properties of desogestrel.
Environmental Risk Assessment (ERA)
The active substance etonogestrel shows an environmental risk to fish.
6. |
Hana 75 microgram film coated tablets | Pharmaceutical particulars - List of excipients | List of excipients
Tablet core
Alpha-tocopherol
Lactose monohydrate
Maize starch
Povidone K25
Stearic acid
Film coating
Hypromellose
Macrogol 400
Titanium dioxide (E 171)
6.2 |
Hana 75 microgram film coated tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable
6.3 |
Hana 75 microgram film coated tablets | Pharmaceutical particulars - Shelf life | Shelf life
2 years.
Shelf-life after first opening of the sachet: 3 months.
6.4 |
Hana 75 microgram film coated tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 30°C.
6.5 |
Hana 75 microgram film coated tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
PVC/Aluminium blister.
Each blister contains 28 tablets. Each carton contains 1 or 3 blisters.
Blisters are packed in sachets.
6.6 |
Hana 75 microgram film coated tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
The active substance etonogestrel shows an environmental risk to fish.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Hana 75 microgram film coated tablets | Marketing authorisation holder | Laboratoire HRA Pharma
200 avenue de Paris
92320 Chatillon
France
8. Marketing authorisation number(s)
PL 17836/0015
9. |
Hana 75 microgram film coated tablets | Date of first authorisation/renewal of the authorisation | 08/07/2021
10. |
Hana 75 microgram film coated tablets | Date of revision of the text | 08/07/2021 |
Hanixol 50 mg Tablets | Name of the medicinal product | Hanixol 50 mg Tablets
2. |
Hanixol 50 mg Tablets | Qualitative and quantitative composition | Each Tablet contains 50 mg of 6-mercaptopurine monohydrate.
Excipients with known effect:
-Lactose anhydrous: 59 mg per tablet
For the full list of excipients, see section 6.1
3. |
Hanixol 50 mg Tablets | Pharmaceutical form | Tablets.
Round 7.4 mm yellowish tablet, scored
4. |
Hanixol 50 mg Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Hanixol 50 mg tablets is indicated for the treatment of APL (acute promyelocytic leukaemia) and AML M3 (acute myeloid leukaemia M3) in adults, adolescents and children.
4.2 |
Hanixol 50 mg Tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
6-mercaptopurine monohydrate treatment should be initiated and supervised by a doctor or other healthcare professional experienced in the management of patients with acute leukemia.
6-mercaptopurine monohydrate may be taken with food or on an empty stomach, but patients should standardise the method of administration. 6-mercaptopurine monohydrate should not be taken with milk or dairy products (see section 4.5). 6-mercaptopurine monohydrate should be taken at least 1 hour before or 2 hours after ingestion of milk or dairy products.
Populations
Adults and children
For adults and children, the usual dose is 2.5 mg/kg bodyweight per day, or 50 to 75 mg/m2 body surface area per day, but the dose and duration of administration depend on the nature and dosage of other cytotoxic agents given in conjunction with 6-mercaptopurine monohydrate.
The dosage should be carefully adjusted to suit the individual patient.
6-mercaptopurine monohydrate has been used in various combination therapy schedules and the literature should be consulted for details.
Studies carried out in children with acute lymphoblastic leukaemia suggested that administration of 6-mercaptopurine monohydrate in the evening lowered the risk of relapse compared with morning administration.
Elderly
It is advisable to monitor renal and hepatic function in these patients, and if there is any impairment, consideration should be given to reducing the 6-mercaptopurine monohydrate dosage.
Renal impairment
Consideration should be given to reducing the dosage in patients with impaired renal function (see section 5.2).
