medication_name stringlengths 6 170 | section_title stringclasses 42 values | text stringlengths 0 47.1k |
|---|---|---|
Halaven 0.44 mg/ml solution for injection | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
HALAVEN is a cytotoxic anticancer medicinal product and, as with other toxic compounds, caution should be exercised in its handling. The use of gloves, goggles, and protective clothing is recommended. If the skin comes into contact with the solution, it should be washed immediately and thoroughly with soap and water. If it contacts mucous membranes, the membranes should be flushed thoroughly with water. HALAVEN should only be prepared and administered by personnel appropriately trained in handling of cytotoxic agents. Pregnant staff should not handle HALAVEN.
Using aseptic technique HALAVEN can be diluted up to 100 ml with sodium chloride 9 mg/ml (0.9%) solution for injection. Following administration, it is recommended that the intravenous line be flushed with sodium chloride 9 mg/ml (0.9%) solution for injection to ensure administration of the complete dose. It must not be mixed with other medicinal products and should not be diluted in glucose 5% infusion solution.
If using a spike to administer the product refer to the instructions provided from the device manufacturer. HALAVEN vials have a 13mm stopper. The device selected should be compatible with small vial stoppers.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Halaven 0.44 mg/ml solution for injection | Marketing authorisation holder | Eisai Europe Limited
European Knowledge Centre
Mosquito Way
Hatfield
AL10 9SN
United Kingdom
8. Marketing authorisation number(s)
PLGB 33967/0017
9. |
Halaven 0.44 mg/ml solution for injection | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 01 January 2021
10. |
Halaven 0.44 mg/ml solution for injection | Date of revision of the text | 01/2023
Hala/0017/2023 |
Haldol 2mg/ml oral solution | Name of the medicinal product | HALDOL 2 mg/ml oral solution
2. |
Haldol 2mg/ml oral solution | Qualitative and quantitative composition | Each ml of the oral solution contains 2 mg of haloperidol
Excipients with known effect:
Each ml of the oral solution contains 1.9 mg of methyl parahydroxybenzoate
For the full list of excipients, see section 6.1.
3. |
Haldol 2mg/ml oral solution | Pharmaceutical form | Clear, colourless solution.
4. |
Haldol 2mg/ml oral solution | 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 |
Haldol 2mg/ml oral solution | 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 HALDOL oral solution 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 HALDOL 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 HALDOL should be evaluated early in treatment (see section 4.4).
• When switching from haloperidol intramuscular injection, HALDOL 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.
Oral solution:
HALDOL oral solution in a bottle with an oral syringe is intended to be used for single doses of 0.5 mg haloperidol and above (equivalent to 0.25 ml and above).
The quantity (ml) required to achieve a given single dose using HALDOL oral solution is presented in Table 2.
Table 2: Conversion table for HALDOL oral solution (2 mg/ml)
mg haloperidol
ml HALDOL
(bottle with oral syringe)
0.1 mg
-
0.2 mg
-
0.3 mg
-
0.4 mg
-
0.5 mg
0.25 ml
1 mg
0.5 ml
2 mg
1 ml
5 mg
2.5 ml
10 mg
5 ml
15 mg
7.5 ml
20 mg
10 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
Clinical studies with oral haloperidol in the treatment of tic disorders, including Tourette's syndrome, did not include patients aged 65 years and above.
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 HALDOL oral solution are presented in Table 3.
Table 3: Haloperidol dose recommendations for paediatric population
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, preferably 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, preferably 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, preferably 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 HALDOL oral solution 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
HALDOL oral solution is for oral use. It may be mixed with water to facilitate dose administration, but it must not be mixed with any other liquid. The diluted solution must be taken immediately.
4.3 |
Haldol 2mg/ml oral solution | 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 |
Haldol 2mg/ml oral solution | 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 antipsychotics are at an increased risk of death. Analyses of seventeen placebo-controlled studies (modal duration of 10 weeks), largely in patients taking atypical antipsychotics, revealed a risk of death in 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. HALDOL 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 HALDOL, 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 HALDOL, 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 HALDOL 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 HALDOL.
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 oligomenorrhea 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. HALDOL 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 HALDOL 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 HALDOL 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
HALDOL 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.
Excipients of HALDOL
HALDOL oral solution contains methyl parahydroxybenzoate, which may cause allergic reactions (possibly delayed).
4.5 |
Haldol 2mg/ml oral solution | 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
HALDOL 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 HALDOL 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 HALDOL 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 HALDOL 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 HALDOL 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 HALDOL, therapy must be stopped immediately if such symptoms occur.
Antagonism of the effect of the anticoagulant phenindione has been reported.
4.6 |
Haldol 2mg/ml oral solution | 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 HALDOL 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 breast-fed newborns of mothers treated with haloperidol. There is insufficient information on the effects of haloperidol in breast-fed infants. A decision must be made whether to discontinue breastfeeding or to discontinue HALDOL therapy 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 |
Haldol 2mg/ml oral solution | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
HALDOL 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 |
Haldol 2mg/ml oral solution | Clinical particulars - Undesirable effects | Undesirable effects
The safety of haloperidol was evaluated in 284 haloperidol-treated patients who participated in 3 placebo-controlled clinical studies and in 1295 haloperidol-treated patients who participated in 16 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 formulation to oral haloperidol), 9 open label studies and 1 dose response study.
Table 4 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 4: Adverse reactions
System Organ Class
Adverse 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
Metabolic 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 hypersecretion
Hepatobiliary disorders
Liver function test abnormal
Hepatitis
Jaundice
Acute hepatic failure
Cholestasis
Skin and subcutaneous tissue disorders
Rash
Photosensitivity reaction
Urticaria
Pruritus
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
Gynaecomastia
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 |
Haldol 2mg/ml oral solution | 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 |
Haldol 2mg/ml oral solution | 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 3.2 ng/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 |
Haldol 2mg/ml oral solution | 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. |
Haldol 2mg/ml oral solution | Pharmaceutical particulars - List of excipients | List of excipients
Methyl parahydroxybenzoate (E218)
Lactic acid
Purified water
6.2 |
Haldol 2mg/ml oral solution | Pharmaceutical particulars - Incompatibilities | Incompatibilities
HALDOL oral solution may be mixed with water to facilitate dose administration, but it must not be mixed with any other liquid (see section 4.2).
6.3 |
Haldol 2mg/ml oral solution | Pharmaceutical particulars - Shelf life | Shelf life
3 years
After first opening: 3 months.
6.4 |
Haldol 2mg/ml oral solution | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Haldol 2mg/ml oral solution | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Oral solution – bottle with oral syringe:
100 ml amber glass bottle, with an LDPE child-resistant, tamper-evident closure, and with a 2.5 ml LDPE oral syringe calibrated in millilitres and/or milligrams.
Not all pack sizes may be marketed.
6.6 |
Haldol 2mg/ml oral solution | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Haldol 2mg/ml oral solution | Marketing authorisation holder | Janssen-Cilag Limited
50-100 Holmers Farm Way
High Wycombe
Buckinghamshire
HP12 4EG
UK
8. Marketing authorisation number(s)
PL 00242/0035R
9. |
Haldol 2mg/ml oral solution | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 7 June 1989
Date of latest renewal: 30 March 2005
10. |
Haldol 2mg/ml oral solution | Date of revision of the text | 23 May 2019 |
Haldol Decanoate | Name of the medicinal product | HALDOL Decanoate 50 mg/ml solution for injection
HALDOL Decanoate 100 mg/ml solution for injection
2. |
Haldol Decanoate | Qualitative and quantitative composition | 50 mg/ml solution:
Each ml of solution contains 70.52 mg of haloperidol decanoate, equivalent to 50 mg of haloperidol base.
100 mg/ml solution:
Each ml of solution contains 141.04 mg of haloperidol decanoate, equivalent to 100 mg of haloperidol base.
Excipients with known effect:
50 mg/ml and 100 mg/ml solution:
Each ml of solution contains 15 mg of benzyl alcohol and up to 1 ml of sesame oil.
For the full list of excipients, see section 6.1.
3. |
Haldol Decanoate | Pharmaceutical form | Solution for injection.
Slightly amber, slightly viscous solution, free from visible foreign material.
