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Depixol Low Volume Injection | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Adults
The usual dosage of flupentixol decanoate lies between 50 mg every 4 weeks and 300 mg every 2 weeks, but some patients may require up to 400 mg weekly. The maximum single dose at any one time is 400 mg. For example, 800 mg ever 2 weeks should not be given. Other patients may be adequately maintained on dosages of 20-40 mg flupentixol decanoate every 2-4 weeks. In patients who have not previously received depot antipsychotic, treatment is usually started with a small dose (e.g. 20 mg) to assess tolerability. An interval of at least one week should be allowed before the second injection is given at a dose consistent with the patients' condition.
Depixol Injection 20 mg/ml is not intended for use in patients requiring doses of greater than 60 mg (3 ml) of flupentixol. Injection volumes of 2 – 3 ml should be distributed between two injection sites.
More concentrated solutions of flupentixol decanoate (Depixol Conc Injection or Depixol Low Volume Injection) should be used if doses greater than 3 ml (60 mg) are required.
The injection volumes selected for Depixol Conc Injection or Depixol Low Volume Injection should not exceed 2 ml.
Adequate control of severe psychotic symptoms may take up to 4 to 6 months at high enough dosage. Once stabilised lower maintenance doses may be considered, but must be sufficient to prevent relapse.
Older patients
In accordance with standard medical practice, initial dosage may need to be reduced to a quarter or half the normal starting dose in the frail or older patients.
Children
Depixol is not recommended for use in children due to lack of clinical experience.
Patients with reduced renal function
Flupentixol has not been studied in renal impairment. Increased cerebral sensitivity to antipsychotics has been noted in severe renal impairment (see section 4.4).
Patients with reduced hepatic function
Flupentixol has not been studied in hepatic impairment. It is extensively metabolised by the liver and particular caution should be used in this situation and serum level monitoring is advised (see section 4.4). Depixol should be initiated at low doses orally to check for tolerability before switching to the depot formulation.
Method of administration
Route of administration
Deep intramuscular injection into the upper outer buttock or lateral thigh.
Dosage and dosage interval should be adjusted according to the patients' symptoms and response to treatment.
Note: As with all oil-based injections it is important to ensure, by aspiration before injection, that inadvertent intravascular entry does not occur.
4.3 |
Depixol Low Volume Injection | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Circulatory collapse, depressed level of consciousness due to any cause (e.g. intoxication with alcohol, barbiturates or opiates), coma.
Not recommended for excitable or agitated patients.
4.4 |
Depixol Low Volume Injection | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Caution should be exercised in patients having: liver disease; cardiac disease or arrhythmias; severe respiratory disease; renal failure; epilepsy (and conditions predisposing to epilepsy e.g. alcohol withdrawal or brain damage); Parkinson's disease; narrow angle glaucoma; prostatic hypertrophy; hypothyroidism; hyperthyroidism; myasthenia gravis; phaeochromocytoma and patients who have shown hypersensitivity to thioxanthenes or other antipsychotics.
The possibility of development of neuroleptic malignant syndrome (hyperthermia, muscle rigidity, fluctuating consciousness, instability of the autonomous nervous system) exists with any neuroleptic. The risk is possibly greater with the more potent agents. Patients with pre-existing organic brain syndrome, mental retardation, and opiate and alcohol abuse are overrepresented among fatal cases.
Treatment: Discontinuation of the neuroleptic. Symptomatic treatment and use of general supportive measures. Dantrolene and bromocriptine may be helpful.
Symptoms may persist for more than a week after oral neuroleptics are discontinued and somewhat longer when associated with the depot forms of the drugs.
Blood dyscrasias, including thrombocytopenia, have been reported rarely. Blood counts should be carried out if a patient develops signs of persistent infection.
As described for other psychotropics flupentixol may modify insulin and glucose responses calling for adjustment of the antidiabetic therapy in diabetic patients.
Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia have been described after abrupt cessation of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. The plasma concentrations of the Depixol Injection and Conc. Injection gradually decrease over several weeks which makes gradual dosage tapering unnecessary.
When transferring patients from oral to depot antipsychotic treatment, the oral medication should not be discontinued immediately, but gradually withdrawn over a period of several days after administering the first injection.
As with other drugs belonging to the therapeutic class of antipsychotics, flupentixol may cause QT prolongation. Persistently prolonged QT intervals may increase the risk of malignant arrhythmias. Therefore, flupentixol should be used with caution in susceptible individuals (with hypokalaemia, hypomagnesia or genetic predisposition) and in patients with a history of cardiovascular disorders, e.g. QT prolongation, significant bradycardia (<50 beats per minute), a recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Depixol and preventive measures undertaken.
Concomitant treatment with other antipsychotics should be avoided (see section 4.5).
Leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics, including flupentixol decanoate.
Long-acting depot antipsychotics should be used with caution in combination with other medicines known to have a myelosuppressive potential, as these cannot rapidly be removed from the body in conditions where this may be required.
Suicide/suicidal thoughts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs.
It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Other psychiatric conditions for which flupentixol is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders. Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.
Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Older people
The elderly require close supervision because they are specially prone to experience such adverse effects as sedation, hypotension, confusion and temperature changes.
Cerebrovascular
An approximately 3-fold increased risk of cerebrovascular adverse events have been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Flupentixol should be used with caution in patients with risk factors for stroke.
Increased Mortality in Older people with Dementia
Data from two large observational studies showed that older people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.
Depixol is not licensed for the treatment of dementia-related behavioural disturbances.
4.5 |
Depixol Low Volume Injection | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
In common with other antipsychotics, flupentixol enhances the response to alcohol, the effects of barbiturates and other CNS depressants. Flupentixol may potentiate the effects of general anaesthetics and anticoagulants and prolong the action of neuromuscular blocking agents.
The anticholinergic effects of atropine or other drugs with anticholinergic properties may be increased. Concomitant use of drugs such as metoclopramide, piperazine or antiparkinson drugs may increase the risk of extrapyramidal effects such as tardive dyskinesia. Combined use of antipsychotics and lithium or sibutramine has been associated with an increased risk of neurotoxicity.
Antipsychotics may enhance the cardiac depressant effects of quinidine; the absorption of corticosteroids and digoxin. The hypotensive effect of vasodilator antihypertensive agents such as hydralazine and α-blockers (e.g. doxazosin), or methyl-dopa may be enhanced.
Increases in the QT interval related to antipsychotic treatment may be exacerbated by the co-administration of other drugs known to significantly increase the QT interval. Co-administration of such drugs should be avoided.
Relevant classes include:
• class Ia and III antiarrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide)
• some antipsychotics (e.g. thioridazine)
• some macrolides (e.g. erythromycin)
• some antihistamines
• some quinolone antibiotics (e.g. moxifloxacin)
The above list is not exhaustive and other individual drugs known to significantly increase QT interval (e.g. cisapride, lithium) should be avoided.
Drugs known to cause electrolyte disturbances such as thiazide diuretics (hypokalaemia) and drugs known to increase the plasma concentration of flupentixol should also be used with caution as they may increase the risk of QT prolongation and malignant arrythmias (see section 4.4).
Antipsychotics may antagonise the effects of adrenaline and other sympathomimetic agents, and reverse the antihypertensive effects of guanethidine and similar adrenergic-blocking agents. Antipsychotics may also impair the effect of levodopa, adrenergic drugs and anticonvulsants.
The metabolism of tricyclic antidepressants may be inhibited and the control of diabetes may be impaired.
4.6 |
Depixol Low Volume Injection | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
As the safety of this drug during pregnancy has not been established, use during pregnancy, especially the first and last trimesters, should be avoided, unless the expected benefit to the patient outweighs the potential risk to the foetus.
Neonates exposed to antipsychotics (including Depixol) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Animal studies have shown reproductive toxicity (see section 5.3).
Breast-feeding
Flupentixol is excreted into the breast milk. If the use of Depixol is considered essential, nursing mothers should be advised to stop breast-feeding.
Fertility
In humans, adverse events such as hyperprolactinaemia, galactorrhoea, amenorrhoea, libido decreased, erectile dysfunction and ejaculation failure have been reported (see section 4.8). These events may have a negative impact on female and/or male sexual function and fertility.
If clinical significant hyperprolactinaemia, galactorrhoea, amenorrhoea or sexual dysfunctions occur, a dose reduction (if possible) or discontinuation should be considered. The effects are reversible on discontinuation.
In preclinical fertility studies in rats, flupentixol slightly affected the pregnancy rate of female rats (see section 5.3).
4.7 |
Depixol Low Volume Injection | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Alertness may be impaired, especially at the start of treatment, or following the consumption of alcohol; patients should be warned of this risk and advised not to drive or operate machinery until their susceptibility is known. Patients should not drive if they have blurred vision.
4.8 |
Depixol Low Volume Injection | Clinical particulars - Undesirable effects | Undesirable effects
Cases of suicidal ideation and suicidal behaviours have been reported during flupentixol therapy or early after treatment discontinuation (see section 4.4).
The majority of undesirable effects are dose dependent. The frequency and severity are most pronounced in the early phase of treatment and decline during continued treatment.
Extrapyramidal reactions may occur, especially in the early phase of treatment. In most cases these side effects can be satisfactorily controlled by reduction of dosage and/or use of antiparkinsonian drugs. The routine prophylactic use of antiparkinsonian drugs is not recommended.Antiparkinsonian drugs do not alleviate tardive dyskinesia and may aggravate them. Reduction in dosage or, if possible, discontinuation of flupentixol therapy is recommended. In persistent akathisia a benzodiazepine or propranolol may be useful.
Frequencies are taken from the literature and spontaneous reporting. Frequencies are defined as: 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), or not known (can not be estimated from the available data).
Blood and lymphatic system disorders
Rare
Thrombocytopenia, neutropenia, leukopenia, agranulocytosis
Immune system disorders
Rare
Hypersensitivity, anaphylactic reaction.
Endocrine disorder
Rare
Hyperprolactinaemia.
Metabolism and nutrition disorders
Common
Increased appetite, weight increased.
Uncommon
Decreased appetite.
Rare
Hyperglycaemia, glucose tolerance abnormal.
Psychiatric disorders
Common
Insomnia, depression, nervousness, agitation, libido decreased.
Uncommon
Confusional state.
Not known
Suicidal ideation, suicidal Behaviour
Nervous system disorders
Very common
Somnolence, akathisia, hyperkinesia, hypokinesia.
Common
Tremor, dystonia, dizziness, headache, disturbance in attention.
Uncommon to Rare
Tardive dyskinesia, dyskinesia, parkinsonism, speech disorder, convulsion.
Very Rare
Neuroleptic malignant syndrome.
Eye disorders
Common
Accommodation disorder, vision abnormal.
Uncommon
Oculogyration.
Cardiac disorders
Common
Tachycardia, palpitations.
Rare
Electrocardiogram QT prolonged.
Vascular disorders
Uncommon
Hypotension, hot flush.
Not known
Venous thromboemoblism
Respiratory, thoracic and mediastinal disorders
Common
Dyspnoea.
Gastrointestinal disorders
Very common
Dry mouth.
Common
Salivary hypersecretion, constipation, vomiting, dyspepsia, diarrhoea.
Uncommon
Abdominal pain, nausea, flatulence.
Hepatobiliary disorders
Uncommon
Liver function test abnormal.
Very rare
Jaundice
Skin and subcutaneous tissue disorders
Common
Hyperhidrosis, pruritus.
Uncommon
Rash, photosensitivity reaction, dermatitis.
Musculoskeletal and connective tissue disorder
Common
Myalgia.
Uncommon
Muscle rigidity.
Renal and urinary disorders
common
Micturition disorder, urinary retention.
Pregnancy, puerperium and perinatal conditions
Not known
Drug withdrawal syndrome neonatal (see 4.6)
Reproductive system and breast disorders
Uncommon
Ejaculation failure, erectile dysfunction.
Rare
Gynaecomastia, galactorrhoea, amenorrhoea.
General disorders and administration site conditions
Common
Asthenia, fatigue.
Uncommon
Injection site reaction1.
1 For injectable flupentixol presentations.
As with other drugs belonging to the therapeutic class of antipsychotics, rare cases of QT prolongation, ventricular arrhythmias - ventricular fibrillation, ventricular tachycardia, Torsade de Pointes and sudden unexplained death have been reported for flupentixol (see section 4.4).
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs- Frequency unknown
Abrupt discontinuation of flupentixol may be accompanied by withdrawal symptoms. The most common symptoms are nausea, vomiting, anorexia, diarrhoea, rhinorrhoea, sweating, myalgias, paraesthesias, insomnia, restlessness, anxiety, and agitation. Patients may also experience vertigo, alternate feelings of warmth and coldness, and tremor. Symptoms generally begin within 1 to 4 days of withdrawal and abate within 7 to 14 days.
Reporting of suspected adverse reactionsReporting 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 |
Depixol Low Volume Injection | Clinical particulars - Overdose | Overdose
Overdosage may cause somnolence or even coma, extrapyramidal symptoms, convulsions, hypotension, shock, hyper or hypothermia. ECG changes, QT prolongation, Torsade de Pointes, cardiac arrest and ventricular arrhythmias have been reported when administered in overdose together with drugs known to affect the heart.
Treatment is symptomatic and supportive, with measures aimed at supporting the respiratory and cardiovascular systems. The following specific measures may be employed if required.
- Anticholinergic antiparkinson drugs if extrapyramidal symptoms occur
- Sedation (with benzodiazepines) in the unlikely event of agitation or excitement or convulsions
- Noradrenaline in saline intravenous drip if the patient is in shock. Adrenaline must not be given.
5. Pharmacological properties
5.1 |
Depixol Low Volume Injection | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
By esterification of flupentixol with decanoic acid flupentixol has been converted to a highly lipophilic substance, flupentixol decanoate. When dissolved in oil and injected intramuscularly this substance diffuses slowly into the surrounding body water, where enzymatic breakdown occurs releasing the active component flupentixol. The duration of action is 2-4 weeks with maximum serum levels being reached by the end of the first week after injection.
Distribution
Flupentixol is distributed in the body in a similar way to other antipsychotics; with the highest concentrations of drug and metabolites in liver lungs, intestines and kidneys and lower concentrations in heart, spleen, brain and blood. The apparent volume of distribution is about 14 L/kg and the protein binding >95%.
Elimination
Flupentixol crosses the placental barrier in small amounts; it is also excreted in breast milk in very small amounts.