Hepatic function
Consideration should be given to reducing the dosage in patients with impaired hepatic function (see section 5.2)
Medicinal product interactions
When xanthine oxidase inhibitors, such as allopurinol, and 6-mercaptopurine monohydrate are administered concomitantly, it is essential that only 25 % of the usual dose of 6-mercaptopurine monohydrate is given since allopurinol decreases the rate of catabolism of 6-mercaptopurine monohydrate. Concomitant administration of other xanthine oxidase inhibitors, such as febuxostat, should be avoided (see section 4.5).
TPMT deficient patients
Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe 6-mercaptopurine monohydrate toxicity from conventional doses of 6-mercaptopurine monohydrate and generally require substantial dose reduction.
The optimal starting dose for homozygous deficient patients has not been established (see section 4.4 and section 5.2).
Most patients with heterozygous TPMT deficiency can tolerate recommended 6-mercaptopurine monohydrate doses, but some may require dose reduction. Genotypic and phenotypic tests of TPMT are available (see section 4.4 and section 5.).
Patients with NUDT15 variant
Patients with inherited mutated NUDT15 gene are at increased risk for severe 6-mercaptopurine toxicity (see 4.4). These patients generally require dose reduction; particularly those being NUDT15 variant homozygotes (see 4.4). Genotypic testing of NUTD15 variants may be considered before initiating 6-mercaptiopurine therapy. In any case, close monitoring of blood counts is necessary.
4.3 |
Hanixol 50 mg Tablets | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to 6-mercaptopurine monohydrate or to any of the excipients listed in section 6.1.
In view of the seriousness of the indications there are no other absolute contraindications.
4.4 |
Hanixol 50 mg Tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
6-mercaptopurine monohydrate is an active cytotoxic agent for use only under the direction of physician experienced in the administration of such agents.
Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended. In all cases, patients in remission should not receive live organism vaccines until the patient is deemed to be able to respond to the vaccine. The interval between discontinuation of chemotherapy and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medications used, the underlying disease, and other factors.
Co-administration of ribavirin and 6-mercaptopurine monohydrate is not advised. Ribavirin may reduce efficacy and increase toxicity of 6-mercaptopurine monohydrate (see section 4.5).
Safe handling of hanixol Tablets
See section 6.6.
Monitoring
Since 6- mercaptopurine monohydrate is strongly myelosuppressive full blood counts must be taken daily during remission induction. patients must be carefully monitored during therapy.
Bone marrow suppression
Treatment with 6-mercaptopurine monohydrate causes bone marrow suppression leading to leukopenia and thrombocytopenia and, less frequently, anaemia. Full blood counts must be taken frequently during remission induction and careful monitoring of haematological parameters should be conducted during maintenance therapy and more frequently if high dosage is used or if severe renal and/or hepatic disorder is present.
The leucocyte and platelet counts continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in the counts, treatment should be interrupted immediately.
Bone marrow suppression is reversible if 6-mercaptopurine monohydrate is withdrawn early enough.
During remission induction in acute myelogenous leukaemia the patient may frequently have to survive a period of relative bone marrow aplasia and it is important that adequate supportive facilities are available.
The dosage of 6-mercaptopurine monohydrate may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression (see section 4.5).
Increased haematological monitoring of the patient is advised when switching between different pharmaceutical formulations of 6- mercaptopurine monohydrate.
Hepatotoxicity
6-mercaptopurine monohydrate is hepatotoxic and liver function tests should be monitored weekly during treatment. The level of gamma glutamyl transferase (GGT) in plasma will be especially important to determine if discontinuation is necessary due to hepatotoxicity. More frequent monitoring may be advisable in those with pre-existing liver disease or receiving other potentially hepatotoxic therapy. The patient should be instructed to discontinue 6-mercaptopurine monohydrate immediately if jaundice becomes apparent.
Tumour lysis syndrome
During remission induction when rapid cell lysis is occurring, uric acid levels in blood and urine should be monitored as hyperuricaemia and/or hyperuricosuria may develop, with the risk of uric acid nephropathy.