4. |
Haldol Decanoate | Clinical particulars - Therapeutic indications | Therapeutic indications
HALDOL Decanoate is indicated for the maintenance treatment of schizophrenia and schizoaffective disorder in adult patients currently stabilised with oral haloperidol (see section 5.1).
4.2 |
Haldol Decanoate | Clinical particulars - Posology and method of administration | Posology and method of administration
Treatment initiation and dose titration must be carried out under close clinical supervision.
Posology
The individual dose will depend on both the severity of the symptoms and the current oral haloperidol dose. Patients must always be maintained on the lowest effective dose.
As the initial dose of haloperidol decanoate is based on a multiple of the daily oral haloperidol dose, specific guidance on switching from other antipsychotics cannot be provided (see section 5.1).
Adults aged 18 years and above
Table 1: Haloperidol decanoate dose recommendations for adults aged 18 years and above
Transition from oral haloperidol
• A haloperidol decanoate dose of 10 to 15 times the previous daily dose of oral haloperidol is recommended.
• Based on this conversion, the haloperidol decanoate dose will be 25 to150 mg for most patients.
Continuation of treatment
• It is recommended to adjust the haloperidol decanoate dose by up to 50 mg every 4 weeks (based on individual patient response) until an optimal therapeutic effect is obtained.
• The most effective dose is expected to range between 50 and 200 mg.
• It is recommended to assess the individual benefit-risk when considering doses above 200 mg every 4 weeks.
• A maximum dose of 300 mg every 4 weeks must not be exceeded because the safety concerns outweigh the clinical benefits of treatment.
Dosing interval
• Usually 4 weeks between injections.
• Adjustment of the dosing interval may be required (based on individual patient response).
Supplementation with non-decanoate haloperidol
• Supplementation with non-decanoate haloperidol may be considered during transition to HALDOL Decanoate, dose adjustment or episodes of exacerbation of psychotic symptoms (based on individual patient response).
• The combined total dose of haloperidol from both formulations must not exceed the corresponding maximum oral haloperidol dose of 20 mg/day.
Special populations
Elderly
Table 2: Haloperidol decanoate dose recommendations for elderly patients
Transition from oral haloperidol
• A low haloperidol decanoate dose of 12.5 to 25 mg is recommended.
Continuation of treatment
• It is recommended only to adjust the haloperidol decanoate dose if required (based on individual patient response) until an optimal therapeutic effect is obtained.
• The most effective dose is expected to range between 25 and 75 mg.
• Doses above 75 mg every 4 weeks should only be considered in patients who have tolerated higher doses and after reassessment of the patient's individual benefit-risk profile.
Dosing interval
• Usually 4 weeks between injections.
• Adjustment of the dosing interval may be required (based on individual patient response).
Supplementation with non-decanoate haloperidol
• Supplementation with non-decanoate haloperidol may be considered during transition to HALDOL Decanoate, dose adjustment or episodes of exacerbation of psychotic symptoms (based on individual patient response).
• The combined total dose of haloperidol from both formulations must not exceed the corresponding maximum oral haloperidol dose of 5 mg/day or the previously administered oral haloperidol dose in patients who have received long-term treatment with oral haloperidol.
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 safety and efficacy of HALDOL Decanoate in children and adolescents below 18 years of age have not been established. No data are available.
Method of administration
HALDOL Decanoate is for intramuscular use only and must not be administered intravenously. It is administered as a deep intramuscular injection in the gluteal region. It is recommended to alternate between the two gluteal muscles. As the administration of volumes greater than 3 ml is uncomfortable for the patient, such large volumes are not recommended. For instructions on handling HALDOL Decanoate, see section 6.6.
4.3 |
Haldol Decanoate | 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 |
Haldol Decanoate | 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 antipsychotics are at an increased risk of death. Analyses of seventeen placebo-controlled studies (modal duration of 10 weeks), largely in patients taking atypical antipsychotics, revealed a risk of death in 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.
HALDOL Decanoate is not indicated for the treatment of dementia-related behavioural disturbances.
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.
HALDOL Decanoate must not be administered intravenously.
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. HALDOL Decanoate 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 HALDOL Decanoate, 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 HALDOL Decanoate 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 HALDOL Decanoate.
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 oligomenorrhea 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. HALDOL Decanoate 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 HALDOL Decanoate and preventive measures undertaken.
Treatment initiation
Patients being considered for HALDOL Decanoate therapy must be initially treated with oral haloperidol to reduce the possibility of an unexpected adverse sensitivity to haloperidol.
Patients with depression
It is recommended that HALDOL Decanoate 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).
Poor metabolisers of CYP2D6
HALDOL Decanoate should be used with caution in patients who are known poor metabolisers of cytochrome P450 (CYP) 2D6 and who are coadministered a CYP3A4 inhibitor.
Excipients of HALDOL Decanoate
HALDOL Decanoate contains benzyl alcohol, which may cause allergic reactions. HALDOL Decanoate must be used with caution in patients with renal or hepatic impairment, or in patients who are pregnant or breast-feeding, because of the risk of accumulation and toxicity (metabolic acidosis).
HALDOL Decanoate contains sesame oil, which may rarely cause severe allergic reactions.
4.5 |
Haldol Decanoate | 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
HALDOL Decanoate 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 HALDOL Decanoate 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 HALDOL Decanoate 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 HALDOL Decanoate 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 HALDOL Decanoate 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 HALDOL Decanoate, therapy must be stopped immediately if such symptoms occur.
Antagonism of the effect of the anticoagulant phenindione has been reported.
4.6 |
Haldol Decanoate | 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 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 HALDOL Decanoate 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 breast-fed newborns of mothers treated with haloperidol. There is insufficient information on the effects of haloperidol in breast-fed infants. A decision must be made whether to discontinue breastfeeding or to discontinue HALDOL Decanoate therapy 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 |
Haldol Decanoate | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
HALDOL Decanoate 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 |
Haldol Decanoate | Clinical particulars - Undesirable effects | Undesirable effects
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 formulation to oral haloperidol), 9 open label studies and 1 dose response study.
Based on pooled safety data from these clinical studies, the most commonly reported adverse reactions were: extrapyramidal disorder (14%), tremor (8%), parkinsonism (7%), muscle rigidity (6%) and somnolence (5%).
In addition, the safety of haloperidol was evaluated in 284 haloperidol-treated patients who participated in 3 placebo-controlled clinical studies and in 1295 haloperidol-treated patients who participated in 16 double-blind active comparator-controlled clinical studies.
Table 3 lists adverse reactions as follows:
• Reported in clinical studies with haloperidol decanoate.
• Reported in clinical studies with haloperidol (non-decanoate formulations) and relate to the active moiety.
• From postmarketing experience with haloperidol decanoate and haloperidol.
Adverse reaction frequencies are based on (or estimated from) clinical trials or epidemiology studies with haloperidol decanoate, 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 3: Adverse reactions
System Organ Class
Adverse Reaction
Frequency
Very Common
Common
Uncommon
Rare
Not known
Blood and lymphatic system disorders
Pancytopenia
Agranulocytosis
Thrombocytopenia
Leukopenia
Neutropenia
Immune system disorders
Anaphylactic reaction
Hypersensitivity
Endocrine disorders
Inappropriate antidiuretic hormone secretion
Hyperprolactinaemia
Metabolic and nutritional disorders
Hypoglycaemia
Psychiatric disorders
Depression
Insomnia
Psychotic disorder
Agitation
Confusional state
Loss of libido
Libido decreased
Restlessness
Nervous system disorders
Extrapyramidal disorder
Akathisia
Parkinsonism
Masked facies
Tremor
Somnolence
Sedation
Akinesia
Dyskinesia
Dystonia
Cogwheel rigidity
Hypertonia
Headache
Neuroleptic malignant syndrome
Tardive dyskinesia
Convulsion
Bradykinesia
Hyperkinesia
Hypokinesia
Dizziness
Muscle contractions involuntary
Motor dysfunction
Nystagmus
Eye disorders
Oculogyric crisis
Vision blurred
Visual disturbance
Cardiac disorders
Tachycardia
Ventricular fibrillation
Torsade de pointes
Ventricular tachycardia
Extrasystoles
Vascular disorders
Hypotension
Orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Laryngeal oedema
Bronchospasm
Laryngospasm
Dyspnoea
Gastrointestinal disorders
Constipation
Dry mouth
Salivary hypersecretion
Vomiting
Nausea
Hepatobiliary disorders
Acute hepatic failure
Hepatitis
Cholestasis
Jaundice
Liver function test abnormal
Skin and subcutaneous tissue disorders
Angioedema
Dermatitis exfoliative
Leukocytoclastic vasculitis
Photosensitivity reaction
Urticaria
Pruritus
Rash
Hyperhidrosis
Musculoskeletal and connective tissue disorders
Muscle rigidity
Rhabdomyolysis
Torticollis
Trismus
Muscle spasms
Muscle twitching
Musculoskeletal stiffness
Renal and urinary disorders
Urinary retention
Pregnancy, puerperium and perinatal conditions
Drug withdrawal syndrome neonatal (see section 4.6)
Reproductive system and breast disorders
Sexual dysfunction
Priapism
Amenorrhoea
Galactorrhoea
Dysmenorrhoea
Menorrhagia
Erectile dysfunction
Gynaecomastia
Menstrual disorder
Breast pain
Breast discomfort
General disorders and administration site conditions
Injection site reaction
Sudden death
Face oedema
Oedema
Hyperthermia
Hypothermia
Gait disturbance
Injection site abscess
Investigations
Weight increased
Electrocardiogram QT prolonged
Weight decreased
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.