Biotransformation
The metabolism of flupentixol proceeds via three main routes -sulphoxidation, side chain N-dealkylation and glucuronic acid conjugation. The metabolites are devoid of psychopharmacological activity. The excretion proceeds mainly with the faeces but also to some degree with the urine. System; clearance is about 0.4-0.5 L/min.
5.3 |
Depixol Low Volume Injection | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Reproductive toxicity
In fertility studies in rats, flupentixol slightly affected the pregnancy rate of female rats. Animal reproduction studies in mice, rats and rabbits have not shown evidence of teratogenic effects. Embryotoxic effects in terms of increased post implantation loss/increased absorption rates or occasional abortions were seen in rats and rabbits at doses associated with maternal toxicity.
6. |
Depixol Low Volume Injection | Pharmaceutical particulars - List of excipients | List of excipients
Thin vegetable oil 'Viscoleo' (fractionated coconut oil).
6.2 |
Depixol Low Volume Injection | Pharmaceutical particulars - Incompatibilities | Incompatibilities
This product may be mixed in the same syringe with other products in the Depixol Injection range. It should not be mixed with any other injection fluids.
6.3 |
Depixol Low Volume Injection | Pharmaceutical particulars - Shelf life | Shelf life
Ampoules 1 ml : 2 years
6.4 |
Depixol Low Volume Injection | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25°C. Keep the ampoules in the outer carton in order to protect from light.
6.5 |
Depixol Low Volume Injection | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Ampoules containing 1 ml of 200 mg/ml flupentixol decanoate in thin vegetable oil. Pack size : 5 ampoules per carton.
6.6 |
Depixol Low Volume Injection | 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. |
Depixol Low Volume Injection | Marketing authorisation holder | Lundbeck Limited
Iveco House,
Station Road,
Watford,
Hertfordshire,
WD17 1ET,
UK
8. Marketing authorisation number(s)
PL 00458/0065
9. |
Depixol Low Volume Injection | Date of first authorisation/renewal of the authorisation | Date of First Authorisation in the UK:
23 October 1991
Renewal of the Authorisation:
09 November 2010
10. |
Depixol Low Volume Injection | Date of revision of the text | 01/2021
Legal category: POM |
Depixol Tablets 3mg | Name of the medicinal product | Depixol® 3 mg film-coated tablets
2. |
Depixol Tablets 3mg | Qualitative and quantitative composition | Each film-coated tablet contains 3 mg flupentixol (as 3.504 mg flupentixol dihydrochloride).
Excipients with known effect:
Lactose monohydrateSunset yellow (E110)
For the full list of excipients, see section 6.1
3. |
Depixol Tablets 3mg | Pharmaceutical form | Film-coated tablet
Round, slightly biconvex, ochre, film-coated tablet marked FI.
4. |
Depixol Tablets 3mg | Clinical particulars - Therapeutic indications | Therapeutic indications
The treatment of schizophrenia and other psychoses.
4.2 |
Depixol Tablets 3mg | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Adults
1 - 3 tablets twice daily to a maximum of 18 mg (6 tablets) per day. It is recommended that commencement of treatment and increase in dosage should be carried out under close supervision. As with all antipsychotic drugs, the dose of Depixol should be titrated to the needs of each patient.
When transferring patients from oral to depot antipsychotic treatment, the oral medication should not be discontinued immediately, but gradually withdrawn over a period of several days after administering the first injection.
Older patients
In accordance with standard medical practice, initial dosage may need to be reduced to a quarter or half the normal starting dose in the frail or older patients.
Children
Flupentixol is not recommended for use in children due to lack of clinical experience.
Patients with reduced renal function
Flupentixol has not been studied in renal impairment. Increased cerebral sensitivity to antipsychotics has been noted in severe renal impairment (see section 4.4).
Patients with reduced hepatic function
Flupentixol has not been studied in hepatic impairment. It is extensively metabolised by the liver and particular caution should be used in this situation and serum level monitoring is advised (see section 4.4).
Method of administration
The tablets are swallowed with water.
4.3 |
Depixol Tablets 3mg | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Circulatory collapse, depressed level of consciousness due to any cause (e.g. intoxication with alcohol, barbiturates or opiates), coma.
Not recommended for excitable or agitated patients.
4.4 |
Depixol Tablets 3mg | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Caution should be exercised in patients having: liver disease; cardiac disease or arrhythmias; severe respiratory disease; renal failure; epilepsy (and conditions predisposing to epilepsy e.g. alcohol withdrawal or brain damage); Parkinson's disease; narrow angle glaucoma; prostatic hypertrophy; hypothyroidism; hyperthyroidism; myasthenia gravis; phaeochromocytoma and patients who have shown hypersensitivity to thioxanthenes or other antipsychotics.
The possibility of development of neuroleptic malignant syndrome (hyperthermia, muscle rigidity, fluctuating consciousness, instability of the autonomous nervous system) exists with any neuroleptic. The risk is possibly greater with the more potent agents. Patients with pre-existing organic brain syndrome, mental retardation, and opiate and alcohol abuse are overrepresented among fatal cases.
Treatment: Discontinuation of the neuroleptic. Symptomatic treatment and use of general supportive measures. Dantrolene and bromocriptine may be helpful.
Symptoms may persist for more than a week after oral neuroleptics are discontinued and somewhat longer when associated with the depot forms of the drugs.
Blood dyscrasias, including thrombocytopenia, have been reported rarely. Blood counts should be carried out if a patient develops signs of persistent infection.
As described for other psychotropics flupentixol may modify insulin and glucose responses calling for adjustment of the antidiabetic therapy in diabetic patients.
Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia have been described after abrupt cessation of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore, gradual withdrawal is usually advisable.
When transferring patients from oral to depot antipsychotic treatment, the oral medication should not be discontinued immediately, but gradually withdrawn over a period of several days after administering the first injection.
As with other drugs belonging to the therapeutic class of antipsychotics, flupentixol may cause QT prolongation. Persistently prolonged QT intervals may increase the risk of malignant arrhythmias. Therefore, flupentixol should be used with caution in susceptible individuals (with hypokalaemia, hypomagnesia or genetic predisposition) and in patients with a history of cardiovascular disorders, e.g. QT prolongation, significant bradycardia (<50 beats per minute), a recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Depixol and preventive measures undertaken.
Concomitant treatment with other antipsychotics should be avoided (see section 4.5).
Suicide/suicidal thoughts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs.
It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Other psychiatric conditions for which flupentixol is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders. Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.
Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Older people
Older people require close supervision because they are specially prone to experience such adverse effects as sedation, hypotension, confusion and temperature changes.
CerebrovascularAn approximately 3-fold increased risk of cerebrovascular adverse events have been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Flupentixol should be used with caution in patients with risk factors for stroke.
Increased Mortality in Older People with Dementia
Data from two large observational studies showed that older people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.
Depixol is not licensed for the treatment of dementia-related behavioural disturbances.
Excipients
The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 |
Depixol Tablets 3mg | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
In common with other antipsychotics, flupentixol enhances the response to alcohol, the effects of barbiturates and other CNS depressants. Flupentixol may potentiate the effects of general anaesthetics and anticoagulants and prolong the action of neuromuscular blocking agents.
The anticholinergic effects of atropine or other drugs with anticholinergic properties may be increased. Concomitant use of drugs such as metoclopramide, piperazine or antiparkinson drugs may increase the risk of extrapyramidal effects such as tardive dyskinesia. Combined use of antipsychotics and lithium or sibutramine has been associated with an increased risk of neurotoxicity.
Antipsychotics may enhance the cardiac depressant effects of quinidine; the absorption of corticosteroids and digoxin. The hypotensive effect of vasodilator antihypertensive agents such as hydralazine and α-blockers (e.g. doxazosin), or methyl-dopa may be enhanced.
Increases in the QT interval related to antipsychotic treatment may be exacerbated by the co-administration of other drugs known to significantly increase the QT interval.
Co-administration of such drugs should be avoided. Relevant classes include:
• class Ia and III antiarrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide)
• some antipsychotics (e.g. thioridazine)
• some macrolides (e.g. erythromycin)
• some antihistamines
• some quinolone antibiotics (e.g. moxifloxacin)
The above list is not exhaustive and other individual drugs known to significantly increase QT interval (e.g. cisapride, lithium) should be avoided.
Drugs known to cause electrolyte disturbances such as thiazide diuretics (hypokalaemia) and drugs known to increase the plasma concentration of flupentixol should also be used with caution as they may increase the risk of QT prolongation and malignant arrythmias (see section 4.4).
Antipsychotics may antagonise the effects of adrenaline and other sympathomimetic agents, and reverse the antihypertensive effects of guanethidine and similar adrenergic-blocking agents. Antipsychotics may also impair the effect of levodopa, adrenergic drugs and anticonvulsants.
The metabolism of tricyclic antidepressants may be inhibited and the control of diabetes may be impaired.
4.6 |
Depixol Tablets 3mg | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
As the safety of this drug during pregnancy has not been established, use during pregnancy, especially the first and last trimesters, should be avoided, unless the expected benefit to the patient outweighs the potential risk to the foetus.
Neonates exposed to antipsychotics (including Depixol) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Animal studies have shown reproductive toxicity (see section 5.3).
Breast-feeding
Flupentixol is excreted into the breast milk. If the use of Depixol is considered essential, nursing mothers should be advised to stop breast-feeding.
Fertility
In humans, adverse events such as hyperprolactinaemia, galactorrhoea, amenorrhoea, libido decreased, erectile dysfunction and ejaculation failure have been reported (see section 4.8). These events may have a negative impact on female and/or male sexual function and fertility.
If clinical significant hyperprolactinaemia, galactorrhoea, amenorrhoea or sexual dysfunctions occur, a dose reduction (if possible) or discontinuation should be considered. The effects are reversible on discontinuation.
In preclinical fertility studies in rats, flupentixol slightly affected the pregnancy rate of female rats (see section 5.3).
4.7 |
Depixol Tablets 3mg | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Alertness may be impaired, especially at the start of treatment, or following the consumption of alcohol; patients should be warned of this risk and advised not to drive or operate machinery until their susceptibility is known. Patients should not drive if they have blurred vision.
4.8 |
Depixol Tablets 3mg | Clinical particulars - Undesirable effects | Undesirable effects
Cases of suicidal ideation and suicidal behaviours have been reported during flupentixol therapy or early after treatment discontinuation (see section 4.4).
The majority of undesirable effects are dose dependent. The frequency and severity are most pronounced in the early phase of treatment and decline during continued treatment.
Extrapyramidal reactions may occur, especially in the early phase of treatment. In most cases these side effects can be satisfactorily controlled by reduction of dosage and/or use of antiparkinsonian drugs. The routine prophylactic use of antiparkinsonian drugs is not recommended. Antiparkinsonian drugs do not alleviate tardive dyskinesia and may aggravate them. Reduction in dosage or, if possible, discontinuation of flupentixol therapy is recommended. In persistent akathisia a benzodiazepine or propranolol may be useful.
Frequencies are taken from the literature and spontaneous reporting. Frequencies are defined as: 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), or not known (can not be estimated from the available data).
Blood and lymphatic system disorders
Rare
Thrombocytopenia, neutropenia, leukopenia, agranulocytosis
Immune system disorders
Rare
Hypersensitivity, anaphylactic reaction.
Endocrine disorder
Rare
Hyperprolactinaemia.
Metabolism and nutrition disorders
Common
Increased appetite, weight increased.
Uncommon
Decreased appetite.
Rare
Hyperglycaemia, glucose tolerance abnormal.
Psychiatric disorders
Common
Insomnia, depression, nervousness, agitation, libido decreased.
Uncommon
Confusional state.
Not known
Suicidal ideation, suicidal Behaviour
Nervous system disorders
Very common
Somnolence, akathisia, hyperkinesia, hypokinesia.
Common
Tremor, dystonia, dizziness, headache, disturbance in attention.
Uncommon to Rare
Tardive dyskinesia, dyskinesia, parkinsonism, speech disorder, convulsion.
Very Rare
Neuroleptic malignant syndrome.
Eye disorders
Common
Accommodation disorder, vision abnormal.
Uncommon
Oculogyration.
Cardiac disorders
Common
Tachycardia, palpitations.
Rare
Electrocardiogram QT prolonged.
Vascular disorders
Uncommon
Hypotension, hot flush.
Not known
Venous thromboemoblism
Respiratory, thoracic and mediastinal disorders
Common
Dyspnoea.
Gastrointestinal disorders
Very common
Dry mouth.
Common
Salivary hypersecretion, constipation, vomiting, dyspepsia, diarrhoea.
Uncommon
Abdominal pain, nausea, flatulence.
Hepatobiliary disorders
Uncommon
Liver function test abnormal.
Very rare
Jaundice
Skin and subcutaneous tissue disorders
Common
Hyperhidrosis, pruritus.
Uncommon
Rash, photosensitivity reaction, dermatitis.
Musculoskeletal and connective tissue disorder
Common
Myalgia.
Uncommon
Muscle rigidity.
Renal and urinary disorders
common
Micturition disorder, urinary retention.
Pregnancy, puerperium and perinatal conditions
Not known
Drug withdrawal syndrome neonatal (see 4.6)
Reproductive system and breast disorders
Uncommon
Ejaculation failure, erectile dysfunction.
Rare
Gynaecomastia, galactorrhoea, amenorrhoea.
General disorders and administration site conditions
Common
Asthenia, fatigue.
Uncommon
Injection site reaction1.
1 For injectable flupentixol presentations.
As with other drugs belonging to the therapeutic class of antipsychotics, rare cases of QT prolongation, ventricular arrhythmias - ventricular fibrillation, ventricular tachycardia, Torsade de Pointes and sudden unexplained death have been reported for flupentixol (see section 4.4).
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs- Frequency unknown
Abrupt discontinuation of flupentixol may be accompanied by withdrawal symptoms. The most common symptoms are nausea, vomiting, anorexia, diarrhoea, rhinorrhoea, sweating, myalgias, paraesthesias, insomnia, restlessness, anxiety, and agitation. Patients may also experience vertigo, alternate feelings of warmth and coldness, and tremor. Symptoms generally begin within 1 to 4 days of withdrawal and abate within 7 to 14 days.
Reporting of suspected adverse reactionsReporting 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 |
Depixol Tablets 3mg | Clinical particulars - Overdose | Overdose
Overdosage may cause somnolence, or even coma, extrapyramidal symptoms, convulsions, hypotension, shock, hyper- or hypothermia. ECG changes, QT prolongation, Torsade de Pointes, cardiac arrest and ventricular arrhythmias have been reported when administered in overdose together with drugs known to affect the heart.