TPMT deficiency
There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of 6-mercaptopurine monohydrate and prone to developing rapid bone marrow depression following the initiation of treatment with 6-mercaptopurine monohydrate. This problem could be exacerbated by co-administration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulfazalazine. Also, a possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving 6–mercaptopurine monohydrate in combination with other cytotoxics (see Section 4.8).
About 0.3% (1: 300) of patients have low or no detectable enzyme activity. Approximately 10% of patients with low or intermediate TPMT activity, and 90% of patients have normal TPMT activity. There may also be a group of around 2% with a very high TPMT activity. Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore, close monitoring of blood counts is still necessary.
Cross resistance
Cross resistance usually exists between 6-mercaptopurine monohydrate and 6-tioguanine.
Hypersensitivity
Patients suspected of having suffered a hypersensitivity reaction to 6-mercaptopurine monohydrate should not be recommended to use its pro-drug azathioprine, unless the patient has been confirmed to be hypersensitive to 6-mercaptopurine monohydrate by allergological tests, and tested negative for azathioprine. As azathioprine is a pro-drug of 6-mercaptopurine monohydrate, patients with a previous history of hypersensitivity to azathioprine must be assessed for hypersensitivity to 6-mercapopurine monohydrate prior to initiating treatment.
Renal and/or hepatic impairment:
Caution is advised during the administration of 6-mercaptopurine monohydrate in patients with renal impairment and/or hepatic impairment. Consideration should be given to reducing the dosage in these patients and haematological response should be carefully monitored (see section 4.2 and section 5.2 Pharmacokinetic).
Mutagenicity and carcinogenicity
Patients receiving immunosuppressive therapy, including 6-mercaptopurine monohydrate are at an increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and nonmelanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ. The increased risk appears to be related to the degree and duration of immunosuppression. It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder.
A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities. A combination of multiple immunosuppressants, given concomitantly increases the risk of Epstein-Barr virus (EBV)associated lymphoproliferative disorders.
Increases in chromosomal aberrations were observed in the peripheral lymphocytes of leukaemic patients, in a hypernephroma patient who received an unstated dose of 6-mercaptopurine monohydrate and in patients with chronic renal disease treated at doses of 0.4 to 1.0 mg/kg/day.
Two cases have been documented of the occurrence of acute non-lymphatic leukaemia in patients who received 6-mercaptopurine monohydrate, in combination with other drugs, for non-neoplastic
disorders. A single case has been reported where a patient was treated for pyoderma gangrenosum with 6-mercaptopurine monohydrate and later developed acute non-lymphatic leukaemia, but it is not clear whether this was part of the natural history of the disease or if the 6-mercaptopurine monohydrate played a causative role.
A patient with Hodgkin's disease treated with 6-mercaptopurine monohydrate and multiple additional cytotoxic agents developed acute myelogenous leukaemia.
Twelve and a half years after 6-mercaptopurine monohydrate treatment for myasthenia gravis, a female patient developed chronic myeloid leukaemia.
Reports of hepatosplenic T-cell lymphoma in the inflammatory bowel disease (IBD) population have been received when 6-mercaptopurine monohydrate is used in combination with anti-TNF agents as unlicensed indication (see section 4.8).
Infections
Patients treated with 6-mercaptopurine monohydrate alone or in combination with other immunosuppressive agents, including corticosteroids, have shown increased susceptibility to viral, fungal and bacterial infections, including severe or atypical infection, and viral reactivation. The infectious disease and complications may be more severe in these patients than in non-treated patients.
Prior exposure to or infection with the varicella zoster should be taken into consideration prior to starting treatment. Local guidelines may be considered, including prophylactic therapy if necessary. Serologic testing prior to starting treatment should be considered with respect to hepatitis B. Local guidelines may be considered, including prophylactic therapy for cases which have been confirmed positive by serologic testing. Cases of neutropenic sepsis have been reported in patients receiving 6-mercaptopurine for ALL.