4.9 |
Haldol Decanoate | Clinical particulars - Overdose | Overdose
While overdose is less likely to occur with parenteral than with oral medication, the following details are based on oral haloperidol, also taking into account the extended duration of action of HALDOL Decanoate.
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. 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, it is recommended that an antiparkinson medicinal product be administered, and continued for several weeks. Antiparkinson medicinal products must be withdrawn very cautiously as extrapyramidal symptoms may emerge.
5. Pharmacological properties
5.1 |
Haldol Decanoate | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
Administration of haloperidol decanoate as a depot intramuscular injection results in a slow and sustained release of free haloperidol. The plasma concentrations rise gradually, usually peaking within 3 to 9 days after injection.
Steady state plasma levels are reached within 2 to 4 months in patients receiving monthly injections.
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 after intramuscular injection with haloperidol decanoate is on average 3 weeks. This is longer than for the non-decanoate formulations, where the haloperidol terminal elimination half-life is on average 24 hours after oral administration and 21 hours after intramuscular 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
The pharmacokinetics of haloperidol following intramuscular injections of haloperidol decanoate are dose-related. The relationship between dose and plasma haloperidol level is approximately linear for doses below 450 mg.
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).
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 treated with short-acting haloperidol formulations, therapeutic response may be obtained at concentrations as low as 0.6 to 3.2 ng/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 decanoate dose based on the patient's response. This must take into account the time after a change in dose to achieve a new steady state plasma concentration and the additional time to elicit a 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 |
Haldol Decanoate | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Non-clinical data reveal no special hazards for humans based on conventional studies of local tolerability, 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. |
Haldol Decanoate | Pharmaceutical particulars - List of excipients | List of excipients
Benzyl alcohol, sesame oil.
6.2 |
Haldol Decanoate | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Haldol Decanoate | Pharmaceutical particulars - Shelf life | Shelf life
3 years..
6.4 |
Haldol Decanoate | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store in the original package to protect from light. This medicinal product does not require any special temperature storage conditions.
6.5 |
Haldol Decanoate | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
50 mg/ml solution:
1 ml or 3 ml of solution in an amber glass ampoule.
1 ml ampoules: Packs of 1, 3 or 5 ampoules.
3 ml ampoules: Packs of 1 or 5 ampoules; multipacks containing 50 (10 packs of 5) ampoules.
100 mg/ml solution:
1 ml of solution in an amber glass ampoule.
Packs of 1 or 5 ampoules.
Not all pack sizes may be marketed
6.6 |
Haldol Decanoate | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
• Before using the ampoule, roll it briefly between both hand palms to warm up the product.
• Hold the ampoule between the thumb and index finger, leaving the tip of the ampoule free.
• With the other hand, hold the tip of ampoule putting the index finger against the neck of ampoule, and the thumb on the coloured point parallel to the identification coloured rings.
• Keeping the thumb on the point, sharply break the tip of ampoule while holding firmly the other part of the ampoule in the hand.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Haldol Decanoate | Marketing authorisation holder | Janssen-Cilag Limited
50-100 Holmers Farm Way
High Wycombe
Buckinghamshire
HP12 4EG
UK
8. Marketing authorisation number(s)
HALDOL Decanoate 50 mg/ml solution for injection
PL 00242/0094
HALDOL Decanoate 100 mg/ml solution for injection
PL 00242/0095
9. |
Haldol Decanoate | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 23 July 1982
Date of latest renewal: 07 January 2003
10. |
Haldol Decanoate | Date of revision of the text | 17th August 2020 |
Half Beta-Prograne 80mg Sustained Release Capsules | Name of the medicinal product | Half Beta - Prograne 80mg Sustained Release Capsules
2. |
Half Beta-Prograne 80mg Sustained Release Capsules | Qualitative and quantitative composition | Each capsule contains 80 mg of propranolol hydrochloride
Excipients with known effect: The capsule contains Neutral micogrananules (sugar-starch) and Sulfur Dioxide (E220)
For the full list of excipients, see section 6.1
3. |
Half Beta-Prograne 80mg Sustained Release Capsules | Pharmaceutical form | Sustained Release Capsule
Size 3 capsules with opaque white caps and colourless transparent bodies filled with regular creamy white microgranules
4. |
Half Beta-Prograne 80mg Sustained Release Capsules | Clinical particulars - Therapeutic indications | Therapeutic indications
• Control of hypertension
• Management of angina
• Management of essential tremor
• Management of situational anxiety and generalised anxiety symptoms
• Adjunctive management of thyrotoxicosis
• Prophylaxis of migraine
• Prophylaxis of upper gastro-intestinal bleeding in patients with portal hypertension and oesophageal varices
4.2 |
Half Beta-Prograne 80mg Sustained Release Capsules | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Adults
Hypertension:
The usual starting dose is one 160 mg Beta-Prograne Sustained-Release capsule daily, taken either morning or evening. An adequate response is seen in most patients at this dosage. If necessary, it can be increased in 80 mg Half Beta-Prograne increments until an adequate response is achieved (up to a maximum of 320 mg daily).
A further reduction in blood pressure can be attained if a diuretic or other antihypertensive agent is given in addition.
Angina, essential tremor, thyrotoxicosis, prophylaxis of migraine:
Adequate control is gained in most patients on one Half Beta-Prograne 80 mg capsule per day (either morning or evening). If necessary, further control may be gained by increasing the dose in 80 mg increments (one Half Beta-Prograne 80mg Capsule) to a maximum of 240 mg per day, taken either morning or evening, which may be administered in the most convenient form using either Beta-Prograne 160 mg Capsules or Half Beta-Prograne 80mg Capsules.
Situational and generalised anxiety:
Half Beta-Prograne 80 mg Sustained-Release Capsule taken daily should be sufficient to provide short-term relief of acute situational anxiety. Generalised anxiety, requiring longer term therapy, usually responds adequately at the same dosage. In individual cases, the dosage may be increased to one Beta-Prograne 160 mg Sustained-Release Capsule per day. Treatment should be continued according to patient's response. Patients should be reviewed after 6 to 12 months' treatment.
Portal Hypertension:
Since portal blood pressure cannot normally be monitored directly, dosage should be titrated to achieve approximately 25% reduction in resting heart rate. Dosing should begin with one Half Beta-Prograne 80 mg Sustained-Release Capsule daily, increasing to one Beta-Prograne 160 mg Sustained-Release Capsule daily depending on heart rate response. Further Half Beta-Prograne 80 mg Sustained-Release Capsule increments may be added up to a maximum dose of 320 mg once daily.
Patients who are already established on equivalent daily doses of Beta-Prograne should be transferred to the equivalent doses of Half Beta-Prograne 80 mg Sustained-Release or Beta-Prograne 160 mg Sustained-Release daily, taken either morning or evening.
Older People
Evidence concerning the relation between blood level and age is conflicting. Treatment should start with one Half Beta-Prograne 80 mg Sustained-Release Capsule once daily. The dose may be increased to one Beta-Prograne 160 mg Sustained-Release Capsule daily or higher as appropriate.