Treatment is symptomatic and supportive, with measures aimed at supporting the respiratory and cardiovascular systems. The following specific measures may be employed if required.
- anticholinergic antiparkinson drugs if extrapyramidal symptoms occur.
- sedation (with benzodiazepines) in the unlikely event of agitation or excitement or convulsions.
- noradrenaline in saline intravenous drip if the patient is in shock. Adrenaline must not be given.
- ingestion of activated charcoal and gastric lavage should be considered.
5. Pharmacological properties
5.1 |
Depixol Tablets 3mg | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Oral administration to volunteers (8 mg single dose and 1.5 mg/day) and patients (5-60 mg/day) resulted in serum drug concentration curves with a maximum around four hours after administration. Mean biological half-life was about 35 hours in patients. No difference was seen in patients between half-lives estimated after single-dose administration and those estimated after repeated administration. Mean oral bioavailability of flupentixol varied between 40% and 55%.
5.3 |
Depixol Tablets 3mg | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Reproductive toxicity
In fertility studies in rats, flupentixol slightly affected the pregnancy rate of female rats. Animal reproduction studies in mice, rats and rabbits have not shown evidence of teratogenic effects. Embryotoxic effects in terms of increased post implantation loss/increased absorption rates or occasional abortions were seen in rats and rabbits at doses associated with maternal toxicity.
6. |
Depixol Tablets 3mg | Pharmaceutical particulars - List of excipients | List of excipients
Tablet core:
Betadex
Lactose monohydrate
Maize starch
Hydroxypropylcellulose
Microcrystalline cellulose
Croscarmellose sodium
Talc
Vegetable oil, hydrogenated
Magnesium stearate
Coating and colour:
Polyvinyl alcohol, partly hydrolyzed
Macrogol/PEG 3350
Talc
Iron oxide yellow (E172)
Iron oxide red (E172)
Titanium dioxide (E171)
Sunset yellow (E110)
Macrogol/PEG 6000
6.2 |
Depixol Tablets 3mg | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Depixol Tablets 3mg | Pharmaceutical particulars - Shelf life | Shelf life
3 years.
6.4 |
Depixol Tablets 3mg | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Depixol Tablets 3mg | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
White, High Density Polyethylene (HDPE) tablet container with a child-resistant closure and tamper-evident seal; 100 tablets.
6.6 |
Depixol Tablets 3mg | 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. |
Depixol Tablets 3mg | Marketing authorisation holder | Lundbeck Limited
Iveco House,
Station Road,
Watford,
Hertfordshire,
WD17 1ET,
UK
8. Marketing authorisation number(s)
PL 00458/0013R
9. |
Depixol Tablets 3mg | Date of first authorisation/renewal of the authorisation | Date of First Authorisation in the UK:
Renewal of the Authorisation:
29 January 1987
09 November 2010
10. |
Depixol Tablets 3mg | Date of revision of the text | 01/2021
Legal category: POM |
Depo-Medrone 40mg/ml Suspension for Injection | Name of the medicinal product | Depo-Medrone 40 mg/ml Suspension for Injection.
2. |
Depo-Medrone 40mg/ml Suspension for Injection | Qualitative and quantitative composition | Methylprednisolone acetate 40 mg/ml.
For the full list of excipients, see section 6.1.
3. |
Depo-Medrone 40mg/ml Suspension for Injection | Pharmaceutical form | Suspension for Injection.
White, sterile, white aqueous suspension.
4. |
Depo-Medrone 40mg/ml Suspension for Injection | Clinical particulars - Therapeutic indications | Therapeutic indications
Depo-Medrone may be used locally or systemically, particularly where oral therapy is not feasible.
Depo-Medrone may be used by any of the following routes: intramuscular, intra-articular, periarticular, intrabursal, intralesional or into the tendon sheath. It must not be used by the intrathecal or intravenous routes (see section 4.3 and section 4.8).
Intramuscular administration:
1. Rheumatic disorders
Rheumatoid arthritis
2. Collagen diseases/arteritis
Systemic lupus erythematosus
3. Dermatological diseases
Severe erythema multiforme (Stevens-Johnson syndrome)
4. Allergic states
Bronchial asthma
Drug hypersensitivity reactions
Angioneurotic oedema
5. Gastro-intestinal diseases
Ulcerative colitis
Crohn's disease
6. Respiratory diseases
Fulminating or disseminated tuberculosis (with appropriate antituberculous chemotherapy)
Aspiration of gastric contents
7. Miscellaneous
TB meningitis (with appropriate antituberculous chemotherapy)
Intra-articular administration:
Rheumatoid arthritis
Osteo-arthritis with an inflammatory component
Soft tissue administration (intrabursal, periarticular, into tendon sheath):
Synovitis not associated with infection
Epicondylitis
Tenosynovitis
Plantar fasciitis
Bursitis
Intralesional:
Keloids
Localized lichen planus
Localized lichen simplex
Granuloma annulare
Discoid lupus erythematosus
Alopecia areata
4.2 |
Depo-Medrone 40mg/ml Suspension for Injection | Clinical particulars - Posology and method of administration | Posology and method of administration
Depo-Medrone should not be mixed with any other suspending agent or solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever suspension and container permit. Depo-Medrone may be used by any of the following routes: intramuscular, intra-articular, periarticular, intrabursal, intralesional and into the tendon sheath. It must not be used by the intrathecal or intravenous routes (see sections 4.3 and 4.8). |
Depo-Medrone 40mg/ml Suspension for Injection | Clinical particulars - Contraindications | Undesirable effects may be minimised by using the lowest effective dose for the minimum period (see section 4.4).
Depo-Medrone vials are intended for single dose use only.
Intramuscular – for sustained systemic effect:
Allergic conditions (asthma, drug reactions), 80 – 120 mg (2 – 3 ml).
Dermatological conditions, 40 – 120 mg (1 – 3 ml).
Rheumatic disorders and collagen diseases (rheumatoid arthritis, SLE), 40 – 120 mg (1 – 3 ml) per week.
Dosage must be individualized and depends on the condition being treated and its severity.
The frequency of intramuscular injections should be determined by the duration of clinical response.
On average the effect of a single 2 ml (80 mg) injection may be expected to last approximately two weeks.
Intra-articular: Rheumatoid arthritis, osteo-arthritis. The dose of Depo-Medrone depends upon the size of the joint and the severity of the condition. Repeated injections, if needed, may be given at intervals of one to five or more weeks depending upon the degree of relief obtained from the initial injection. A suggested dosage guide is: large joint (knee, ankle, shoulder), 20 – 80 mg (0.5 – 2 ml); medium joint (elbow, wrist), 10 – 40 mg (0.25 – 1 ml); small joint (metacarpophalangeal, interphalangeal, sternoclavicular, acromioclavicular), 4 – 10 mg (0.1 – 0.25 ml).
Intrabursal: Subdeltoid bursitis, prepatellar bursitis, olecranon bursitis. For administration directly into bursae, 4 – 30 mg (0.1 – 0.75 ml). In most cases, repeat injections are not needed.
Intralesional: Keloids, localised lichen planus, localized lichen simplex, granuloma annulare, alopecia areata, and discoid lupus erythematosus. For administration directly into the lesion for local effect in dermatological conditions, 20 – 60 mg (0.5 – 1.5 ml). For large lesions, the dose may be distributed by repeated local injections of 20 – 40 mg (0.5 – 1 ml). One to four injections are usually employed. Care should be taken to avoid injection of sufficient material to cause blanching, since this may be followed by a small slough.
Peri-articular: Epicondylitis. Infiltrate 4 – 30 mg (0.1 – 0.75 ml) into the affected area.
Into the tendon sheath: Tenosynovitis, epicondylitis. For administration directly into the tendon sheath, 4 – 30 mg (0.1 – 0.75 ml). In recurrent or chronic conditions, repeat injections may be necessary.
Special precautions should be observed when administering Depo-Medrone. Intramuscular injections should be made deeply into the gluteal muscles. The usual technique of aspirating prior to injection should be employed to avoid intravascular administration. Doses recommended for intramuscular injection must not be administered superficially or subcutaneously.
Intra-articular injections should be made using precise, anatomical localisation into the synovial space of the joint involved. The injection site for each joint is determined by that location where the synovial cavity is most superficial and most free of large vessels and nerves. Suitable sites for intra-articular injection are the knee, ankle, wrist, elbow, shoulder, phalangeal and hip joints. The spinal joints, unstable joints and those devoid of synovial space are not suitable. Treatment failures are most frequently the result of failure to enter the joint space. Intra-articular injections should be made with care as follows: ensure correct positioning of the needle into the synovial space and aspirate a few drops of joint fluid. The aspirating syringe should then be replaced by another containing Depo-Medrone. To ensure position of the needle, synovial fluid should be aspirated and the injection made. After injection the joint is moved slightly to aid mixing of the synovial fluid and the suspension. Subsequent to therapy care should be taken for the patient not to overuse the joint in which benefit has been obtained. Negligence in this matter may permit an increase in joint deterioration that will more than offset the beneficial effects of the steroid.
Intrabursal injections should be made as follows: the area around the injection site is prepared in a sterile way and a wheal at the site made with 1 per cent procaine hydrochloride solution. A 20-24 gauge needle attached to a dry syringe is inserted into the bursa and the fluid aspirated. The needle is left in place and the aspirating syringe changed for a small syringe containing the desired dose. After injection, the needle is withdrawn and a small dressing applied. In the treatment of tenosynovitis care should be taken to inject Depo-Medrone into the tendon sheath rather than into the substance of the tendon. Due to the absence of a true tendon sheath, the Achilles tendon should not be injected with Depo-Medrone.
The usual sterile precautions should be observed, with each injection.
Paediatric population:
Dosage may be reduced for infants and children but should be governed more by the severity of the condition and response of the patient, than by age or size.
Elderly:
When used according to instructions, there is no information to suggest that a change in dosage is warranted in the elderly. However, treatment of elderly patients, particularly if long-term, should be planned bearing in mind the more serious consequences of the common side-effects of corticosteroids in old age and close clinical supervision is required (see Special warnings and special precautions for use).
4.3 |
Depo-Medrone 40mg/ml Suspension for Injection | Clinical particulars - Special warnings and precautions for use | Contraindications
Depo-Medrone is contraindicated:
• in patients with known hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• in patients who have systemic infection unless specific anti-infective therapy is employed
• for use by the intrathecal route (due to its potential for neurotoxicity, see section 4.8)
• for use by the intravenous route
Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids.
4.4 |
Depo-Medrone 40mg/ml Suspension for Injection | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Special warnings and precautions for use
Warnings and Precautions: |
Depo-Medrone 40mg/ml Suspension for Injection | Clinical particulars - Fertility, pregnancy and lactation | Undesirable effects may be minimised by using the lowest effective dose for the minimum period. Frequent patient review is required to appropriately titrate the dose against disease activity (see section 4.2).
Depo-Medrone vials are intended for single dose use only. Any multidose use of the product may lead to contamination.
Severe medical events have been reported in association with the intrathecal/epidural routes of administration (see section 4.8). Appropriate measures must be taken to avoid intravascular injection.
Due to the absence of a true tendon sheath, the Achilles tendon should not be injected with Depo-Medrone.
While crystals of adrenal steroids in the dermis suppress inflammatory reactions, their presence may cause disintegration of the cellular elements and physiochemical changes in the ground substance of the connective tissue. The resultant infrequently occurring dermal and/or subdermal changes may form depressions in the skin at the injection site. The degree to which this reaction occurs will vary with the amount of adrenal steroid injected. Regeneration is usually complete within a few months or after all crystals of the adrenal steroid have been absorbed.
In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Multiple small injections into the area of the lesion should be made whenever possible. The technique of intra-articular and intramuscular injection should include precautions against injection or leakage into the dermis. Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy.
Intralesional doses should not be placed too superficially, particularly in easily visible sites in patients with deeply pigmented skins, since there have been rare reports of subcutaneous atrophy and depigmentation.
Systemic absorption of methylprednisolone occurs following intra-articular injection of Depo-Medrone. Systemic as well as local effects can therefore be expected.
Adrenal cortical atrophy develops during prolonged therapy and may persist for months after stopping treatment. In patients who have received more than physiological doses of systemic corticosteroids (approximately 6 mg methylprednisolone) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids, but there is uncertainty about HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose of 6 mg methylprednisolone is reached, dose reduction should be slower to allow the HPA-axis to recover.
The following precautions apply for parenteral corticosteroids:
Following intra-articular injection, the occurrence of a marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted.
Local injection of a steroid into a previously infected joint is to be avoided.
Intra-articular corticosteroids are associated with a substantially increased risk of inflammatory response in the joint, particularly bacterial infection introduced with the injection. Charcot-like arthropathies have been reported particularly after repeated injections. Appropriate examination of any joint fluid present is necessary to exclude any bacterial infection, prior to injection.
Corticosteroids should not be injected into unstable joints.
Sterile technique is necessary to prevent infections or contamination.
The slower rate of absorption by intramuscular administration should be recognised.
Immunosuppressant Effects/Increased Susceptibility to Infections
Corticosteroids may increase susceptibility to infection, may mask some signs of infection, and new infections may appear during their use. Suppression of the inflammatory response and immune function increases the susceptibility to fungal, viral and bacterial infections and their severity. The clinical presentation may often be atypical and may reach an advanced stage before being recognised. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases.
Do not use intra-synovially, intrabursally or intratendinous administration for local effect in the presence of acute infection.
Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids.
Chickenpox is of serious concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. Passive immunization with varicella/zoster immunoglobin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.
Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.
The use of Depo-Medrone in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.
The role of corticosteroids in septic shock has been controversial, with early studies reporting both beneficial and detrimental effects. More recently, supplemental corticosteroids have been suggested to be beneficial in patients with established septic shock who exhibit adrenal insufficiency. However, their routine use in septic shock is not recommended. A systematic review of short-course high-dose corticosteroids did not support their use. However, meta-analyses and a review suggest that longer courses (5–11 days) of low-dose corticosteroids might reduce mortality, especially in patients with vasopressor-dependent septic shock.
Immune System Effects
Allergic reactions may occur. Because rare instances of skin reactions and anaphylactic/anaphylactoid reactions have occurred in patients receiving corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of drug allergy.