Paediatric population
Cases of symptomatic hypoglycaemia have been reported in children with ALL receiving 6-mercaptopurine monohydrate (see Section 4.8 Undesirable Effects). The majority of reported cases were in children under the age of six or with a low body mass index.
Macrophage activation syndrome
Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD) (unlicensed indication), and there could potentially be an increased susceptibility for developing the condition with the use of 6-mercaptopurine monohydrate. If MAS occurs, or is suspected, evaluation and treatment should be started as early as possible, and treatment with 6-mercaptopurine monohydrate should be discontinued. Physicians should be attentive to symptoms of infection such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.
Lesch-Nyhan syndrome
Limited evidence suggests that neither the 6-mercaptopurine monohydrate nor its pro-drug azathioprine are effective in patients with the rare inherited disease associated with complete hypoxanthine-guanine-phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). The use of 6-mercaptopurine monohydrate or azathioprine is not recommended in these patients.
UV exposure
Patients treated with 6-mercaptopurine monohydrate is more sensitive to sunlight. Exposure to sunlight and UV light should be limited, and patients should be advised to wear protective clothing and use sunscreen with a high protection factor.
Lactose
Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Xanthine oxidase inhibitors
When xanthine oxidase inhibitors, such as allopurinol, and 6-mercaptopurine monohydrate are administered concomitantly it is essential that only 25 % of the usual dose of 6-mercaptopurine monohydrate is given, since allopurinol decreases the rate of catabolism of 6-mercaptopurine monohydrate (see section 4.2 and 4.5)
Anticoagulants
Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-administered with 6-mercaptopurine monohydrate ; therefore higher doses of the anticoagulant may be needed. It is recommended that coagulation tests are closely monitored when anticoagulants are concurrently administered with 6-mercaptopurine monohydrate.
Patients with NUDT15 variant
Patients with inherited mutated NUDT15 gene are at increased risk for severe 6-mercaptopurine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy. They generally require dose reduction, particularly those being NUDT15 variant homozygotes (see 4.2). The frequency of NUDT15 c.415C>T has an ethnic variability of approximately 10% in East Asians, 4% in Hispanics, 0.2% in Europeans and 0% in Africans. In any case, close monitoring of blood counts is necessary.
4.5 |
Hanixol 50 mg Tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Vaccination with a live vaccine is not recommended in patients with impaired immune response (see section 4.4)
Taking 6-mercaptopurine monohydrate with food may decrease systemic exposure slightly. 6-mercaptopurine monohydrate can be taken with food or on an empty stomach, but patients should use a standard method of administration to avoid large variations in exposure. The dose must not be taken with milk or dairy products since they contain xanthine oxidase, an enzyme that metabolizes 6-mercaptopurine monohydrate and therefore may lead to reduced plasma concentrations of 6-mercaptopurine monohydrate.
Effect of concomitant medicinal products on 6-mercaptopurine monohydrate:
Ribavirin
Ribavirin inhibits the enzyme, inosine monophosphate dehydrogenase (IMPDH), leading to a lower production of the active 6-thioguanine nucleotides. Severe myelosuppression has been reported following concomitant administration of a pro-drug of 6-mercaptopurine monohydrate and ribavirin; therefore concomitant administration of ribavirin and 6-mercaptopurine monohydrate is not advised (see section 4.4 and 5.2).
Myelosuppressive agents
When 6-mercaptopurine monohydrate is combined with other myelosuppressive agents caution should be used; dose reductions may be needed based on haematological monitoring (see section 4.4).
Allopurinol / oxipurinol / thiopurinol and other xanthine oxidase inhibitors
Xanthine oxidase activity is inhibited by allopurinol, oxipurinol and thiopurinol, which results in reduced conversion of biologically active 6-thioinosinic acid to biologically inactive 6-thiouric acid. When allopurinol, oxipurinol and/or thiopurinol and 6-mercaptopurine monohydrate are administered concomitantly it is essential that only 25 % of the usual dose of 6-mercaptopurine monohydrate is given (see section 4.2).