Paediatric population
Beta-Prograne 160 mg Sustained-Release Capsules and Half Beta-Prograne 80mg Sustained-Release Capsules are not intended for use in children.
Method of administration
For oral administration.
4.3 |
Half Beta-Prograne 80mg Sustained Release Capsules | Clinical particulars - Contraindications | Contraindications
Beta-Prograne 160 mg Sustained-Release Capsules and Half Beta-Prograne 80 mg Sustained-Release Capsules, as with other beta-adrenoceptor blocking drugs, must not be used in patients with any of the following conditions:
• hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• history of bronchial asthma or bronchospasm
• bradycardia
• cardiogenic shock
• hypotension
• metabolic acidosis
• severe peripheral arterial circulatory disturbances
• second or third degree heart block
• sick sinus syndrome
• untreated phaechromocytoma
• uncontrolled heart failure
• Prinzmetal's angina
• Patients prone to hypoglycaemia i.e. patients after sustained fasting or patients with restricted counter-regulatory reserves.
4.4 |
Half Beta-Prograne 80mg Sustained Release Capsules | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Beta-Prograne 160 mg Sustained-Release Capsules or Half Beta-Prograne 80 mg Sustained-release Capsules as with other beta-adrenoceptor blocking drugs:
• although contra-indicated in uncontrolled heart failure (see section 4.3) may be used in patients whose signs of heart failure have been controlled. Caution must be exercised in patients whose cardiac reserve is poor.
• heart failure due to thyrotoxicosis often responds to propranolol alone, but if other adverse factors co-exist myocardial contractility must be maintained and signs of failure controlled with digitalis and diuretics.
• should not be used in combination with calcium channel blockers with negative inotropic effects (e.g. verapamil, diltiazem), as it can lead to an exaggeration of these effects particularly in patients with impaired ventricular function and/or SA or AV conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure. Neither the beta-blocker not the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.
• beta-blockers may increase the number and duration of anginal attacks in patients with Prinzmetal's angina, due to unopposed alpha-receptor mediated coronary artery vasoconstriction. Non-selective beta-blockers, such as propranolol, should not be used in patients with Prinzmetal's angina and beta-1 selective agents should be used with care (see section 4.3).
• in patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), beta-blockers should be used with great caution as aggravation of these disorders may occur. Although contra-indicated in severe peripheral arterial circulatory disturbances (see section 4.3) may also aggravate less severe peripheral arterial circulatory disturbances.
• due to its negative effect on conduction time, caution must be exercised if it is given to patients with first degree heart block.
• may block/modify the signs and symptoms of the hypoglycaemia (especially tachycardia). Beta-Prograne 160 mg Sustained-Release Capsules and Half Beta-Prograne 80 mg Sustained-Release Capsules occasionally causes hypoglycaemia, even in non-diabetic patients, e.g., neonates, infants, children, elderly patients, patients on haemodialysis or patients suffering from chronic liver disease and patients suffering from overdose. Severe hypoglycaemia associated with Beta-Prograne 160 mg Sustained-release Capsules and Half-Beta-Prograne 80 mg Sustained-Release Capsules has rarely presented with seizures and/or coma in isolated patients. Caution must be exercised in the concurrent use of Beta-Progane 160 mg Sustained-Release Capsules and Half Beta-Prograne 80 mg Sustained-Release Capsules and hypoglycaemic therapy in diabetic patients. Beta-Prograne 160 mg Sustained-Release Capsules and Half Beta-Prograne 80 mg Sustained-Release Capsules may prolong the hypoglycaemic response to insulin (see section 4.3).
• may mask the signs of thyrotoxicosis.
• should not be used in untreated phaeochromocytoma. However, in patients with phaeochromocytoma, an alpha-blocker may be given concomitantly.
• should be used to treat the elderly with caution starting with a lowest possible dose (see section 4.2).
• will reduce heart rate as a result of its pharmacological action. In the rare instances, if the pulse rate decreases to below 50-55 beats per minute at rest, when a treated patient develops symptoms that may be attributable to a slow heart rate, the dose may be reduced.
• may cause a more severe reaction to a variety of allergens, when given to patients with a history of anaphylactic reaction to such allergens. Such patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reactions.
Abrupt withdrawal of beta-blockers is to be avoided. The dosage should be withdrawn gradually over a period of 7 to 14 days. An equivalent dosage of another beta-blocker may be substituted during the withdrawal period to facilitate a reduction in dosage below Half Beta-Prograne 80 mg Sustained-Release Capsules. Patients should be followed during withdrawal especially those with ischaemic heart disease.
Anaesthesia: As with all beta-adrenoceptor blocking drugs it may be decided to withdraw Beta-Prograne before surgery. In this case 24-48 hours should be allowed to elapse between the last dose and anaesthesia. If treatment is continued care should be taken when using anaesthetic agents which cause myocardial depression such as cyclopropane and trichloroethylene, which are best avoided. Anaesthetics may cause attenuation of the reflex tachycardia and increase the risk of hypotension. Continuation of beta-blockade reduces the risk of arrhythmia during induction and intubation. The anaesthesiologist should be informed when the patient is receiving a beta-blocking agent. Vagal dominance, if it occurs, may be corrected with atropine (1-2 mg I.V.).
The risk/benefit of stopping beta blockade should be made for each patient.
Since the half-life may be increased in patients with significant hepatic or renal impairment, caution must be exercised when starting treatment and selecting the initial dose.
Beta-Prograne 160 mg Sustained-Release Capsules and Half Beta-Prograne 80mg Sustained-Release Capsules must be used with caution in patients with decompensated cirrhosis (see section 4.2).
In patients with portal hypertension, liver function may deteriorate and hepatic encephalopathy may develop. There have been reports suggesting that treatment with propranolol may increase the risk of developing hepatic encephalopathy (see section 4.2).
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Patients with rare hypersensitivity for sulphur dioxide should not take this medicine; which may cause hypersensitivity reactions and bronchospasm.
Patients with a history of wheezing or asthma should not take propranolol unless it is considered essential. The product label states the following warning: “Do not take Beta-Prograne 160 mg Sustained-Release Capsules if you have a history of asthma or wheezing”. A similar warning appears in the Patient Information Leaflet.
Bronchospasm can usually be reversed by beta2 agonist bronchodilators such as salbutamol. Large doses of the beta2 agonist bronchodilator may be required to overcome the beta blockade produced by propranolol and the dose should be titrated according to the clinical response; both intravenous and inhalational administration should be considered. The use of intravenous aminophylline and/or the use of ipratropium (given by nebuliser) may also be considered. Glucagon (1 to 2 mg given intravenously) has also been reported to produce a bronchodilator effect in asthmatic patients. Oxygen or artificial ventilation may be required in severe cases.
Intolerance to propranolol, shown as bradycardia and hypotension may occur, in which case propranolol should be withdrawn. If necessary, treatment for overdose should be started.
Interference with laboratory tests:
Beta-Prograne 160 mg Sustained-release Capsules or Half Beta-Prograne 80 mg Sustained-Release Capsules have been reported to interfere with the estimation of serum bilirubin by the diazo method and with the determination of catecholamines by methods using fluorescence.
4.5 |
Half Beta-Prograne 80mg Sustained Release Capsules | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Beta-Prograne 160 mg Sustained-Release Capsules and Half Beta-Prograne 80 mg Sustained-Release Capsules modify the tachycardia of hypoglycaemia. Caution must be exercised in the concurrent use of Beta-Prograne 160 mg Sustained-Release Capsules and Half Beta-Prograne 80 mg Sustained-Release Capsules and hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin (see section 4.3 and 4.4).
Simultaneous administration of rizatriptan and propranolol can cause an increased rizatriptan AUC and Cmax by approximately 70-80%. The increased rizatriptan exposure is presumed to be caused by inhibition of first-passage metabolism of rizatriptan through inhibition of monoamine oxidase-A. If both drugs are to be used, a rizatriptan dose of 5mg has been recommended.
Caution must be exercised when prescribing a beta-adrenoceptor blocking drug with Class 1 antiarrhythmic agents such as disopyramide and amiodarone (may have potentiating effect on atrial-conduction time and induce negative inotropic effect).
Digitalis glycosides, e.g. digitoxin or digoxin taken at the same time as beta-blockers can increase atrioventricular conduction time.