Endocrine Effects
Pharmacologic doses of corticosteroids administered for prolonged periods may result in hypothalamic-pituitary-adrenal (HPA) suppression (secondary adrenocortical insufficiency). The degree and duration of adrenocortical insufficiency produced is variable among patients and depends on the dose, frequency, time of administration, and duration of glucocorticoid therapy. This effect may be minimized by use of alternate-day therapy.
In addition, acute adrenal insufficiency leading to a fatal outcome may occur if glucocorticoids are withdrawn abruptly. Drug-induced secondary adrenocortical insufficiency may therefore be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Salt and/or a mineralocorticoid are only needed if mineralocorticoid secretion is impaired.
A steroid “withdrawal syndrome”, seemingly unrelated to adrenocortical insufficiency, may also occur following abrupt discontinuance of glucocorticoids. This syndrome includes symptoms such as: anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, desquamation, myalgia, weight loss, and/or hypotension. These effects are thought to be due to the sudden change in glucocorticoid concentration rather than to low corticosteroid levels.
Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it considered that the disease is unlikely to relapse. Abrupt withdrawal of doses up to 32 mg daily of methylprednisolone for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:
• Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks.
• When a short course has been prescribed within one year of cessation of long-term therapy (months or years).
• Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy.
• Patients receiving doses of systemic corticosteroid greater than 32 mg daily of methylprednisolone.
• Patients repeatedly taking doses in the evening.
Because glucocorticoids can produce or aggravate Cushing's syndrome, glucocorticoids should be avoided in patients with Cushing's disease.
There is an enhanced effect of corticosteroids on patients with hypothyroidism.
Metabolism and Nutrition
Corticosteroids, including methylprednisolone, can increase blood glucose, worsen pre-existing diabetes, and predispose those on long-term corticosteroid therapy to diabetes mellitus.
Psychiatric Effects
Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting treatment. Risks may be higher with high doses/systemic exposure (see section 4.5), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.
Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.
Nervous System Effects
Corticosteroids should be used with caution in patients with seizure disorders.
Corticosteroids should be used with caution in patients with myasthenia gravis (also see myopathy statement in Musculoskeletal Effects section).
There have been reports of epidural lipomatosis in patients taking corticosteroids, typically with long-term use at high doses.
Ocular Effects
Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids. Central serous chorioretinopathy, may lead to retinal detachment.
Prolonged use of corticosteroids may produce posterior subcapsular cataracts and nuclear cataracts (particularly in children), exophthalmos, or increased intraocular pressure, which may result in glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.
Corticosteroids should be used cautiously in patients with ocular herpes simplex, because of possible corneal perforation.
Cardiac Effects
Adverse effects of glucocorticoids on the cardiovascular system, such as dyslipidaemia and hypertension, may predispose treated patients with existing cardiovascular risk factors to additional cardiovascular effects, if high doses and prolonged courses are used. Accordingly, corticosteroids should be employed judiciously in such patients and attention should be paid to risk modification and additional cardiac monitoring if needed.
Systemic corticosteroids should be used with caution, and only if strictly necessary, in cases of congestive heart failure.
Vascular Effects
Corticosteroids should be used with caution in patients with hypertension.
Thrombosis including venous thromboembolism has been reported to occur with corticosteroids. As a result corticosteroids should be used with caution in patients who have or may be predisposed to thromboembolic disorders.
Gastrointestinal Effects
High doses of corticosteroids may produce acute pancreatitis.
There is no universal agreement on whether corticosteroids per se are responsible for peptic ulcers encountered during therapy; however, glucocorticoid therapy may mask the symptoms of peptic ulcer so that perforation or haemorrhage may occur without significant pain. Glucocorticoid therapy may mask peritonitis or other signs or symptoms associated with gastrointestinal disorders such as perforation, obstruction or pancreatitis. In combination with NSAIDs, the risk of developing gastrointestinal ulcers is increased.
Corticosteroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection. Caution must also be used in diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, when steroids are used as direct or adjunctive therapy.
Hepatobiliary Effects
Drug induced liver injury including acute hepatitis or liver enzyme increase can result from cyclical pulsed IV methylprednisolone (usually at initial dose > 1 g/day). Rare cases of hepatotoxicity have been reported. The time to onset can be several weeks or longer. In the majority of case reports resolution of the adverse events has been observed after treatment was discontinued. Therefore, appropriate monitoring is required.
Corticosteroids should be used with caution in patients with liver failure or cirrhosis.
Musculoskeletal Effects
An acute myopathy has been reported with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with anticholinergics, such as neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevations of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.
Osteoporosis is a common but infrequently recognized adverse effect associated with a long-term use of large doses of glucocorticoid.
Renal and Urinary Disorders
Caution is required in patients with systemic sclerosis because an increased incidence of scleroderma renal crisis has been observed with corticosteroids, including methylprednisolone. Blood pressure and renal function (s-creatinine) should therefore be routinely checked. When renal crisis is suspected, blood pressure should be carefully controlled.
Corticosteroids should be used with caution in patients with renal insufficiency.
Investigations
Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.
Care should be taken for patients receiving cardioactive drugs such as digoxin because of steroid induced electrolyte disturbance/potassium loss (see section 4.8).
Injury, Poisoning and Procedural Complications
Systemic corticosteroids are not indicated for, and therefore should not be used to treat, traumatic brain injury, a multicenter study revealed an increased mortality at 2 weeks and 6 months after injury in patients administered methylprednisolone sodium succinate compared to placebo. A causal association with methylprednisolone sodium succinate treatment has not been established.
Other
Patients should carry 'Steroid Treatment' cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.
Corticosteroids should be used with caution in patients with a predisposition to thrombophlebitis.
Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects (see section 4.5).
Aspirin and nonsteroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids.
Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.
In post marketing experience tumour lysis syndrome (TLS) has been reported in patients with malignancies, including haematological malignancies and solid tumours, following the use of systemic corticosteroids alone or in combination with other chemotherapeutic agents. Patients at high risk of TLS, such as patients with tumours that have a high proliferative rate, high tumour burden and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precautions should be taken.
Depo-Medone contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium-free'.
Paediatric population
Corticosteroids cause growth retardation in infancy, childhood and adolescence which may be irreversible. Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. Treatment should be limited to the minimum dosage for the shortest possible time. The use of such a regimen should be restricted to those most serious indications.
Infants and children on prolonged corticosteroid therapy are at special risk from raised intracranial pressure.
High doses of corticosteroids may produce pancreatitis in children.
4.5 |
Depo-Medrone 40mg/ml Suspension for Injection | Clinical particulars - Effects on ability to drive and use machines | Interaction with other medicinal products and other forms of interaction
Methylprednisolone is a cytochrome P450 enzyme (CYP) substrate and is mainly metabolized by the CYP3A enzyme. CYP3A4 is the dominant enzyme of the most abundant CYP subfamily in the liver of adult humans. It catalyzes 6β-hydroxylation of steroids, the essential Phase I metabolic step for both endogenous and synthetic corticosteroids. Many other compounds are also substrates of CYP3A4, some of which (as well as other drugs) have been shown to alter glucocorticoid metabolism by induction (upregulation) or inhibition of the CYP3A4 enzyme.
CYP3A4 INHIBITORS – Drugs that inhibit CYP3A4 activity generally decrease hepatic clearance and increase the plasma concentration of CYP3A4 substrate medications, such as methylprednisolone. In the presence of a CYP3A4 inhibitor, the dose of methylprednisolone may need to be titrated to avoid steroid toxicity.
CYP3A4 INDUCERS – Drugs that induce CYP3A4 activity generally increase hepatic clearance, resulting in decreased plasma concentration of medications that are substrates for CYP3A4. Co-administration may require an increase in methylprednisolone dosage to achieve the desired result.
CYP3A4 SUBSTRATES – In the presence of another CYP3A4 substrate, the hepatic clearance of methylprednisolone may be affected, with corresponding dosage adjustments required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with co-administration.
1. Convulsions have been reported with concurrent use of methylprednisolone and ciclosporin (CYP3A4 inhibitor and substrate). Since concurrent administration of these agents results in a mutual inhibition of metabolism (which may increase the plasma concentrations of either or both drugs), it is possible that convulsions and other adverse effects associated with the individual use of either drug may be more apt to occur.
2. Drugs that induce hepatic enzymes, such as rifampicin (antibiotic CYP3A4 inducer), rifabutin, carbamazepine (anticonvulsant CYP3A4 inducer and substrate), phenobarbitone and phenytoin (anticonvulsants CYP3A4 inducers), primidone, and aminoglutethimide (aromatase inhibitor) enhance the metabolism of corticosteroids and its therapeutic effects may be reduced. Aminoglutethimide-induced adrenal suppression may exacerbate endocrine changes caused by prolonged glucocorticoid treatment.
The acetylation rate and clearance of isoniazid (CYP3A4 inhibitor), an antibacterial drug, can be increased by methylprednisolone.
3. Antibiotics/Antimycotics - Drugs such as erythromycin (macrolide antibacterial CYP3A4 inhibitor and substrate), itraconazole and ketoconazole (antifungal CYP3A4 inhibitors and substrates) may inhibit the metabolism of corticosteroids and thus decrease their clearance.
Troleandomycin (CYP3A4 inhibitor), as well as clarithromycin, erythromycin, itraconazole and ketoconazole (CYP3A4 inhibitors and substrates) increase the effects and the side effects of methylprednisolone.
4. Steroids may reduce the effects of anticholinesterases in myasthenia gravis. The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids, and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics and carbenoxolone are enhanced.
An acute myopathy has been reported with the concomitant use of high doses of corticosteroids and anticholinergics, such as neuromuscular blocking drugs. (see section 4.4).
Antagonism of the neuromuscular blocking effects of pancuronium and vecuronium has been reported in patients taking corticosteroids. This interaction may be expected with all competitive neuromuscular blockers.
5. The effect of methylprednisolone on oral anticoagulants is variable. The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding and to maintain the desired anticoagulant effects.
There are also reports of diminished effects of anticoagulants when given concurrently with corticosteroids.
6. There may be increased incidence of gastrointestinal bleeding and ulceration when corticosteroids are given with NSAIDs.
Methylprednisolone may increase the clearance of high-dose aspirin, which can lead to decreased salicylate serum levels. Discontinuation of methylprednisolone treatment can lead to raised salicylate serum levels, which could lead to an increased risk of salicylate toxicity. Salicylates and non-steroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids in hypothrombinaemia.
7. Antidiabetics- Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required.
8. Antiemetics - Aprepitant and fosaprepitant (CYP3A4 inhibitors and substrates)
9. Antivirals - HIV protease inhibitors:
1) Indinavir, ritonavir and pharmacokinetic enhancers (cobicistat) (CYP3A4 inhibitors and substrates) may increase plasma concentrations of corticosteroids.
2) Corticosteroids may induce the metabolism of HIV-protease inhibitors resulting in reduced plasma concentrations.
10. Calcium channel blocker - Diltiazem (CYP3A4 inhibitor and substrate).
11. Contraceptives (oral) - Ethinylestradiol/norethindrone (CYP3A4 inhibitors and substrate).
12. Other immunosuppressants like cyclophosphamide and tacrolimus are substrates of CYP3A4.
13. Potassium-depleting agents -When corticosteroids are administered concomitantly with potassium-depleting agents (e.g. diuretics), patients should be observed closely for development of hypokalaemia. There is also an increased risk of hypokalaemia with concurrent use of corticosteroids with amphotericin B, xanthenes, or beta2 agonists.
14. Grapefruit juice – CYP3A4 inhibitor.
4.6 |
Depo-Medrone 40mg/ml Suspension for Injection | Clinical particulars - Undesirable effects | Fertility, pregnancy and lactation
Fertility
Corticosteroids have been shown to impair fertility in animal studies (see section 5.3).
Pregnancy
The ability of corticosteroids to cross the placenta varies between individual drugs, however, methylprednisolone does cross the placenta. One retrospective study found an increased incidence of low birth weights in infants born of mothers receiving corticosteroids. In humans, the risk of low birth weight appears to be dose related and may be minimized by administering lower corticosteroid doses.
Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and affects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate in man, however, when administered for long periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. Although neonatal adrenal insufficiency appears to be rare in infants who were exposed in utero to corticosteroids, those exposed to substantial doses of corticosteroids must be carefully observed and evaluated for signs of adrenal insufficiency. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential, however, patients with normal pregnancies may be treated as though they were in the non-gravid state. However, corticosteroids do not appear to cause congenital anomalies when given to pregnant women.
Since adequate human reproductive studies have not been done with methylprednisolone acetate, this medicinal product should be used during pregnancy only after a careful assessment of the benefit-risk ratio to the mother and fetus.
Cataracts have been observed in infants born to mothers treated with long-term corticosteroids during pregnancy.
Breast-feeding
Corticosteroids are excreted in small amounts in breast milk, however, doses of up to 40 mg daily of methylprednisolone are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression, but the benefits of breast-feeding are likely to outweigh any theoretical risk.
Corticosteroids distributed into breast milk may interfere with endogenous glucocorticoid production in nursing infants. This medicinal product should be used during breast feeding only after a careful assessment of the benefit-risk ratio to the mother and infant.
4.7 |
Depo-Medrone 40mg/ml Suspension for Injection | Clinical particulars - Overdose | Effects on ability to drive and use machines
The effect of corticosteroids on the ability to drive or use machinery has not been systematically evaluated. |
Depo-Medrone 40mg/ml Suspension for Injection | Clinical particulars - Subsection 10 | Undesirable effects, such as dizziness, vertigo, visual disturbances, and fatigue are possible after treatment with corticosteroids. If affected, patients should not drive or operate machinery.
4.8 |
Depo-Medrone 40mg/ml Suspension for Injection | Clinical particulars - Subsection 11 | Undesirable effects
The incidence of predictable undesirable side effects associated with the use of corticosteroids, including hypothalamic-pituitary-adrenal suppression correlates with the relative potency of the drug, dosage, timing of administration and duration of treatment (see section 4.4).
MedDRA
System Organ Class
Frequency
Undesirable Effects
Infections and infestations
Not Known
Infection (including increased susceptibility and severity of infections with suppression of clinical symptoms and signs); Opportunistic infection; Injection site infection; Peritonitis; Recurrence of dormant tuberculosis
Blood and lymphatic system disorders
Not Known
Leukocytosis
Immune system disorders
Not Known
Drug hypersensitivity, Anaphylactic reaction, Anaphylactoid reaction
Endocrine disorders
Not Known
Cushingoid; Hypothalamic pituitary adrenal axis suppression; Withdrawal symptoms - Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. However, this is more applicable to corticosteroids with an indication where continuous therapy is given (see section 4.4).