Other xanthine oxidase inhibitors, such as febuxostat, decrease metabolism of 6-mercaptopurine monohydrate. Co-administration is not recommended, because data are insufficient to determine an adequate dose reduction.
Aminosalicylates
There is in vitro and in vivo evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulfazalazine) inhibit the TPMT enzyme. Therefore, lower doses of 6-mercaptopurine monohydrate may need to be considered when administered concomitantly with aminosalicylate derivatives (see section 4.4).
Methotrexate
Methotrexate (20 mg/m2 orally) increased 6-mercaptopurine monohydrate AUC by approximately 31% and methotrexate (2 or 5 g/m2 intravenously) increased 6-mercaptopurine monohydrate AUC by 69 and 93%, respectively. Therefore, when 6-mercaptopurine monohydrate is administered concomitantly with high dose methotrexate, the dose should be adjusted to maintain a suitable white blood cell count.
Infliximab
Interactions have been observed between azathioprine and infliximab. Patients treated with azathioprine had transient increases in the levels of 6-TGN (6-tioguaninnukleotid, an active metabolite of azathioprine) and decreases in the average number of leukocytes in the first weeks after infusion of infliximab, which returned to previous levels after 3 months.
Effect of 6-mercaptopurine monohydrate on other medicinal products
Anticoagulants
Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-administered with 6-mercaptopurine monohydrate; therefore higher doses of the anticoagulant may be needed. It is recommended that coagulation tests are closely monitored when anticoagulants are concurrently administered with 6-mercaptopurine monohydrate.
4.6 |
Hanixol 50 mg Tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Fertility
The effect of 6-mercaptopurine monohydrate therapy on human fertility is largely unknown but there are reports of successful fatherhood/motherhood after receiving treatment during childhood or adolescence.
Transient oligospermia has been reported following exposure to 6- mercaptopurine monohydrate.
Pregnancy
Substantial transplacental and transamniotic transmission of 6-mercaptopurine monohydrate and its metabolites from the mother to the foetus have been shown to occur.
The use of 6-mercaptopurine monohydrate should be avoided whenever possible during pregnancy, particularly during the first trimester. In any individual case the potential hazard to the foetus must be balanced against the expected benefit to the mother.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised if either partner is receiving 6-mercaptopurine monohydrate Tablets, during treatment and for at least three months after receiving the last dose.
Studies of 6-mercaptopurine monohydrate in animals have shown reproductive toxicity (see Section 5.3 Preclinical safety data). The potential risk for humans is largely unknown.
Maternal exposure: Normal offspring have been born after 6-mercaptopurine monohydrate therapy administered as a single chemotherapy agent during human pregnancy, particularly when given prior to conception or after the first trimester.
Abortions and prematurity have been reported after maternal exposure. Multiple congenital abnormalities have been reported following maternal 6-mercatopurine monohydrate treatment in combination with other chemotherapy agents.
Paternal exposure: Congenital abnormalities and spontaneous abortion have been reported after paternal exposure to 6-mercaptopurine monohydrate.
Breastfeeding
6-mercaptopurine monohydrate has been detected in the breast milk of renal transplant patients receiving immunosuppressive therapy with a pro-drug of 6-mercaptopurine monohydrate. It is recommended that mothers receiving 6-mercaptopurine monohydrate should not breast feed.
4.7 |
Hanixol 50 mg Tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
There is no data about the effects of 6-mercaptopurine monohydrate on the ability to drive vehicles and use machines. A detrimental effect on these activities cannot be predicted from the pharmacology of 6-mercaptopurine monohydrate.