There is an increased risk of myocardial depression and bradycardia, there is also an increased risk of lidocaine toxicity. The antidysrhythmic propafenone increases plasma concentration of propranolol.
Combined use of beta-adrenoceptor blocking drugs and calcium channel blockers with negative inotropic effects e.g. verapamil, diltiazem, can lead to an exaggeration of these effects, particularly in patients with impaired ventricular function and/or sino-atrial or atrio-ventricular conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure. Neither the beta-adrenoceptor blocking drug nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.
Concomitant therapy with dihydropyridine calcium channel blockers e.g. nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.
Concomitant use of sympathomimetic agents, e.g. adrenaline, may counteract the effect of beta-adrenoceptor blocking drugs. Caution must be exercised in the parenteral administration of preparations containing adrenaline to patients taking beta- adrenoceptor blocking drugs as, in rare cases, vasoconstriction, hypertension and bradycardia may result.
Administration of propranolol during infusion of lidocaine may increase the plasma concentration of lidocaine by approximately 30%. Patients already receiving propranolol tend to have higher lignocaine levels than controls. The combination should be avoided.
Monoamine oxidase inhibitors, excepting MAO-B inhibitors.
Concomitant use of cimetidine and hydralazine will increase the plasma levels of propranolol. Fluvoxamine taken with propanol also has this effect. Concomitant use of alcohol may increase the plasma levels of propranolol and enhances hypotensive effect.
Beta-adrenoceptor blocking drugs may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are co-administered, the beta-adrenoceptor blocking drug should be withdrawn several days before discontinuing clonidine. If replacing clonidine by beta-adrenceptor blocking drug therapy, the introduction of beta-adrenoceptor blocking drugs should be delayed for several days after clonidine administration has stopped.
Caution must be exercised if ergotamine, dihydroergotamine or related compounds are given in combination with propranolol since vasospastic reactions have been reported in a few patients.
Concomitant use of prostaglandin synthetase inhibiting drugs, e.g. ibuprofen or indometacin, may decrease the hypotensive effects of propranolol.
Tricyclic antidepressants, barbiturates, phenothiazines and other medicines used to reduce blood pressure - may increase the blood pressure-lowering effect of propranolol.
Concomitant administration of propranolol and chlorpromazine may result in an increase in plasma levels of both drugs. This may lead to an enhanced antipsychotic effect for chlorpromazine and an increased antihypertensive effect for propranolol.
Concomitant administration of rifampicin with propranolol may result in reduced plasma concentrations of propranolol. Thyroxine taken at the same time as propranolol also has this effect.
ACE inhibitors and Angiotensin-II Antagonists taken at the same time as propranolol may result in enhanced hypotensive effects. Aldesleukin and Alprostadil also has this effect.
Concomitant administration of corticosteroid may result in antagonism of hypotensive effect.
Beta blockers including propranolol when taken with moxisylyte may result in severe postural hypotension
Concomitant administration of muscle relaxants may result in enhanced hypotensive effect.
Oestrogen and progestrogens, as used in the contraceptive pill, when taken with propranolol may antagonise the hypotensive effect.
The manufacturer of tropisetron advises caution for the co-administration with propranolol.
The concomitant administration of xamoterol with propranolol may result in a reduction in the beta-blockade.
Parasympathomimetics when used with propranolol increase the possibility of arrhythmias.
Caution must be exercised when using anaesthetic agents with Beta-Prograne 160 mg Sustained-Release Capsules and Half Beta-Prograne 80 mg Sustained-Release Capsules. The anaesthetist should be informed and the choice of anaesthetic should be the agent with as little negative inotropic activity as possible. Use of beta-adrenoceptor blocking drugs with anaesthetic drugs may result in attenuation of the reflex tachycardia and increase the risk of hypotension. Anaesthetic agents causing myocardial depression are best avoided.
Interference with laboratory test:
Propranolol has been reported to interfere with the estimation of serum bilirubin by the diazo method and with the determination of catecholamines by methods using fluorescence.
Pharmacodynamic studies have shown that the following agents may interact with propranolol due to effects on enzyme systems in the liver which metabolise propranolol and these agents: quinidine (increased risk of myocardial depression and bradycardia), propafenone, rifampicin, theophylline, warfarin, thioridazine and dihydropyridine calcium channel blockers such as nifedipine, nisoldipine, nicardipine, isradipine and lacidipine. Owing to the fact that blood concentrations of either agent may be affected, dosage adjustments may be needed according to clinical judgement, (see also the interaction above concerning therapy with dihydropyridine calcium channel blockers).
4.6 |
Half Beta-Prograne 80mg Sustained Release Capsules | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
As with all drugs, Beta-Prograne 160 mg Sustained-Release Capsules and Half Beta-Prograne 80 mg Sustained-Release Capsules should not be given during pregnancy unless their use is essential. There is no evidence of teratogenicity.
However beta-adrenoceptor blocking drugs reduce placental perfusion, which may result in intra-uterine foetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia in the neonate and bradycardia in the foetus) may occur. There is an increased risk of cardiac and pulmonary complications in the neonate in the post-natal period.
Breastfeeding
Most beta-adrenoceptor blocking drugs particularly lipophilic compounds, will pass into breast milk although to a variable extent. Breast feeding is therefore not recommended following administration of these compounds.
4.7 |
Half Beta-Prograne 80mg Sustained Release Capsules | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
The use of Beta-Prograne 160 mg Sustained-Release Capsules or Half Beta-Prograne 80 mg Sustained-Release Capsules is unlikely to result in any impairment of the ability of patients to drive or operate machinery.
However, when driving vehicles or operating machines it should be taken into account that occasionally dizziness or fatigue may occur. If so, the patient should not drive or operate machines.
4.8 |
Half Beta-Prograne 80mg Sustained Release Capsules | Clinical particulars - Undesirable effects | Undesirable effects
Beta-Prograne 160 mg Sustained-Release Capsules and Half Beta-Prograne 80mg Sustained-Release Capsules are usually well tolerated. In clinical studies, the undesired events reported are usually attributable to the pharmacological actions of propranolol.
Adverse reactions frequency is defined 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).
Frequency
Common
Uncommon
Rare
Very rare
Not known
Organ System
General
Fatigue and/or lassitude (often transient)
Dizziness
Cardiovascular
Bradycardia, cold extremities, Raynaud's phenomenon
Heart failure deterioration, precipitation of heart block, postural hypotension, which may be associated with syncope, exacerbation of intermittent claudication
CNS
Sleep disturbances, nightmares.
Hallucinations, psychoses, mood changes, confusion, memory loss
GI
Gastrointestinal disturbance, such as nausea, vomiting, diarrhoea
Blood
Thrombocytopaenia
Skin
Purpura, alopecia, psoriasiform skin reactions, exacerbation of psoriasis, skin rashes.
Neurological
Paraesthesia
Eyes
Dry eyes, visual disturbances
Respiratory
Bronchospasm may occur in patients with bronchial asthma or a history of asthmatic complaints, sometimes with fatal outcome
Endocrine system
Hypoglycaemia in neonates, infants, children, elderly patients, patients on haemodialysis, patients on concomitant antidiabetic therapy, patients with prolonged fasting and patients with chronic liver disease has been reported.
Seizure linked to hypoglycaemia.
Investigations
An increase in ANA (Antinuclear Antibodies) has been observed, however the clinical relevance of this is not clear
Nervous system
Isolated reports of myasthenia gravis like syndrome or exacerbation of myasthenia gravis have been reported
Headaches
Reproductive System & Breast Disorders
Impotence
Discontinuance of the drug should be considered if, according to clinical judgement, the well being of the patient is adversely affected by any of the above reactions. Cessation of therapy with a beta-adrenoceptor blocking drug should be gradual. In the rare event of intolerance manifested as bradycardia and hypotension, the drug should be withdrawn and, if necessary, treatment for overdosage instituted.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the yellow card scheme at: www.mhra.gov.uk/yellowcard.
.
4.9 |
Half Beta-Prograne 80mg Sustained Release Capsules | Clinical particulars - Overdose | Overdose
Propranolol is known to cause severe toxicity when used in overdose. Patients should be informed of the signs of overdose and advised to seek urgent medical assistance if an overdose of propranolol has been taken.