A 'withdrawal syndrome' may also occur including, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.
Metabolism and nutrition disorders
Not Known
Metabolic acidosis; Glucose tolerance impaired; Sodium retention; Fluid retention; Increased requirements for insulin (or oral hypoglycemic agents in diabetics) [not a MedDRA PT]; Alkalosis hypokalaemic; Dyslipidaemia, Increased appetite (which may result in Weight increased); Lipomatosis
Psychiatric disorders
Not Known
Affective disorder (including Depressed mood, Euphoric mood, Affect lability, Drug dependence, Suicidal ideation). The following events were most common in children: Mood swings; Abnormal behaviour; Insomnia; Psychotic disorder (including Mania, Delusion, Hallucination, and Schizophrenia [aggravation of]); Confusional state; Mental disorder; Anxiety; Personality change; Mood swings; Abnormal behaviour; Insomnia; Irritability (children and adults)
Nervous system disorders
Not Known
Intracranial pressure increased (with Papilloedema [Benign intracranial hypertension]); Seizure; Amnesia; Cognitive disorder; Dizziness; Headache
Eye disorders
Not Known
Cataract; Glaucoma; Exophthalmos; Vision blurred (see also section 4.4); Chorioretinopathy; rare instances of blindness associated with intralesional therapy around the face and head [not a MedDRA PT]; Increased intra-ocular pressure, with possible damage to the optic nerve; Corneal or scleral thinning; Exacerbation of ophthalmic viral or fungal disease
Ear and labyrinth disorders
Not Known
Vertigo
Cardiac disorders
Not Known
Cardiac failure congestive (in susceptible patients)
Vascular disorders
Not Known
Hypertension; Hypotension; Embolism arterial, Thrombotic events, Flushing
Respiratory, thoracic and mediastinal disorders
Not Known
Pulmonary embolism, Hiccups
Gastrointestinal disorders
Not Known
Peptic ulcer (with possible Peptic ulcer perforation and Peptic ulcer haemorrhage); Gastric haemorrhage; Intestinal perforation; Pancreatitis; Oesophagitis ulcerative; Oesophagitis; Abdominal pain; Abdominal distension; Diarrhoea; Dyspepsia; Nausea
Hepatobiliary disorders
Not known
Hepatitis, Increase of liver enzymes
Skin and subcutaneous tissue disorders
Not Known
Angioedema; Hirsutism; Petechiae; Ecchymosis; Skin atrophy; Erythema; Hyperhidrosis; Skin striae; Skin hyperpigmentation; Rash; Pruritus; Urticaria; Acne; Skin hypopigmentation
Musculoskeletal and connective tissue disorders
Not Known
Growth retardation; Osteoporosis; Muscular weakness; Osteonecrosis; Pathological fracture; Muscle atrophy; Myopathy; Neuropathic arthropathy; Arthralgia; Myalgia
Reproductive system and breast disorders
Not Known
Menstruation irregular
General disorders and administration site conditions
Not Known
Abscess sterile; Impaired healing; Oedema peripheral; Fatigue; Malaise; Injection site reaction
Investigations
Not Known
Blood potassium decreased; Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood alkaline phosphatase increased; Carbohydrate tolerance decreased; Urine calcium increased; suppression of reactions to skin tests [not a MedDRA PT]; Blood urea increased
Injury, poisoning and procedural complications
Not Known
Tendon rupture (particularly of the Achilles tendon); Spinal compression fracture.
Systemic corticosteroids are not indicated for, and therefore should not be used to treat, traumatic brain injury.
† Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Not known (frequency cannot be estimated from the available data)
#Peritonitis may be the primary presenting sign or symptom of a gastrointestinal disorder such as perforation, obstruction or pancreatitis (see section 4.4).
CERTAIN SIDE EFFECTS REPORTED WITH SOME CONTRAINDICATED AND NON-RECOMMENDED ROUTES OF ADMINISTRATION.
Intrathecal/Epidural: Usual systemic corticoid adverse reactions, headache, meningismus, meningitis, paraparesis/paraplegia, spinal fluid abnormalities, nausea, vomiting, sweating, arachnoiditis, functional gastrointestinal disorder/bladder dysfunction, seizure, sensory disturbance.
Extradural: Wound dehiscence, loss of sphincter control.
Intranasal: Permanent/temporary blindness, rhinitis.
Ophthalmic: (Subconjunctival) - Redness and itching, abscess, slough at injection site, residue at injection site, increased intra-ocular pressure, decreased vision - blindness, infection.
Miscellaneous injection sites: Scalp, tonsillar fauces, sphenopalatine ganglion: blindness.
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 |
Depo-Medrone 40mg/ml Suspension for Injection | Clinical particulars - Subsection 12 | Overdose
Following overdosage the possibility of adrenal suppression should be guarded against by gradual diminution of dose levels over a period of time. In such event the patient may require to be supported during any further traumatic episode.
Reports of acute toxicity and/or death following overdosage of corticosteroids are rare. In the event of overdosage, no specific antidote is available; treatment is supportive and symptomatic.
Methylprednisolone is dialysable.
5. Pharmacological properties
5.1 |
Depo-Medrone 40mg/ml Suspension for Injection | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption:
One in-house study of eight volunteers determined the pharmacokinetics of a single 40 mg intramuscular dose of Depo-Medrone. The average of the individual peak plasma concentrations was 14.8 ± 8.6 ng/ml, the average of the individual peak times was 7.25 ± 1.04 hours, and the average area under the curve (AUC) was 1354.2 ± 424.1 ng/ml x hrs (Day 1-21).
Distribution:
Methylprednisolone is widely distributed into the tissues, crosses the blood-brain barrier, and is secreted in breast milk. Its apparent volume of distribution is approximately 1.4 l/kg. The plasma protein binding of methylprednisolone in humans is approximately 77%.
Metabolism:
In humans, methylprednisolone is metabolized in the liver to inactive metabolites; the major ones are 20α-hydroxymethylprednisolone and 20β-hydroxymethylprednisolone. Metabolism in the liver occurs primarily via the CYP3A4. (For a list of drug interactions based on CYP3A4-mediated metabolism, see section 4.5).
Methylprednisolone, like many CYP3A4 substrates, may also be a substrate for the ATP-binding cassette (ABC) transport protein p-glycoprotein, influencing tissue distribution and interactions with other medicines.
Elimination:
The mean elimination half-life for total methylprednisolone is in the range of 1.8 to 5.2 hours. Total clearance is approximately 5 to 6 ml/min/kg.
No dosing adjustments are necessary in renal failure. Methylprednisolone is haemodialysable.
Methylprednisolone acetate is less soluble than methylprednisolone.
5.3 |
Depo-Medrone 40mg/ml Suspension for Injection | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Based on conventional studies of safety pharmacology and repeated dose toxicity, no unexpected hazards were identified. The toxicities seen in the repeated-dose studies were those expected to occur with continued exposure to exogenous adrenocortical steroids.
Mutagenesis:
Methylprednisolone has not been formally evaluated for genotoxicity. Studies using structurally related analogues of methylprednisolone showed no evidence of a potential for genetic and chromosome mutations in limited studies in bacteria and mammalian cells.
Carcinogenesis:
Methylprednisolone has not been formally evaluated in rodent carcinogenicity studies. Variable results have been obtained with other glucocorticoids tested for carcinogenicity in mice and rats. However, published data indicate that several related glucocorticoids including budesonide, prednisolone, and triamcinolone acetonide can increase the incidence of hepatocellular adenomas and carcinomas after oral administration in drinking water to male rats. These tumorigenic effects occurred at doses which were less than the typical clinical doses on a mg/m2 basis. The clinical relevance of these findings is unknown.
Reproductive toxicity:
Methylprednisolone has not been evaluated in animal fertility studies. Corticosteroids have been shown to reduce fertility when administered to rats. Adverse effects on fertility in male rats administered corticosterone were observed and were reversible. Decreased weights and microscopic changes in prostate and seminal vesicles were observed. The numbers of implantations and live foetuses were reduced and these effects were not present following mating at the end of the recovery period.
An increased frequency of cleft palate was observed among the offspring of mice treated during pregnancy with methylprednisolone in doses similar to those typically used for oral therapy in humans.
An increased frequency of cardiovascular defects and decreased body weight were observed among the offspring of pregnant rats treated with methylprednisolone in a dose that was similar to that used for oral therapy in humans but was toxic to the mothers. In contrast, no teratogenic effect was noted in rats with doses < 1-18 times those typically used for oral therapy in humans in another study. High frequencies of foetal death and a variety of central nervous system and skeletal anomalies were reported in the offspring of pregnant rabbits treated with methylprednisolone in doses less than those used in humans. The relevance of these findings to the risk of malformations in human infants born to mothers treated with methylprednisolone in pregnancy is unknown. Safety margins for the reported teratogenic effects are unknown.
6. |
Depo-Medrone 40mg/ml Suspension for Injection | Pharmaceutical particulars - List of excipients | List of excipients
Polyethylene glycol
Sodium chloride
Myristyl-gamma-picolinium chloride
Water for injections.
6.2 |
Depo-Medrone 40mg/ml Suspension for Injection | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Depo-Medrone 40mg/ml Suspension for Injection | Pharmaceutical particulars - Shelf life | Shelf life
5 years.
6.4 |
Depo-Medrone 40mg/ml Suspension for Injection | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25°C.
Do not freeze.
6.5 |
Depo-Medrone 40mg/ml Suspension for Injection | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Type I flint glass vial with a butyl rubber plug and metal seal. Each vial contains 1 ml, 2 ml, or 3 ml of Depo-Medrone 40 mg/ml.
Not all pack sizes may be marketed.
6.6 |
Depo-Medrone 40mg/ml Suspension for Injection | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Depo-Medrone should not be mixed with any other fluid. Discard any remaining suspension after use.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Depo-Medrone 40mg/ml Suspension for Injection | Marketing authorisation holder | Pfizer Limited
Ramsgate Road,
Sandwich,
Kent CT13 9NJ
United Kingdom
8. Marketing authorisation number(s)
PL 00057/0963
9. |
Depo-Medrone 40mg/ml Suspension for Injection | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 7 March 1989
Date of latest renewal: 5 September 1996
10. |
Depo-Medrone 40mg/ml Suspension for Injection | Date of revision of the text | 06/2023
Ref: DM 26_1 UK |
Depo-Medrone with Lidocaine Suspension for Injection | Name of the medicinal product | Depo-Medrone with Lidocaine
2. |
Depo-Medrone with Lidocaine Suspension for Injection | Qualitative and quantitative composition | Methyprednisolone 4%, Lidocaine Hydrochloride Monohydrate 1%
Excipient with known effect:
Benzyl alcohol: 8.7 mg per ml.
For the full list of excipients, see section 6.1
3. |
Depo-Medrone with Lidocaine Suspension for Injection | Pharmaceutical form | Suspension for Injection.
White, sterile aqueous suspension
4. |
Depo-Medrone with Lidocaine Suspension for Injection | Clinical particulars - Therapeutic indications | Therapeutic indications
Corticosteroid (glucocorticoid). Depo-Medrone with Lidocaine is indicated in conditions requiring a glucocorticoid effect: e.g. anti-inflammatory or anti-rheumatic. It is recommended for local use where the added anaesthetic effect would be considered advantageous.
Depo-Medrone with Lidocaine may be used as follows:
Intra-articular administration
Rheumatoid arthritis
Osteo-arthritis with an inflammatory component
Periarticular administration
Epicondylitis
Intrabursal administration
Subacromial bursitis
Prepatellar bursitis
Olecranon bursitis
Tendon sheath administration
Tendinitis
Tenosynovitis
Epicondylitis
Therapy with Depo-Medrone with Lidocaine does not obviate the need for the conventional measures usually employed. Although this method of treatment will ameliorate symptoms, it is in no sense a cure and the hormone has no effect on the cause of the inflammation.
4.2 |
Depo-Medrone with Lidocaine Suspension for Injection | Clinical particulars - Posology and method of administration | Posology and method of administration
Depo-Medrone with Lidocaine should not be mixed with any other preparation as flocculation of the product may occur. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever suspension and container permit. Depo-Medrone with Lidocaine may be used by any of the following routes: intra-articular, periarticular, intrabursal, and into the tendon sheath. It must not be used by the intrathecal or intravenous routes (see sections 4.3 and 4.8).
Adults
Intra articular: Rheumatoid arthritis, osteo-arthritis. The dose of Depo Medrone with Lidocaine depends on the size of the joint and the severity of the condition. Repeated injections, if needed, may be given at intervals of one to five or more weeks depending upon the degree of relief obtained from the initial injection. A suggested dosage guide is: large joint (knee, ankle, shoulder), 0.5 – 2 ml (20 – 80 mg of steroid); medium joint (elbow, wrist), 0.25 – 1 ml (10 – 40 mg of steroid); small joint (metacarpophalangeal, interphalangeal, sternoclavicular, acromioclavicular), 0.1 – 0.25 ml (4 – 10 mg of steroid).
Periarticular: Epicondylitis. Infiltrate 0.1 – 0.75 ml (4 – 30 mg of steroid) into the affected area.
Intrabursal: Subdeltoid bursitis, prepatellar bursitis, olecranon bursitis. For administration directly into bursae, 0.1 – 0.75 ml (4 – 30 mg of steroid). In most acute cases, repeat injections are not needed.
Into the tendon sheath: Tendinitis, tenosynovitis, epicondylitis. For administration directly into the tendon sheath, 0.1 – 0.75 ml (4 – 30 mg of steroid). In recurrent or chronic conditions, repeat injections may be necessary.
Paediatric population
For infants and children, the recommended dosage should be reduced, but dosage should be governed by the severity of the condition rather than by strict adherence to the ratio indicated by age or body weight.
Elderly:
When used according to instructions, there is no information to suggest that a change in dosage is warranted in the elderly. However, treatment of elderly patients, particularly if long-term, should be planned bearing in mind the more serious consequences of the common side-effects of corticosteroids in old age and close clinical supervision is required (see section 4.4).