4.8 |
Hanixol 50 mg Tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
For 6-mercaptopurine monohydrate there is a lack of modern clinical documentation which can serve as support for accurately determining the frequency of undesirable effects. The frequency categories assigned to the adverse drug reactions below are estimates: for most reactions, suitable data for calculating incidence are not available. |
Hanixol 50 mg Tablets | Clinical particulars - Overdose | Undesirable effects may vary in their incidence depending on the dose received and also when given in combination with other therapeutic agents.
The main side effect of treatment with 6-mercaptopurine monohydrate is bone marrow suppression leading to leucopenia and thrombocytopenia.
Tabulated list of adverse reactions
The following convention has been utilised for the classification of 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 (frequency cannot be estimated from the available data)
Organ system
Frequency
Adverse effect
Neoplasms benign, malignant and unspecified
Rare
Neoplasms including lymphoproliferative disorders, skin cancers (melanomas and nonmelanomas), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ (see section 4.4).
Very rare
Secondary Leukaemia and myelodysplasia (see section 4.4) ; hepatosplenic T-cell lymphoma in patients with IBD (an unlicensed indication) when used in combination with anti-TNF agents (see section 4.4.)
Blood and lymphatic system disorders
Very common
Myelosuppression: leukopenia and thrombocytopenia
Common
Anaemia
Immune system disorders
Rare
Hypersensitivity reactions with the following manifestations have been reported: Arthralgia; skin rash; drug fever.
Very rare
Hypersensitivity reactions with the following manifestations have been reported: Facial oedema
Metabolism and nutrition disorders
Uncommon
Anorexia
Not known
Hypoglycaemia*
Gastrointestinal disorders
Common
Nausea; vomiting; pancreatitis in the IBD population (an unlicensed indication)
Rare
Oral ulceration, pancreatitis during treatment (in the licensed indications)
Very rare
Intestinal ulceration.
Hepatobiliary disorders
Common
Biliary stasis; hepatotoxicity
Rare
Hepatic necrosis
Skin and subcutaneous tissue disorders
Rare
Alopecia.
Not known
Photosensitivity, erythema nodosum
Reproductive system and breast disorders
Very rare
Temporary oligospermia.
Infections and Infestations
Uncommon
Bacterial and viral infections, infections associated with neutropenia
*In paediatric population
Description of selected adverse reactions:
Hepatobiliary disorders
6-mercaptopurine monohydrate is hepatotoxic in animals and man. The histological findings in man have shown hepatic necrosis and biliary stasis.
The incidence of hepatotoxicity varies considerably and can occur with any dose but more frequently when the recommended dose of 2.5 mg/kg bodyweight daily or 75 mg/m2 body surface area per day is exceeded.
Monitoring of liver function tests may allow early detection of hepatotoxicity. Gamma glutamyl transferase (GGT) levels in plasma may be particularly predictive of withdrawal due to hepatotoxicity. This is usually reversible if 6-mercaptopurine monohydrate therapy is stopped soon enough but fatal liver damage has occurred.
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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store
4.9 |
Hanixol 50 mg Tablets | Clinical particulars - Subsection 10 | Overdose
Symptoms:
Gastrointestinal effects, including nausea, vomiting and diarrhoea and anorexia may be early symptoms of overdosage having occurred. The principal toxic effect is on the bone marrow, resulting in myelosuppression. Haematological toxicity is likely to be more profound with chronic overdosage than with a single ingestion of 6-mercaptopurine monohydrate. Liver dysfunction and gastroenteritis may also occur.
The risk of overdosage is also increased when allopurinol is being given concomitantly with 6-mercaptopurine monohydrate (see Section 4.5).
Treatment:
As there is no known antidote, blood counts should be closely monitored and general supportive measures, together with appropriate blood transfusion, instituted if necessary. Active measures (such as the use of activated charcoal) may not be effective in the event of 6-mercaptopurine monohydrate overdose unless the procedure can be undertaken within 60 minutes of ingestion.
Further management should be as clinically indicated or as recommended by the National Poisons Center.
5. Pharmacological properties
5.1 |
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