Clinical features:
Cardiac
Bradycardia, hypotension, pulmonary oedema, syncope and cardiogenic shock may develop. QRS complex prolongation, ventricular tachycardia, first to third degree AV block, ventricular fibrillation or asystole may also occur. Development of cardiovascular complications is more likely if other cardioactive drugs, especially calcium channel blockers, digoxin, cyclic antidepressants or neuroleptics have also been ingested. Older patients and those with underlying ischaemic heart disease are at risk of developing severe cardiovascular compromise.
CNS
Drowsiness, confusion, seizures, hallucinations, dilated pupils and in severe cases coma may occur. Neurological signs such as coma or absence of pupil reactivity are unreliable prognostic indicators during resuscitation.
Other features
Bronchospasm, hyperkalaemia and occasionally CNS-mediated respiratory depression may occur.
Management
In cases of overdose or extreme falls in heart rate or blood pressure, treatment with propranolol must be stopped. Management should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. In symptomatic patients, or patients with an abnormal ECG, early discussion with critical care should be considered.
Consult national clinical guidance for further information on the management of overdose.
5. Pharmacological properties
5.1 |
Half Beta-Prograne 80mg Sustained Release Capsules | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Sustained release form. The coating of the multiple microgranules provides a sustained release of the active principle, propranolol, and allows a 24 hours sustained action.
Propranolol is completely absorbed after oral administration. Following oral dosing with the sustained release preparation of propranolol, the blood profile is flatter than after conventional Propranolol. Peak blood level is reached after 5 hours for the controlled-release form. The apparent half-life of elimination is 3-6 hours. The liver removes up to 90% of an oral dose. Propranolol is widely and rapidly distributed throughout the body with highest levels occurring in the lungs, liver, kidney, brain and heart. Propranolol is highly protein bound (80 to 95%).
Propranolol crosses the placental barrier and is found in the blood of the umbilical cord (concentration: about 1.5 times that of the concentration in the maternal blood). The concentration in the mother's milk is about half the concentration in the blood.
5.3 |
Half Beta-Prograne 80mg Sustained Release Capsules | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Propranolol is a drug on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in this Summary of Product Characteristics.
6. |
Half Beta-Prograne 80mg Sustained Release Capsules | Pharmaceutical particulars - List of excipients | List of excipients
Neutral microgranules
Povidone
Ethylcellulose
Talc
Capsule Components
Gelatine
Titanium Dioxide
Sulfur Dioxide (E220)
6.2 |
Half Beta-Prograne 80mg Sustained Release Capsules | Pharmaceutical particulars - Incompatibilities | Incompatibilities
None known.
6.3 |
Half Beta-Prograne 80mg Sustained Release Capsules | Pharmaceutical particulars - Shelf life | Shelf life
5 years.
6.4 |
Half Beta-Prograne 80mg Sustained Release Capsules | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store below 25° C. Store in the original package in order to protect from light and moisture.
6.5 |
Half Beta-Prograne 80mg Sustained Release Capsules | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
- Blister packs
PVC: Colourless 250 micron thickness
Aluminium: 25 microns thickness
28 capsules per pack, 14 capsules per blister strip.
Not all packs sizes may be marketed.
6.6 |
Half Beta-Prograne 80mg Sustained Release Capsules | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Half Beta-Prograne 80mg Sustained Release Capsules | Marketing authorisation holder | Tillomed Laboratories Ltd
220 Butterfield
Great Marlings
Luton
LU2 8DL
8. Marketing authorisation number(s)
PL 11311/0017
9. |
Half Beta-Prograne 80mg Sustained Release Capsules | Date of first authorisation/renewal of the authorisation | 25/02/2009
10. |
Half Beta-Prograne 80mg Sustained Release Capsules | Date of revision of the text | 23/03/2020 |
Half Securon SR 120 mg modified-release tablets | Name of the medicinal product | Half Securon SR
2. |
Half Securon SR 120 mg modified-release tablets | Qualitative and quantitative composition | Verapamil Hydrochloride Ph Eur – 120 mg
3. |
Half Securon SR 120 mg modified-release tablets | Pharmaceutical form | Modified-release tablets.
The tablets are round, white, biconvex and embossed with the word 'Knoll' on one side and '120 SR' on the reverse.
4. |
Half Securon SR 120 mg modified-release tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Half Securon SR is indicated for:
The treatment of mild to moderate hypertension.
The treatment and prophylaxis of angina pectoris.
Secondary prevention of reinfarction after an acute myocardial infarction in patients without heart failure, and not receiving diuretics (apart from low-dose diuretics when used for indications other than heart failure), and where beta-blockers are not appropriate. Treatment is to be started at least one week after an acute myocardial infarction.
4.2 |
Half Securon SR 120 mg modified-release tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
For oral use only.
Half Securon SR tablets should be taken without sucking or chewing, with sufficient liquid, preferably with or shortly after meals.
Adults
Hypertension: One tablet of Securon SR daily. For patients new to verapamil therapy, the physician should consider halving the initial dose to 120 mg (one tablet Half Securon SR). Most patients respond to 240 mg daily (one tablet Securon SR) given as a single dose. If control is not achieved after a period of at least one week, the dosage may be increased to a maximum of two Securon SR tablets daily (one in the morning and one in the evening at an interval of about twelve hours). A further reduction in blood pressure may be achieved by combining Securon SR with other antihypertensive agents, in particular diuretics. Half Securon SR may be used for dose titration purposes.
Angina pectoris: One tablet of Securon SR twice daily. A small number of patients respond to a lower dose and where indicated, adjustment down to one tablet of Securon SR daily could be made. Half Securon SR may be used for dose titration purposes.
Secondary prevention of reinfarction after an acute myocardial infarction in patients without heart failure, and not receiving diuretics (apart from low-dose diuretics when used for indications other than heart failure), and where beta-blockers are not appropriate: Treatment is to be started at least one week after an acute myocardial infarction. 360 mg/day in divided doses, to be taken either as one Half Securon SR (120 mg) tablet three times daily, or as one Securon SR (240 mg) tablet in the morning and one Half Securon SR (120 mg) tablet in the evening, on a daily basis.
Elderly patients
The adult dose is recommended unless renal or hepatic function is impaired (see Section 4.4, 'Special Warnings and Precautions for Use').
Children
Securon SR and Half Securon SR are not recommended for children.
Liver impairment
In patients with impaired liver function, metabolism of the drug is delayed to a greater or lesser extent depending on the severity of hepatic dysfunction, thus potentiating and prolonging the effects of verapamil hydrochloride. Therefore, the dosage needs to be adjusted with special caution in patients with impaired liver function and low doses should be given initially (see Special Warnings and Precautions for Use Section).
4.3 |
Half Securon SR 120 mg modified-release tablets | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Cardiogenic shock; acute myocardial infarction complicated by bradycardia, marked hypotension or left ventricular failure; second or third degree atrioventricular (AV) block (except in patients with a functioning artificial pacemaker); sino-atrial block; sick sinus syndrome (except in patients with a functioning artificial pacemaker); uncompensated heart failure; bradycardia of less than 50 beats/minute; hypotension of less than 90 mmHg systolic.
Patients with atrial flutter/fibrillation in the presence of an accessory pathway (e.g. WPW syndrome) may develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated.
Combination with ivabradine (see section Interactions with other medicinal products and other forms of interaction).
4.4 |
Half Securon SR 120 mg modified-release tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Since verapamil is extensively metabolised in the liver, careful dose titration is required in patients with liver disease. Although the pharmacokinetics of verapamil in patients with renal impairment are not affected, caution should be exercised and careful patient monitoring is recommended. Verapamil is not removed during dialysis.
Verapamil may affect impulse conduction and should therefore be used with caution in patients with bradycardia or first degree AV block. Verapamil may affect left ventricular contractility; this effect is small and normally not important but cardiac failure may be precipitated or aggravated. In patients with incipient cardiac failure, therefore, verapamil should be given only after such cardiac failure has been controlled with appropriate therapy, e.g. digitalis.
When treating hypertension with verapamil, monitoring of the patient's blood pressure at regular intervals is required.
Caution should be exercised in treatment with HMG CoA reductase inhibitors (e.g., simvastatin, atorvastatin or lovastatin) for patients taking verapamil. These patients should be started at the lowest possible dose of verapamil and titrated upwards. If verapamil treatment is to be added to patients already taking an HMG CoA reductase inhibitor (e.g., simvastatin, atorvastatin or lovastatin), refer to advice in the respective statin product information.