Special precautions should be observed when administering Depo-Medrone with Lidocaine:
Intra-articular injections should be made using precise, anatomical localisation into the synovial space of the joint involved. The injection site for each joint is determined by that location where the synovial cavity is most superficial and most free of large vessels and nerves. Suitable sites for intra-articular injection are the knee, ankle, wrist, elbow, shoulder, phalangeal and hip joints. The spinal joints, unstable joints and those devoid of synovial space are not suitable. Treatment failures are most frequently the result of failure to enter the joint space. Intra-articular injections should be made with care as follows: ensure correct positioning of the needle into the synovial space and aspirate a few drops of joint fluid. The aspirating syringe should then be replaced by another containing Depo-Medrone with Lidocaine. To ensure position of the needle synovial fluid should be aspirated and the injection made.
After injection the joint is moved slightly to aid mixing of the synovial fluid and the suspension. Subsequent to therapy care should be taken for the patient not to overuse the joint in which benefit has been obtained. Negligence in this matter may permit an increase in joint deterioration that will more than offset the beneficial effects of the steroid.
Intrabursal injections should be made as follows: the area around the injection site is prepared in a sterile way and a wheal at the site made with 1 percent procaine hydrochloride solution. A 20-24 gauge needle attached to a dry syringe is inserted into the bursa and the fluid aspirated. The needle is left in place and the aspirating syringe changed for a small syringe containing the desired dose. After injection, the needle is withdrawn and a small dressing applied. In the treatment of tenosynovitis and tendinitis, care should be taken to inject Depo Medrone with Lidocaine into the tendon sheath rather than into the substance of the tendon. Due to the absence of a true tendon sheath, the Achilles tendon should not be injected with Depo Medrone with Lidocaine.
The usual sterile precautions should be observed with each injection.
4.3 |
Depo-Medrone with Lidocaine Suspension for Injection | Clinical particulars - Contraindications | Contraindications
Depo-Medrone with Lidocaine is contraindicated:
• in patients with known hypersensitivity to the active substances or to any of the excipients listed in section 6.1
• in patients with known hypersensitivity to other local anaesthetics of the amide type
• in patients who have systemic infection unless specific anti-infective therapy is employed
• for use by the intrathecal route (due to its potential for neurotoxicity, see section 4.8)
• for use by the intravenous route
Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids.
4.4 |
Depo-Medrone with Lidocaine Suspension for Injection | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use |
Depo-Medrone with Lidocaine Suspension for Injection | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Undesirable effects may be minimised by using the lowest effective dose for the minimum period. Frequent patient review is required to appropriately titrate the dose against disease activity (see section 4.2).
Depo-Medrone with Lidocaine vials are intended for single dose use only.
Any multidose use of the product may lead to contamination.
Depo-Medrone with Lidocaine is not recommended for intranasal, intra-ocular, or any other unapproved route of administration.
Severe medical events have been reported in association with the intrathecal/epidural routes of administration (see section 4.8). Appropriate measures must be taken to avoid intravascular injection.
Due to the absence of a true tendon sheath, the Achilles tendon should not be injected with Depo-Medrone with Lidocaine.
While crystals of adrenal steroids in the dermis suppress inflammatory reactions, their presence may cause disintegration of the cellular elements and physiochemical changes in the ground substance of the connective tissue. The resultant infrequently occurring dermal and/or subdermal changes may form depressions in the skin at the injection site and the possibility of depigmentation. The degree to which this reaction occurs will vary with the amount of adrenal steroid injected. Regeneration is usually complete within a few months or after all crystals of the adrenal steroid have been absorbed. In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Multiple small injections into the area of the lesion should be made whenever possible. The technique of intra-articular injection should include precautions against injection or leakage into the dermis.
Systemic absorption of methylprednisolone occurs following intra-articular injection of Depo-Medrone with Lidocaine. Systemic as well as local effects can therefore be expected.
Adrenal cortical atrophy develops during prolonged therapy and may persist for months after stopping treatment. In patients who have received more than physiological doses of systemic corticosteroids (approximately 6 mg methylprednisolone) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids, but there is uncertainty about HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose of 6 mg methylprednisolone is reached, dose reduction should be slower to allow the HPA-axis to recover.
The following precautions apply for parenteral corticosteroids:
Following intra-articular injection, the occurrence of a marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted.
No additional benefit derives from the intramuscular administration of Depo-Medrone with Lidocaine. Where parenteral corticosteroid therapy for sustained systemic effect is desired, plain Depo-Medrone should be used.
Local injection of a steroid into a previously infected joint is to be avoided.
Intra-articular corticosteroids are associated with a substantially increased risk of inflammatory response in the joint, particularly bacterial infection introduced with the injection. Charcot-like arthropathies have been reported particularly after repeated injections. Appropriate examination of any joint fluid present is necessary to exclude any bacterial infection, prior to injection.
Corticosteroids should not be injected into unstable joints.
Sterile technique is necessary to prevent infections or contamination.
Immunosuppressant Effects/Increased Susceptibility to Infections
Corticosteroids may increase susceptibility to infection, may mask some signs of infection, and new infections may appear during their use. Suppression of the inflammatory response and immune function increases the susceptibility to fungal, viral and bacterial infections and their severity. The clinical presentation may often be atypical and may reach an advanced stage before being recognised.
With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids.
Chickenpox is of serious concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. Passive immunization with varicella/zoster immunoglobin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.
Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.
If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.
The role of corticosteroids in septic shock has been controversial, with early studies reporting both beneficial and detrimental effects. More recently, supplemental corticosteroids have been suggested to be beneficial in patients with established septic shock who exhibit adrenal insufficiency. However, their routine use in septic shock is not recommended. A systematic review of short-course, high-dose corticosteroids did not support their use. However, meta-analyses, and a review suggest that longer courses (5-11 days) of low-dose corticosteroids might reduce mortality, especially in patients with vasopressor-dependent septic shock.
Immune System Effects
Allergic reactions may occur. Because rare instances of skin reactions and anaphylactic/anaphylactoid reactions have occurred in patients receiving corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of drug allergy.
Endocrine Effects
Pharmacologic doses of corticosteroids administered for prolonged periods may result in hypothalamic-pituitary-adrenal (HPA) suppression (secondary adrenocortical insufficiency). The degree and duration of adrenocortical insufficiency produced is variable among patients and depends on the dose, frequency, time of administration, and duration of glucocorticoid therapy.
Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it considered that the disease is unlikely to relapse. Abrupt withdrawal of doses up to 32 mg daily of methylprednisolone for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:
• Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks.
• When a short course has been prescribed within one year of cessation of long-term therapy (months or years).
• Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy.
• Patients receiving doses of systemic corticosteroid greater than 32 mg daily of methylprednisolone.
• Patients repeatedly taking doses in the evening.
Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.
A steroid “withdrawal syndrome”, seemingly unrelated to adrenocortical insufficiency, may also occur following abrupt discontinuance of glucocorticoids. This syndrome includes symptoms such as: anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, desquamation, myalgia, weight loss, and/or hypotension. These effects are thought to be due to the sudden change in glucocorticoid concentration rather than to low corticosteroid levels.
Because glucocorticoids can produce or aggravate Cushing's syndrome, glucocorticoids should be avoided in patients with Cushing's disease.
There is an enhanced effect of corticosteroids on patients with hypothyroidism.
Metabolism and Nutrition
Corticosteroids, including methylprednisolone, can increase blood glucose, worsen pre-existing diabetes, and predispose those on long-term corticosteroid therapy to diabetes mellitus.
Psychiatric Effects
Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting treatment. Risks may be higher with high doses/systemic exposure (see section 4.5), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.
Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.
Nervous System Effects
Corticosteroids should be used with caution in patients with seizure disorders.
Corticosteroids should be used with caution in patients with myasthenia gravis (also see myopathy statement in Musculoskeletal Effects section).
There have been reports of epidural lipomatosis in patients taking corticosteroids, typically with long-term use at high doses.
Ocular Effects
Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids. Central serous chorioretinopathy, may lead to retinal detachment.
Prolonged use of corticosteroids may produce posterior subcapsular cataracts and nuclear cataracts (particularly in children), exophthalmos, or increased intraocular pressure, which may result in glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.
Corticosteroids should be used cautiously in patients with ocular herpes simplex, because of possible corneal perforation.
Cardiac Effects
Adverse effects of glucocorticoids on the cardiovascular system, such as dyslipidaemia and hypertension, may predispose treated patients with existing cardiovascular risk factors to additional cardiovascular effects, if high doses and prolonged courses are used. Accordingly, corticosteroids should be employed judiciously in such patients and attention should be paid to risk modification and additional cardiac monitoring if needed.
Systemic corticosteroids should be used with caution, and only if strictly necessary, in cases of congestive heart failure.
Vascular Effects
Corticosteroids should be used with caution in patients with hypertension.
Thrombosis including venous thromboembolism has been reported to occur with corticosteroids. As a result corticosteroids should be used with caution in patients who have or may be predisposed to thromboembolic disorders.
Gastrointestinal Effects
High doses of corticosteroids may produce acute pancreatitis.
There is no universal agreement on whether corticosteroids per se are responsible for peptic ulcers encountered during therapy; however, glucocorticoid therapy may mask the symptoms of peptic ulcer so that perforation or haemorrhage may occur without significant pain.
Glucocorticoid therapy may mask peritonitis or other signs or symptoms associated with gastrointestinal disorders such as perforation, obstruction or pancreatitis.
In combination with NSAIDs, the risk of developing gastrointestinal ulcers is increased.
Corticosteroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection. Caution must also be used in diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, when steroids are used as direct or adjunctive therapy.
Hepatobiliary Effects
Hepatobiliary disorders have been reported which may be reversible after discontinuation of therapy. Therefore appropriate monitoring is required.
Drug induced liver injury including acute hepatitis or liver enzyme increase can result from cyclical pulsed IV methylprednisolone (usually at initial dose ≥ 1 g/day). Rare cases of hepatotoxicity have been reported. The time to onset can be several weeks or longer. In the majority of case reports resolution of the adverse events has been observed after treatment was discontinued.
Corticosteroids should be used with caution in patients with liver failure or cirrhosis.
Musculoskeletal Effects
An acute myopathy has been reported with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g. myasthenia gravis), or in patients receiving concomitant therapy with anticholinergics, such as neuromuscular blocking drugs (e.g. pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevations of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.
Osteoporosis is a common but infrequently recognized adverse effect associated with a long-term use of large doses of glucocorticoid.
Renal and Urinary Disorders
Caution is required in patients with systemic sclerosis because an increased incidence of scleroderma renal crisis has been observed with corticosteroids, including methylprednisolone. Blood pressure and renal function (s-creatinine) should therefore be routinely checked. When renal crisis is suspected, blood pressure should be carefully controlled.
Corticosteroids should be used with caution in patients with renal insufficiency.
Injury, Poisoning and Procedural Complications
Systemic corticosteroids are not indicated for, and therefore should not be used to treat, traumatic brain injury, a multicenter study revealed an increased mortality at 2 weeks and 6 months after injury in patients administered methylprednisolone sodium succinate compared to placebo. A causal association with methylprednisolone sodium succinate treatment has not been established.
Investigations
Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.
Care should be taken for patients receiving cardioactive drugs such as digoxin because of steroid induced electrolyte disturbance/potassium loss (see section 4.8).
Other
Patients should carry 'Steroid Treatment' cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.
Corticosteroids should be used with caution in patients with a predisposition to thrombophlebitis.
Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects (see section 4.5).
Aspirin and nonsteroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids.
Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.
Paediatric population
Corticosteroids cause growth retardation in infancy, childhood and adolescence which may be irreversible. Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. Treatment should be limited to the minimum dosage for the shortest possible time. The use of such a regimen should be restricted to those most serious indications.
Infants and children on prolonged corticosteroid therapy are at special risk from raised intracranial pressure.
High doses of corticosteroids may produce pancreatitis in children.
Excipient Information
Benzyl alcohol
Depo-Medrone with Lidocaine contains benzyl alcohol (see section 2). The preservative benzyl alcohol may cause hypersensitivity reactions. Intravenous administration of benzyl alcohol has been associated with serious adverse events and death in paediatric patients including neonates (“gasping syndrome”). Although normal therapeutic doses of this product ordinarily deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Benzyl alcohol containing formulations should only be used in neonates if it is necessary and if there are no alternatives possible. Premature and low-birth weight neonates may be more likely to develop toxicity. Benzyl alcohol containing formulations should not be used for more than 1 week in children under 3 years of age unless necessary. It is important to consider the total quantity of benzyl alcohol received from all sources, and high volumes should be used with caution and only if necessary, especially in patients with liver or kidney impairment, as well as in pregnant or breast-feeding women, because of the risk of accumulation and toxicity (metabolic acidosis).
Sodium
Depo-Medrone with Lidocaine contains less than 1 mmol sodium (23 mg) in each vial, that is to say essentially 'sodium free'.
4.5 |
Depo-Medrone with Lidocaine Suspension for Injection | Clinical particulars - Fertility, pregnancy and lactation | Interaction with other medicinal products and other forms of interaction
Methylprednisolone is a cytochrome P450 enzyme (CYP) substrate and is mainly metabolized by the CYP3A enzyme. CYP3A4 is the dominant enzyme of the most abundant CYP subfamily in the liver of adult humans. It catalyzes 6β-hydroxylation of steroids, the essential Phase I metabolic step for both endogenous and synthetic corticosteroids. Many other compounds are also substrates of CYP3A4, some of which (as well as other drugs) have been shown to alter glucocorticoid metabolism by induction (upregulation) or inhibition of the CYP3A4 enzyme.
CYP3A4 INHIBITORS – Drugs that inhibit CYP3A4 activity generally decrease hepatic clearance and increase the plasma concentration of CYP3A4 substrate medications, such as methylprednisolone. In the presence of a CYP3A4 inhibitor, the dose of methylprednisolone may need to be titrated to avoid steroid toxicity.
CYP3A4 INDUCERS – Drugs that induce CYP3A4 activity generally increase hepatic clearance, resulting in decreased plasma concentration of medications that are substrates for CYP3A4. Co-administration may require an increase in methylprednisolone dosage to achieve the desired result.
CYP3A4 SUBSTRATES – In the presence of another CYP3A4 substrate, the hepatic clearance of methylprednisolone may be affected, with corresponding dosage adjustments required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with co-administration.
1. Convulsions have been reported with concurrent use of methylprednisolone and ciclosporin (CYP3A4 inhibitor and substrate). Since concurrent administration of these agents results in a mutual inhibition of metabolism (which may increase the plasma concentrations of either or both drugs), it is possible that convulsions and other adverse effects associated with the individual use of either drug may be more apt to occur.