Use with caution in the presence of diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy)
4.5 |
Half Securon SR 120 mg modified-release tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
In vitro metabolic studies indicate that verapamil hydrochloride is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.
The following are potential drug interactions associated with verapamil:
Acetylsalicylic acid
Concomitant use of verapamil with aspirin may increase the risk of bleeding
Alcohol
Increase in blood alcohol has been reported.
Alpha blockers
Verapamil may increase the plasma concentrations of prazosin and terazosin which may have an additive hypotensive effect.
Antiarrhythmics
Verapamil may slightly decrease the plasma clearance of flecainide whereas flecainide has no effect on the verapamil plasma clearance.
Verapamil may increase the plasma concentrations of quinidine. Pulmonary oedema may occur in patients with hypertrophic cardiomyopathy
The combination of verapamil and antiarrhythmic agents may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).
Anticonvulsants
Verapamil may increase the plasma concentrations of carbamazepine. This may produce side effects such as diplopia, headache, ataxia or dizziness. Verapamil may also increase the plasma concentrations of phenytoin.
Antidepressants
Verapamil may increase the plasma concentrations of imipramine.
Antidiabetics
Verapamil may increase the plasma concentrations of glibenclamide (glyburide). Co-administration of verapamil with metformin may reduce the efficacy of metformin.
Antihypertensives, diuretics, vasodilators
Potentiation of the hypotensive effect.
Anti-infectives
Rifampicin may reduce the plasma concentrations of verapamil which may produce a reduced blood pressure lowering effect. Erythromycin, clarithromycin and telithromycin may increase the plasma concentrations of verapamil.
Antineoplastics
Verapamil may increase the plasma concentrations of doxorubicin.
Barbiturates
Phenobarbital may reduce the plasma concentrations of verapamil.
Benzodiazepines and other anxiolytics
Verapamil may increase the plasma concentrations of buspirone and midazolam.
Beta blockers
Verapamil may increase the plasma concentrations of metoprolol and propranolol which may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).
Intravenous beta-blockers should not be given to patients under treatment with verapamil.
Cardiac glycosides
Verapamil may increase the plasma concentrations of digitoxin and digoxin. Verapamil has been shown to increase the serum concentration of digoxin and caution should be exercised with regard to digitalis toxicity. The digitalis level should be determined and the glycoside dose reduced, if required.
Colchicine
Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (P-gp). Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine. Combined use is not recommended.
H2 Receptor antagonists
Cimetidine may increase the plasma concentrations of verapamil.
HIV antiviral agents
Due to the metabolic inhibitory potential of some of the HIV antiviral agents, such as ritonavir, plasma concentrations of verapamil may increase. Caution should be used or dose of verapamil may be decreased.
Immunosuppressants
Verapamil may increase the plasma concentrations of ciclosporin, everolimus, sirolimus and tacrolimus.
Inhaled anaesthetics
When used concomitantly, inhalation anaesthetics and calcium antagonists, such as verapamil hydrochloride, should each be titrated carefully to avoid additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).
Lipid lowering agents
Verapamil may increase the plasma concentrations atorvastatin, lovastatin and simvastatin.
Treatment with HMG CoA reductase inhibitors (e.g., simvastatin, atorvastatin or lovastatin) in a patient taking verapamil should be started at the lowest possible dose and titrated upwards. If verapamil treatment is to be added to patients already taking an HMG CoA reductase inhibitor (e.g., simvastatin, atorvastatin or lovastatin), consider a reduction in the statin dose and retitrate against serum cholesterol concentrations.
Atorvastatin has been shown to increase verapamil levels. Although there is no direct in vivo clinical evidence, there is strong potential for verapamil to significantly affect atorvastatin pharmacokinetics in a similar manner to simvastatin or lovastatin. Consider using caution when atorvastatin and verapamil are concomitantly administered.
Fluvastatin, pravastatin and rosuvastatin are not metabolized by CYP3A4 and are less likely to interact with verapamil.
Lithium
Serum levels of lithium may be reduced. However, there may be increased sensitivity to lithium causing enhanced neurotoxicity.
Neuromuscular blocking agents employed in anaesthesia
The effects may be potentiated.
Serotonin receptor agonists
Verapamil may increase the plasma concentrations of almotriptan.
Theophylline
Verapamil may increase the plasma concentrations of theophylline.
Uricosurics
Sulfinpyrazone may reduce the plasma concentrations of verapamil which may produce a reduced blood pressure lowering effect.
Anticoagulants
When oral verapamil was co-administered with dabigatran etexilate (150 mg), a P- gp substrate, the Cmax and AUC of dabigatran were increased but magnitude of this change differs depending on time between administration and the formulation of verapamil. Co- administration of verapamil 240 mg extended-release at the same time as dabigatran etexilate resulted in increased dabigatran exposure (increase of Cmax by about 90 % and AUC by about 70 %).
Close clinical surveillance is recommended when verapamil is combined with dabigatran etexilate and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.
Other Cardiac therapy
Concomitant use with ivabradine is contraindicated due to the additional heart rate lowering effect of verapamil to ivabradine (see section 4.3).
Other
St. John's Wort may reduce the plasma concentrations of verapamil, whereas grapefruit juice may increase the plasma concentrations of verapamil.
4.6 |
Half Securon SR 120 mg modified-release tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
There are no adequate and well-controlled study data in pregnant women. Although animal studies have not shown any teratogenic effects (see section 5.3), verapamil should not be given during the first trimester of pregnancy unless, in the clinician's judgement, it is essential for the welfare of the patient.
Verapamil hydrochloride is excreted in human breast milk. Limited human data from oral administration has shown that the infant relative dose of verapamil is low (0.1 - 1% of the mother's oral dose) and that verapamil use may be compatible with breastfeeding. Due to the potential for serious adverse reactions in nursing infants, verapamil should only be used during lactation if it is essential for the welfare of the mother
4.7 |
Half Securon SR 120 mg modified-release tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Depending on individual susceptibility, the patient's ability to drive a vehicle, operate machinery or work under hazardous conditions may be impaired. This is particularly true in the initial stages of treatment, when changing over from another drug or when the dose is raised. Like many other common medicines, verapamil has been shown to increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.
4.8 |
Half Securon SR 120 mg modified-release tablets | Clinical particulars - Undesirable effects | Undesirable effects
Reactions from Postmarketing Surveillance or Phase IV Clinical Trials
The following adverse events reported with verapamil are listed below by system organ class:
Immune system disorders: allergic reactions (e.g. erythema, pruritus, urticaria) are very rarely seen.
Nervous system disorders: headache, dizziness, paresthesia, tremor and extrapyramidal syndrome.
Ear and labyrinth disorders: vertigo and tinnitus.
Cardiac disorders/vascular disorders: bradycardic arrhythmias such as sinus bradycardia, sinus arrest with asystole, 2nd and 3rd degree AV block, bradyarrhythmia in atrial fibrillation, peripheral oedema, palpitations, tachycardia, development or aggravation of heart failure and hypotension. There have been rare reports of flushing.
Gastrointestinal disorders: nausea, vomiting, constipation, ileus and abdominal pain/discomfort. Gingival hyperplasia may occur very rarely when the drug is administered over prolonged periods, and is fully reversible when the drug is discontinued.
Skin and subcutaneous tissue disorders: ankle oedema, Quincke's oedema, Steven-Johnson syndrome, erythema multiforme, erythromelalgia, alopecia and purpura.
Musculoskeletal and connective tissue disorders: muscular weakness, myalgia and arthralgia.
Reproductive system and breast disorders: impotence (erectile dysfunction) has been rarely reported and isolated cases of galactorrhoea. On very rare occasions, gynaecomastia has been observed in elderly male patients under long-term verapamil treatment, and is fully reversible in all cases when the drug was discontinued.
General disorders and administration site conditions: fatigue.
Investigations: A reversible impairment of liver function characterized by an increase of transaminase and/or alkaline phosphatase may occur on very rare occasions during verapamil treatment and is most probably a hypersensitivity reaction. Rises in blood prolactin levels have been reported.
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 |
Half Securon SR 120 mg modified-release tablets | Clinical particulars - Overdose | Overdose
The course of symptoms in verapamil intoxication depends on the amount taken, the point in time at which detoxification measures are taken and myocardial contractility (age-related). The main symptoms are as follows: blood pressure fall (at times to values not detectable), shock symptoms, loss of consciousness, 1st and 2nd degree AV block (frequently as Wenckebach's phenomenon with or without escape rhythms), total AV block with total AV dissociation, escape rhythm, asystole, bradycardia up to high degree AV block and sinus arrest, hyperglycaemia, stupor and metabolic acidosis and acute respiratory distress syndrome. Fatalities have occurred as a result of overdose.
The therapeutic measures to be taken depend on the point in time at which verapamil was taken and the type and severity of intoxication symptoms. In intoxications with large amounts of slow-release preparations (Securon SR and Half Securon SR), it should be noted that the release of the active drug and the absorption in the intestine may take more than 48 hours. Verapamil hydrochloride cannot be removed by haemodialysis. Depending on the time of ingestion, it should be taken into account that there may be some lumps of incompletely dissolved tablets along the entire length of the gastrointestinal tract, which function as active drug depots.
General measures to be taken: Gastric lavage with the usual precautions, even later than 12 hours after ingestion, if no gastrointestinal motility (peristaltic sounds) is detectable. Where intoxication by Securon SR or Half Securon SR is suspected, extensive elimination measures are indicated, such as induced vomiting, removal of the contents of the stomach and the small intestine under endoscopy, intestinal lavage, laxative, high enemas. The usual intensive resuscitation measures apply, such as extrathoracic heart massage, respiration, defibrillation and/or pacemaker therapy.
Specific measures to be taken: Elimination of cardiodepressive effects, hypotension or bradycardia. The specific antidote is calcium, e.g. 10 -20 ml of a 10% calcium gluconate solution administered intravenously (2.25 - 4.5 mmol), repeated if necessary or given as a continuous drip infusion (e.g. 5 mmol/hour).
The following measures may also be necessary: In case of 2nd or 3rd degree AV block, sinus bradycardia, asystole - atropine, isoprenaline, orciprenaline or pacemaker therapy. In case of hypotension - dopamine, dobutamine, noradrenaline. If there are signs of continuing myocardial failure - dopamine, dobutamine, if necessary repeated calcium injections.
5. Pharmacological properties
5.1 |
Half Securon SR 120 mg modified-release tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Verapamil hydrochloride is a racemic mixture consisting of equal portions of the R-enantiomer and the S-enantiomer. Verapamil is extensively metabolized. Norverapamil is one of 12 metabolites identified in urine, has 10 to 20% of the pharmacologic activity of verapamil and accounts for 6% of excreted drug. The steady-state plasma concentrations of norverapamil and verapamil are similar.
Steady state after multiple once daily dosing is reached after three to four days.
Absorption
Greater than 90% of verapamil is rapidly absorbed from the small intestine after oral administration. Mean systemic availability of the unchanged compound after a single dose of SR verapamil is approximately 33%, owing to an extensive hepatic first-pass metabolism. Bioavailability is about two times higher with repeated administration. Peak verapamil plasma levels are reached four to five hours after SR administration. The peak plasma concentration of norverapamil is attained approximately five hours after SR administration. The presence of food has no effect on the bioavailability of verapamil.
Distribution
Verapamil is widely distributed throughout the body tissues, the volume of distribution ranging from 1.8–6.8 L/kg in healthy subjects. Plasma protein binding of verapamil is approximately 90%.
Metabolism
Verapamil is extensively metabolized. In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. In healthy men, orally administered verapamil hydrochloride undergoes extensive metabolism in the liver, with 12 metabolites having been identified, most in only trace amounts. The major metabolites have been identified as various N and O-dealkylated products of verapamil. Of these metabolites, only norverapamil has any appreciable pharmacological effect (approximately 20% that of the parent compound), which was observed in a study with dogs.
Elimination
Following oral administration, the elimination half-life is three to seven hours. Approximately 50% of an administered dose is eliminated renally within 24 hours, 70% within five days. Up to 16% of a dose is excreted in the feces. About 3% to 4% of renally excreted drug is excreted as unchanged drug. The total clearance of verapamil is nearly as high as the hepatic blood flow, approximately 1 L/h/kg (range: 0.7-1.3 L/h/kg).
Special Populations
Geriatric:
Aging may affect the pharmacokinetics of verapamil given to hypertensive patients. Elimination half-life may be prolonged in the elderly. The antihypertensive effect of verapamil was found not to be age-related.
Renal insufficiency:
Impaired renal function has no effect on verapamil pharmacokinetics, as shown by comparative studies in patients with end-stage renal failure and subjects with healthy kidneys. Verapamil and norverapamil are not significantly removed by hemodialysis.
Hepatic insufficiency:
The half-life of verapamil is prolonged in patients with impaired liver function owing to lower oral clearance and a higher volume of distribution.
5.3 |
Half Securon SR 120 mg modified-release tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 0.6 ( 180 mg/m2/day) and 1.2 times (360 mg/m2/day ) respectively the equivalent maximum recommended human oral daily dose of 300mg/m2/day) and have revealed no evidence of teratogenicity. In the rat, the highest dose was embryocidal and retarded foetal growth and development. These effects occurred in the presence of maternal toxicity (reflected by reduced food consumption and weight gain of dams). This oral dose has also been shown to cause hypotension in rats.
6. |
Half Securon SR 120 mg modified-release tablets | Pharmaceutical particulars - List of excipients | List of excipients
Microcrystalline cellulose,
Sodium alginate,
Povidone K30,
Magnesium stearate,
Purified water,
Hypromellose 2910,
Macrogol 400,
Macrogol 6000,
Talc,
Titanium dioxide (E171),
Montan glycol wax.
6.2 |
Half Securon SR 120 mg modified-release tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
None stated.
6.3 |
Half Securon SR 120 mg modified-release tablets | Pharmaceutical particulars - Shelf life | Shelf life
2 years
6.4 |
Half Securon SR 120 mg modified-release tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25°C and store in the original package – blister pack.
6.5 |
Half Securon SR 120 mg modified-release tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Calendar pack consisting of a PVC/PVDC blister in a cardboard outer container. Pack size: 28 tablets.
6.6 |
Half Securon SR 120 mg modified-release tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special requirements. The tablets should not be chewed or sucked.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Half Securon SR 120 mg modified-release tablets | Marketing authorisation holder | Mylan Products Ltd.
20 Station Close
Potters Bar
Herts
EN6 1TL
United Kingdom
8. Marketing authorisation number(s)
PL 46302/0025
9. |
Half Securon SR 120 mg modified-release tablets | Date of first authorisation/renewal of the authorisation | 14 March 2002
10. |
Half Securon SR 120 mg modified-release tablets | Date of revision of the text | 08/12/2020 |
Half Sinemet CR 25 mg/100 mg Prolonged-Release Tablets | Name of the medicinal product | SINEMET® CR 50 mg/200 mg Prolonged-Release Tablets
HALF SINEMET® CR 25 mg/100 mg Prolonged-Release Tablets
2. |
Half Sinemet CR 25 mg/100 mg Prolonged-Release Tablets | Qualitative and quantitative composition | Each tablet of 'Sinemet CR' contains carbidopa (equivalent to 50 mg of anhydrous carbidopa) and 200 mg levodopa.
Each tablet of 'Half Sinemet CR' contains carbidopa (equivalent to 25 mg of anhydrous carbidopa) and 100 mg levodopa.
3. |
Half Sinemet CR 25 mg/100 mg Prolonged-Release Tablets | Pharmaceutical form | Modified-release tablets.
'Sinemet CR': peach-coloured, oval shaped, biconvex tablets, one side deep-scored and the other marked '521'.
'Half Sinemet CR': pink-coloured, oval-shaped, biconvex tablets, plain one side and the other marked '601'.
4. |
Half Sinemet CR 25 mg/100 mg Prolonged-Release Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Antiparkinson agent.
Idiopathic Parkinson's disease, in particular to reduce off-period in patients who previously have been treated with levodopa/decarboxylase inhibitors, or with levodopa alone and who have experienced motor fluctuations. The experience is limited with 'Sinemet CR' and 'Half Sinemet CR' in patients who have not been treated with levodopa before.
4.2 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.