2. Drugs that induce hepatic enzymes, such as rifampicin (antibiotic CYP3A4 inducer), rifabutin, carbamazepine (anticonvulsant CYP3A4 inducer and substrate), phenobarbitone and phenytoin (anticonvulsants CYP3A4 inducers), primidone, and aminoglutethimide (aromatase inhibitor) enhance the metabolism of corticosteroids and its therapeutic effects may be reduced.
Aminoglutethimide-induced adrenal suppression may exacerbate endocrine changes caused by prolonged glucocorticoid treatment.
3. Antibiotics/Antimycotics - Drugs such as erythromycin (macrolide antibacterial CYP3A4 inhibitor and substrate), itraconazole and ketoconazole antifungal CYP3A4 inhibitors and substrates) may inhibit the metabolism of corticosteroids and thus decrease their clearance.
Troleandomycin (CYP3A4 inhibitor), as well as clarithromycin, erythromycin, itraconazole and ketoconazole (CYP3A4 inhibitors and substrates) increase the effects and the side effects of methylprednisolone.
The acetylation rate and clearance of isoniazid (CYP3A4 inhibitor), an antibacterial drug, can be increased by methylprednisolone.
4. Steroids may reduce the effects of anticholinesterases in myasthenia gravis.
An acute myopathy has been reported with the concomitant use of high doses of corticosteroids and anticholinergics, such as neuromuscular blocking drugs (see section 4.4).
Antagonism of the neuromuscular blocking effects of pancuronium and vecuronium has been reported in patients taking corticosteroids. This interaction may be expected with all competitive neuromuscular blockers.
The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids, and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics and carbenoxolone are enhanced.
5. The effect of methylprednisolone on oral anticoagulants is variable. The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding and to maintain the desired anticoagulant effects.
There are also reports of diminished effects of anticoagulants when given concurrently with corticosteroids.
6. There may be increased incidence of gastrointestinal bleeding and ulceration when corticosteroids are given with NSAIDs. Methylprednisolone may increase the clearance of high-dose aspirin, which can lead to decreased salicylate serum levels. Discontinuation of methylprednisolone treatment can lead to raised salicylate serum levels, which could lead to an increased risk of salicylate toxicity.
7. Antidiabetics - Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required.
8. Antiemetics - Aprepitant and fosaprepitant (CYP3A4 inhibitors and substrates).
9. Antivirals - HIV protease inhibitors: Indinavir, ritonavir and pharmacokinetic enhancers (cobicistat) (CYP3A4 inhibitors and substrates) may increase plasma concentrations of corticosteroids. Corticosteroids may induce the metabolism of HIV-protease inhibitors resulting in reduced plasma concentrations.
10. Calcium channel blocker - Diltiazem (CYP3A4 inhibitor and substrate).
11. Contraceptives (oral) - Ethinylestradiol/norethindrone (CYP3A4 inhibitors and substrate).
12. Other immunosuppressants like cyclophosphamide and tacrolimus are substrates of CYP3A4.
13. Potassium-depleting agents - When corticosteroids are administered concomitantly with potassium-depleting agents (i.e. diuretics), patients should be observed closely for development of hypokalaemia. There is also an increased risk of hypokalaemia with concurrent use of corticosteroids with amphotericin B, xanthenes, or beta2 agonists.
14. Grapefruit juice - CYP3A4 inhibitor.
4.6 Fertility, pregnancy, and lactation
Fertility
Corticosteroids have been shown to impair fertility in animal studies (see section 5.3).
Pregnancy
Methylprednisolone
The ability of corticosteroids to cross the placenta varies between individual drugs, however, methylprednisolone does cross the placenta. One retrospective study found an increased incidence of low birth weights in infants born of mothers receiving corticosteroids. In humans, the risk of low birth weight appears to be dose related and may be minimized by administering lower corticosteroid doses.
Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and affects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate in man, however, when administered for long periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. Although neonatal adrenal insufficiency appears to be rare in infants who were exposed in utero to corticosteroids, those exposed to substantial doses of corticosteroids must be carefully observed and evaluated for signs of adrenal insufficiency. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential, however, patients with normal pregnancies may be treated as though they were in the non-gravid state. However, corticosteroids do not appear to cause congenital anomalies when given to pregnant women.
Cataracts have been observed in infants born to mothers treated with long-term corticosteroids during pregnancy.
Lidocaine
The use of local anaesthetics such as lidocaine during labour and delivery may be associated with adverse effects on mother and foetus.
Lidocaine readily crosses the placenta.
Methylprednisolone acetate with lidocaine
Since adequate human reproductive studies have not been done with methylprednisolone acetate with lidocaine, this medicinal product should be used during pregnancy only after a careful assessment of the benefit-risk ratio to the mother and fetus.
Depo-Medrone with Lidocaine contains benzyl alcohol as a preservative. Benzyl alcohol can cross the placenta (see section 4.4).
Breast-feeding
Methylprednisolone
Corticosteroids are distributed in small amounts in breast milk and may suppress growth and interfere with endogenous glucocorticoid production in nursing infants. However, doses of up to 40 mg daily of methylprednisolone are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression.
Lidocaine
Lidocaine is excreted in human breast milk.
Methylprednisolone acetate with lidocaine
This medicinal product should be used during breast feeding only after a careful assessment of the benefit-risk ratio to the mother and infant.
Depo-Medrone with Lidocaine contains benzyl alcohol as a preservative (see section 4.4).
4.7 |
Depo-Medrone with Lidocaine Suspension for Injection | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
The effect of corticosteroids on the ability to drive or use machinery has not been systematically evaluated. |
Depo-Medrone with Lidocaine Suspension for Injection | Clinical particulars - Undesirable effects | Undesirable effects, such as dizziness, vertigo, visual disturbances, and fatigue are possible after treatment with corticosteroids. If affected, patients should not drive or operate machinery.
4.8 |
Depo-Medrone with Lidocaine Suspension for Injection | Clinical particulars - Overdose | Undesirable effects
The incidence of predictable undesirable side effects associated with the use of corticosteroids, including hypothalamic-pituitary-adrenal suppression correlates with the relative potency of the drug, dosage, timing of administration and duration of treatment (see section 4.4).
MedDRA
System Organ Class
Frequency
Undesirable Effects
Infections and infestations
Not Known
Opportunistic infectione; Infectione (including increased susceptibility and severity of infections with suppression of clinical symptoms and signs); Injection site infection; Peritonitisc,e; Recurrence of dormant tuberculosis
Blood and lymphatic system disorders
Not Known
Leukocytosise
Immune system disorders
Not Known
Drug hypersensitivitye; Anaphylactic reaction; Anaphylactoid reactione
Endocrine disorders
Not Known
Cushingoide; Hypopituitarisme; Withdrawal symptoms - too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. However, this is more applicable to corticosteroids with an indication where continuous therapy is given (see section 4.4).
A 'withdrawal syndromee' may also occur including, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.
Metabolism and nutrition disorders
Not Known
Metabolic acidosise; Sodium retentione; Fluid retentione; Alkalosis hypokalaemice; Dyslipidaemiae; Glucose tolerance impairede; Increased requirements for insulin (or oral hypoglycemic agents in diabetics)a,e; Lipomatosise; Increased appetite (which may result in Weight increased)e
Psychiatric disorders
Not Known
Affective disordere (including Depressed moode, Euphoric mood, Affect labilitye, psychological dependencea,e, Suicidal ideatione), Psychotic disordere (including Maniae, Delusione, Hallucinatione, and Schizophreniae [aggravation of]); Confusional state; Mental disordere; Anxiety; Personality changee; Mood swingse; Abnormal behavioure; Insomniae; Irritabilitye; Nervousnessd
Nervous system disorders
Not Known
Epidural lipomatosise, Intracranial pressure increased (with Papilloedema [Benign intracranial hypertension]e); Loss of consciousnessd; Seizure; Amnesiae; Cognitive disordere; Tremord; Somnolenced; Hypoaesthesiad; Dizziness; Headachee
Eye disorders
Not Known
Exophthalmose; Vision blurredd (see also section 4.4); Chorioretinopathye; Cataracte; Glaucomae; Diplopiad; Rare instances of blindness associated with intralesional therapy around the face and heada; Corneal or scleral thinning; Exacerbation of ophthalmic viral or fungal disease
Ear and labyrinth disorders
Not Known
Vertigoe; Tinnitusd
Cardiac disorders
Not Known
Cardiac arrestd; Cardiac failure congestive (in susceptible patients)e; Bradycardiad
Vascular disorders
Not Known
Circulatory collapsed; Hypertensione; Hypotension; Embolism arterial; Thrombotic eventse; Flushing
Respiratory, thoracic and mediastinal disorders
Not Known
Respiratory arrestd; Respiratory depressiond; Pulmonary embolisme; Hiccupse
Gastrointestinal disorders
Not Known
Peptic ulcerb,e (with possible Peptic ulcer perforation and Peptic ulcer haemorrhage); Gastric haemorrhagee; Intestinal perforatione; Pancreatitise; Oesophagitis ulcerativee; Oesophagitis; Oesophageal candidiasis; Abdominal paine; Abdominal distensione; Diarrhoeae; Dyspepsiae; Nauseae; Vomitingd
Hepatobiliary disorders
Not Known
Hepatitis, Increase of liver enzymes
Skin and subcutaneous tissue disorders
Not Known
Angioedemae; Petechiaee; Ecchymosise; Skin atrophye; Skin striaee; Skin hyperpigmentatione; Skin hypopigmentatione; Hirsutisme; Rashe; Erythemae; Prurituse; Urticaria; Acnee; Hyperhidrosise; Skin lesiond
Musculoskeletal and connective tissue disorders
Not Known
Muscular weaknesse, Osteonecrosise; Osteoporosise; Pathological fracturee; Muscle atrophye; Myopathye; Neuropathic arthropathye; Growth retardatione; Arthralgia; Myalgiae; Muscle twitchingd
Reproductive system and breast disorders
Not Known
Menstruation irregulare
General disorders and administration site conditions
Not Known
Impaired healinge; Oedema peripherale; Injection site reactione; Abscess sterilee; Fatiguee; Malaisee; Feeling coldd; Feeling hotd
Investigations
Not Known
Intraocular pressure increasede; Alanine aminotransferase increasede; Aspartate aminotransferase increased; Blood alkaline phosphatase increasede; Blood potassium decreasede; Carbohydrate tolerance decreasede; Urine calcium increasede; Blood urea increasede; Nitrogen balance negative (due to protein catabolism); Suppression of reactions to skin testsa,e
Injury, poisoning and procedural complications
Not Known
Tendon rupturee (particularly of the Achilles tendon); Spinal compression fracturee.
Systemic corticosteroids are not indicated for, and therefore should not be used to treat, traumatic brain injury.
a Not a MedDRA Preferred term.
b Peptic ulcer perforation and Peptic ulcer haemorrhage.
c Peritonitis may be the primary presenting sign or symptom of a gastrointestinal disorder such as perforation, obstruction or pancreatitis (see section 4.4).
d Reported for lidocaine only.
e Reported for methylprednisolone acetate only.
CERTAIN SIDE EFFECTS REPORTED WITH SOME NON-RECOMMENDED ROUTES OF ADMINISTRATION:
Intrathecal/Epidural: Usual systemic corticoid adverse reactions, headache, meningismus, meningitis, paraparesis/paraplegia, spinal fluid abnormalities, nausea, vomiting, sweating, arachnoiditis, functional gastrointestinal disorder/bladder dysfunction, seizure, sensory disturbance.
Extradural: Wound dehiscence, loss of sphincter control.
Intranasal: Permanent/temporary blindness, allergic reactions, rhinitis.
Ophthalmic (Subconjunctival): Redness and itching, abscess, slough at injection site, residue at injection site, increased intra-ocular pressure, decreased vision - blindness, infection.
Miscellaneous: Scalp, tonsillar fauces, sphenopalatine ganglion: blindness.
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. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Depo-Medrone with Lidocaine Suspension for Injection | Clinical particulars - Subsection 10 | Overdose
Methylprednisolone
Following overdosage the possibility of adrenal suppression should be guarded against by gradual diminution of dose levels over a period of time. In such event the patient may require to be supported during any further traumatic episode.
Reports of acute toxicity and/or death following overdosage of corticosteroids are rare. In the event of overdosage, no specific antidote is available; treatment is supportive and symptomatic.
Methylprednisolone is dialysable.
Lidocaine |
Depo-Medrone with Lidocaine Suspension for Injection | Clinical particulars - Subsection 11 | Overdose with lidocaine can manifest itself in a transient stimulation of the central nervous system with early symptoms: yawning, restlessness, dizziness, nausea, vomiting, dysarthria, ataxia, hearing and visual disturbances. With moderate intoxication also twitching and convulsions can occur. This can be followed by unconsciousness, respiratory depression and coma. In very severe intoxication due to decreased myocardial contractility and delayed impulse conduction, hypotension and cardiovascular collapse can be expected to be followed by a complete heart block and cardiac arrest. Convulsions, hypotension and respiratory depression and cardiac events should be treated as necessary. Continual optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance.
5. Pharmacological properties
5.1 |
Depo-Medrone with Lidocaine Suspension for Injection | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
No pharmacokinetic studies have been performed with the combination product of methylprednisolone and lidocaine, however, data are provided from pharmacokinetic studies performed with the individual product components methylprednisolone and lidocaine.
Absorption:
Methylprednisolone:
One in-house study of eight volunteers determined the pharmacokinetics of a single 40 mg intramuscular dose of Depo-Medrone. The average of the individual peak plasma concentrations was 14.8 ± 8.6 ng/ml, the average of the individual peak times (tmax) was 7.25 ± 1.04 hours, and the average area under the curve (AUC) was 1354.2 ± 424.1 ng/ml x hrs (Day 1-21).
Lidocaine:
Pharmacokinetics of lidocaine after synovial absorption following intra-articular bolus injection in patients with knee joint arthroscopy was studied with different maximum concentration (Cmax) values reported. The Cmax values are 2.18 µg/ml at 1 hour (serum) and 0.63 µg/ml at 0.5 hour (plasma) following administration of lidocaine doses of 7 mg/kg and 400 mg, respectively. Other reported serum Cmax values are 0.69 µg/ml at 5 minutes and 0.278 µg/ml at 2 hours following administration of lidocaine doses of 25 ml of 1% and 20 ml of 1.5%, respectively.
Pharmacokinetic data of lidocaine after intra-bursa and intra-cyst administrations for local effect are not available.
Distribution:
Methylprednisolone:
Methylprednisolone is widely distributed into the tissues, crosses the blood-brain barrier, and is secreted in breast milk. Its apparent volume of distribution is approximately 1.4 l/kg. The plasma protein binding of methylprednisolone in humans is approximately 77%.
Lidocaine:
The plasma protein binding of lidocaine is concentration-dependent, and binding decreases as concentration increases. At concentrations of 1 to 5 µg/ml, 60%-80% lidocaine is protein bound. Binding is also dependent on the plasma concentration of the α1-acid glycoprotein.
Lidocaine has a volume of distribution at steady state of 91 l.
Lidocaine readily crosses the placenta, and equilibrium of unbound drug concentration is rapidly reached. The degree of plasma protein binding in the foetus is less than in the mother, which results in lower total plasma concentrations in the foetus.
Metabolism:
Methylprednisolone:
In humans, methylprednisolone is metabolized in the liver to inactive metabolites; the major ones are 20α-hydroxymethylprednisolone and 20β-hydroxymethylprednisolone. Metabolism in the liver occurs primarily via the CYP3A4. (For a list of drug interactions based on CYP3A4-mediated metabolism, see section 4.5.)
Methylprednisolone, like many CYP3A4 substrates, may also be a substrate for the ATP-binding cassette (ABC) transport protein p-glycoprotein, influencing tissue distribution and interactions with other medicines modulated by P-gp.
Lidocaine:
Lidocaine is mainly metabolized by the liver. The main metabolites of lidocaine are monoethylglycine xylidide, glycinexylidide, 2,6-dimethylaniline, and 4-hydroxy-2,6-dimethylaniline. The lidocaine N-dealkylation to monoethylglycine xylidide is considered to be mediated by both CYP1A2 and CYP3A4. The metabolite 2,6-dimethylaniline is converted to 4-hydroxy-2,6-dimethylaniline by CYP2A6 and CYP2E1.
Elimination:
Methylprednisolone:
The mean elimination half-life for total methylprednisolone is in the range of 1.8 to 5.2 hours. Total clearance is approximately 5 to 6 ml/min/kg.
Lidocaine:
The clearance of lidocaine in plasma following intravenous bolus administration is 9 to 10 ml/min/kg.
The elimination half-life of lidocaine following intravenous bolus injection is typically 1.5 to 2 hours.
The pharmacological actions of monoethylglycine xylidide and glycinexylidide are similar to but less potent than those of lidocaine. Monoethylglycine xylidide has a half-life of approximately 2.3 hours and glycinexylidide has a half-life of about 10 hours and may accumulate after long-term administration.
Only 3% of lidocaine is excreted unchanged by the kidneys. About 73% of lidocaine appears in the urine as 4-hydroxy-2,6-dimethylaniline metabolite.
Special Population
Methylprednisolone:
No pharmacokinetic studies have been performed for methylprednisolone in special populations.
Special Population
Lidocaine:
Hepatic impairment
Following intravenous administration, the half-life of lidocaine has approximately 3-fold increase in patients with liver impairment. Pharmacokinetic data of lidocaine after intra-articular, intra-bursa and intra-cyst administrations for local effect are not available in hepatic impairment.
Renal impairment
Mild to moderate renal impairment (CLcr 30-60 ml/min) does not affect lidocaine pharmacokinetics but may increase the accumulation of glycinexylidide metabolite following intravenous administration. However, lidocaine clearance decreases about half and its half-life is approximately doubled with increased accumulation of glycinexylidide metabolite in patients with severe renal impairment (Clcr < 30 ml/min).
The pharmacokinetics of lidocaine and its main metabolite of monoethylglycine xylidide are not altered significantly in haemodialysis patients who receive an intravenous dose of lidocaine.
Pharmacokinetic data of lidocaine after intra-articular, intra-bursa and intra-cyst administrations for local effect are not available in renal impairment.
No dosing adjustments are necessary in renal failure. Methylprednisolone is haemodialysable.
5.3 |
Depo-Medrone with Lidocaine Suspension for Injection | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Methylprednisolone
Based on conventional studies of safety pharmacology and repeated dose toxicity, no unexpected hazards were identified. The toxicities seen in the repeated-dose studies were those expected to occur with continued exposure to exogenous adrenocortical steroids.
Mutagenesis:
Methylprednisolone has not been formally evaluated for genotoxicity. Studies using structurally related analogues of methylprednisolone showed no evidence of a potential for genetic and chromosome mutations in limited studies in bacteria and mammalian cells.
Carcinogenesis:
Methylprednisolone has not been formally evaluated in rodent carcinogenicity studies. Variable results have been obtained with other glucocorticoids tested for carcinogenicity in mice and rats. However, published data indicate that several related glucocorticoids including budesonide, prednisolone, and triamcinolone acetonide can increase the incidence of hepatocellular adenomas and carcinomas after oral administration in drinking water to male rats. These tumorigenic effects occurred at doses which were less than the typical clinical doses on a mg/m2 basis. The clinical relevance of these findings is unknown.
Reproductive toxicity:
Methylprednisolone has not been evaluated in animal fertility studies. Corticosteroids have been shown to reduce fertility when administered to rats. Adverse effects on fertility in male rats administered corticosterone were observed and were reversible. Decreased weights and microscopic changes in prostate and seminal vesicles were observed. The numbers of implantations and live foetuses were reduced and these effects were not present following mating at the end of the recovery period.
An increased frequency of cleft palate was observed among the offspring of mice treated during pregnancy with methylprednisolone in doses similar to those typically used for oral therapy in humans.
An increased frequency of cardiovascular defects and decreased body weight were observed among the offspring of pregnant rats treated with methylprednisolone in a dose that was similar to that used for oral therapy in humans but was toxic to the mothers. In contrast, no teratogenic effect was noted in rats with doses < 1-18 times those typically used for oral therapy in humans in another study. High frequencies of foetal death and a variety of central nervous system and skeletal anomalies were reported in the offspring of pregnant rabbits treated with methylprednisolone in doses less than those used in humans. The relevance of these findings to the risk of malformations in human infants born to mothers treated with methylprednisolone in pregnancy is unknown. Safety margins for the reported teratogenic effects are unknown.
Lidocaine
Carcinogenesis:
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of lidocaine.
A metabolite of lidocaine, 2,6-xylidine, has been shown to be carcinogenic in rats with unknown clinical relevance in relation to short-term/intermittent use of lidocaine as a local anaesthetic.
Mutagenesis:
Genotoxicity tests with lidocaine showed no evidence of mutagenic potential. A metabolite of lidocaine, 2,6-xylidine, showed weak genotoxic potential in vitro and in vivo.
Reproductive toxicity:
A study was conducted on male and female rats administered orally 30 mg/kg bw of lidocaine daily for 8 months. During that period, 3 matings were conducted and reproductive parameters were analysed for each gestation, as well as offspring development up to weaning. No effects could be detected.
Methylprednisolone plus Lidocaine
Carcinogenesis:
Long-term studies in animals have not been performed to evaluate carcinogenic potential.
The toxicity of lidocaine was not significantly altered in rats that were treated with the combination of lidocaine and methylprednisolone.
Mutagenesis:
Genotoxicity studies have not been conducted with the combination of methylprednisolone and lidocaine (see above for genotoxicity as it pertains to the individual drugs).
Reproductive toxicity:
Reproductive toxicity studies have not been conducted with the combination of methylprednisolone and lidocaine (see above for reproductive toxicity as it pertains to the individual drugs).
6. |
Depo-Medrone with Lidocaine Suspension for Injection | Pharmaceutical particulars - List of excipients | List of excipients
Sodium chloride
Myristyl-gamma-picolinium chloride
Benzyl alcohol (E1519)
Macrogol
Sodium hydroxide
Hydrochloric acid
Water for injections.
6.2 |
Depo-Medrone with Lidocaine Suspension for Injection | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Depo-Medrone with Lidocaine Suspension for Injection | Pharmaceutical particulars - Shelf life | Shelf life
2 years.
6.4 |
Depo-Medrone with Lidocaine Suspension for Injection | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25°C.
Do not freeze.
6.5 |
Depo-Medrone with Lidocaine Suspension for Injection | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Glass vials with rubber cap containing 1 or 2 ml of suspension.
Not all pack sizes may be marketed.
6.6 |
Depo-Medrone with Lidocaine Suspension for Injection | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Depo-Medrone with Lidocaine Suspension for Injection | Marketing authorisation holder | Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
UK
8. Marketing authorisation number(s)
PL 00057/0964
9. |
Depo-Medrone with Lidocaine Suspension for Injection | Date of first authorisation/renewal of the authorisation | MA granted: 03 March 1981
MA renewed: 25 November 1991
10. |
Depo-Medrone with Lidocaine Suspension for Injection | Date of revision of the text | 06/2023
Ref: DML 31_0 UK |
Deponit 10 mg/24 h transdermal patch | Name of the medicinal product | Deponit 10 mg/24 h transdermal patch
2. |
Deponit 10 mg/24 h transdermal patch | Qualitative and quantitative composition | One patch contains glyceryl trinitrate 37.4 mg
The average amount of glyceryl trinitrate absorbed from each patch in 24 hours is 10 mg.
For the full list of excipients, see section 6.1.
3. |
Deponit 10 mg/24 h transdermal patch | Pharmaceutical form | Transdermal patch
White, translucent square patch with convex round corners with “Deponit 10” marked on the outer face.
4. |
Deponit 10 mg/24 h transdermal patch | Clinical particulars - Therapeutic indications | Therapeutic indications
Prophylaxis of angina pectoris alone or in combination with other anti-anginal therapy.
4.2 |
Deponit 10 mg/24 h transdermal patch | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Adults
Treatment should be initiated with one patch daily. If necessary, the dosage may be increased to two patches. The maximum daily dose is 20 mg, any increases or decreases in dose should be made gradually.
Elderly population
No specific information on use in the elderly is available, however there is no evidence to suggest that an alteration in dose is required.
Paediatric population
The safety and efficacy of this Deponit patch in children has not yet been established.
Method of administration
Dermal
It is recommended that the patch is applied to healthy, undamaged, relatively crease free and hairless skin. The best places to apply Deponit patches are the easily reached, fairly static areas at the front or side of the chest. However, Deponit patches may also be applied to the upper arm, thigh, abdomen or shoulder. Skin care products should not be used before applying the patch. The replacement patch should be applied to a new area of skin. Allow several days to elapse before applying a fresh patch to the same area of skin.
Tolerance may occur during chronic nitrate therapy. To avoid development of tolerance, the GTN patch should remain on the skin only for about 12-14 hours, to ensure a nitrate free interval of 10-12 hours. Additional anti-anginal therapy with drugs not containing nitro compounds should be considered for the nitrate-free interval if required.
As with any nitrate therapy, treatment with these patches should not be stopped abruptly. If the patient is being changed to another type of treatment, the two should overlap.
4.3 |
Deponit 10 mg/24 h transdermal patch | Clinical particulars - Contraindications | Contraindications
• Hypersensitivity to the active substance, to other nitro compounds or to any of the excipients listed in section 6.1
• Raised intracranial pressure including that caused by head trauma or cerebral haemorrhage
• Acute circulatory failure associated with marked hypotension (shock).
• Myocardial insufficiency due to obstruction, as in aortic or mitral stenosis or constrictive pericarditis.
• Marked anaemia
• Closed angle glaucoma
• Severe Hypotensive conditions (systolic blood pressure less than 90mmHg)
• Severe hypovolaemia
• Hypertrophic obstructive cardiomyopathy
• Aortic stenosis and mitral stenosis
• Constrictive pericarditis
• Cardiac tamponade
• Concomitant use of phosphodiesterase type-5 inhibitors. Phosphodiesterase type-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) have been shown to potentiate the hypotensive effects of nitrates, and their co-administration with nitrates or nitric oxide donors is therefore contra-indicated.
• During nitrate therapy, the soluble guanylate cyclase stimulator riociguat must not be used (see section 4.5).
4.4 |
Deponit 10 mg/24 h transdermal patch | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Warnings:
In cases of recent myocardial infarction or acute heart failure, treatment with the preparation should be carried out cautiously under strict medical surveillance and/or haemodynamic monitoring.
Removal of the patch should be considered as part of the management of patients who develop significant hypotension.
Precautions:
This patch should be used with caution in patients with
• Severe hepatic or renal impairment
• Hypothyroidism
• Hypothermia
• Malnutrition
• A recent history of myocardial infarction
• Hypoxaemia or a ventilation/perfusion imbalance due to lung disease or ischaemic heart failure.
• Arterial Hypoxaemia due to severe anaemia (including G6PD deficiency induced forms), because in such patients the biotransformation of nitroglycerin is reduced.
• Alveolar hypoventilation a vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung (Euler–Liljestrand mechanism).
• Angina pectoris, myocardial infarction, or cerebral ischaemia frequently suffer from abnormalities of the small airways (especially alveolar hypoxia).Under these circumstances vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung. As a potent vasodilator, nitroglycerin could reverse this protective vasoconstriction and thus result in increased perfusion of poorly ventilated areas, worsening of the ventilation/perfusion imbalance, and a further decrease in the arterial partial pressure of oxygen.
• Methemoglobinemia
Following treatment with GTN, methemoglobinemia has been reported. Treatment of methaemoglobinemia with methylene blue is contraindicated in patients with glucose-6-phosphate deficiency or methemoglobin-reductase deficiency (see also section 4.9).
The patch is not indicated for use in acute angina attacks. In the event of an acute angina attack, sublingual treatment such as a spray or tablet should be used.
As with all nitrate preparations withdrawal of long-term treatment should be gradual by replacement with decreasing doses of long acting oral nitrates.
Also when transferring the patient on long-term therapy to another form of medication, nitroglycerin should be gradually withdrawn and overlapping treatment started.
If the patches are not used as indicated (see Section 4.2) tolerance to the medication could develop.
Patients should be warned not to discontinue or interrupt GTN patch therapy in order to use phosphodiesterase inhibitor-containing products (e. g. sildenafil, vardenafil, tadalafil).
During treatment with GTN alcohol should be avoided as it may potentiate the hypotensive and vasodilating effect of GTN (see section 4.5).
4.5 |
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