Source: Υπουργείο Υγείας (CY) Revision Year: 2014 Publisher: MEDOCHEMIE LTD, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
This medicinal product must never be used in patients with:
This medicinal product contains benzyl alcohol which can cause severe toxicity in children up to 3 years old, particularly a risk of metabolic acidosis produced by accumulation of benzoic acid and of nuclear jaundice by displacement of conjugated bilirubin from its binding sites to albumin in neonates and premature babies, because of their enzymatic immaturity.
The introduction of an antiepileptic drug may rarely be followed by a recrudescence of crises or the occurrence of a new type of crisis in children, independently of observed fluctuations in some epileptic diseases. As far as benzodiazepines are concerned, the causes of these aggravations can be: an inappropriate choice of drug for treating the patient’s crises or epileptic syndrome, a modification in the concomitant antiepileptic treatment or a pharmacokynetic interaction therewith, toxicity or an overdose. There may be no other explanation than a paradoxical reaction.
When administering benzodiazepines and their derivatives over several weeks, the anxiolytic effect of drugs may gradually decrease despite using the same dose.
Any treatment with benzodiazepines and related drugs and especially in case of prolonged use may cause physical and psychic pharmacodependence. Several factors appear to promote the development of dependence:
alcohol.
Pharmacodependence may occur at therapeutic doses and/or in patients without specific risk factors.
Dependence may lead to withdrawal symptoms upon treatment discontinuation. Some symptoms occur frequently and are mild in appearance: insomnia, headache, significant anxiety, myalgia, muscle tension, irritability.
Other symptoms occur more rarely: restlessness, even episodes of confusion, paresthesia of the extremities, hypersensitivity to light, noise and physical contact, depersonalisation, derealisation, hallucinations, convulsions.
Withdrawal symptoms may occur within the days following discontinuation of treatment. When short-acting benzodiazepines are used, and especially when given at high doses, withdrawal symptoms can even appear between two consecutive doses.
Concomitant use of several benzodiazepines, whether in anxiolytic or hypnotic indications, may increase the risk of pharmacodependence.
Some cases of abuse have also been reported.
This transient syndrome may appear as an exacerbation of the anxiety which had led to the treatment by benzodiazepines and related drugs.
Anterograde amnesia and altered psychomotor function may occur during the hours following the administration.
In some patients, benzodiazepines and related drugs may cause a syndrome with varying degrees of altered consciousness attitude and disturbances in behaviour and memory:
The following symptoms may occur:
This syndrome can be accompanied by disturbances that are potentially harmful to the patient or others, such as:
These symptoms require discontinuation of treatment.
Benzodiazepines and related drugs (like any medicinal product) remain in the body for a period of approximately 5 half-lives (see section 5.2).
In elderly patients or those with renal or hepatic insufficiency, half-life may be considerably longer. During repeated administration, the drug or its metabolites reach steady state much later and at a much higher level. The efficacy and safety of the drug can only be evaluated once steady state has been reached.
Dosage may need to be adjusted (see section 4.2).
Benzodiazepines and related drugs should be used with caution in elderly patients, due to the risk of sedation and/or a muscle-relaxant effect which may promote falls, often having serious consequences in this population.
Extreme caution is recommended in patients with a history of alcoholism or other addictions to medicinal products or other substances (see section 4.5).
Patients with Major Depressive Episode
Benzodiazepines and related drugs must not be prescribed alone since this allows the depression to follow its own course, along with persistent or increased risk of suicide.
Patients should be clearly instructed on how to gradually discontinue treatment. In addition to the need to gradually decrease dosage, patients should be warned of the possibility of rebound phenomena, in order to minimise any anxiety that ight result from the symptoms associated with this treatment discontinuation even when this is gradual. , Patients should be informed of possible discomfort during this phase.
Even more than in adults, the benefit/risk ratio should be scrupulously evaluated and the duration of treatment should be as short as possible.
The risk of accumulation leads to reducing the dosage, e.g. by half (see section 4.4).
In patients with respiratory insufficiency the depressive effect of benzodiazepines and related drugs should be taken into account (especially since anxiety and restlessness may be warning signs of respiratory decompensation, requiring transfer to an intensive care unit.
Kratium contains benzyl alcohol which may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.
This product contains sodium, to be taken into consideration by patients on a controlled sodium diet.
This product contains 0,16 g of alcohol per 2 ml ampoule. It should be used with caution in patients suffering from liver disease, alcoholism, epilepsy, as well as in pregnant women and children aged less than 12 years.
Alcohol increases the sedative effect of benzodiazepines and related drugs. Impaired alertness may render driving or machine operation dangerous. Avoid the consumption of alcoholic drinks and medicinal products containing alcohol.
Increased risk of drowsiness.
Warn the patients of the increased risk in case of driving or machine operation.
Unpredictable variations: plasma phenytoin concentrations may increase with toxic signs, but may also decrease or remain stable.
Clinical monitoring and control of plasma phenytoin concentrations.
Increase in plasma diazepam concentrations with risk of overdose, by inhibition of its hepatic metabolism.
Clinical monitoring, determination of the benzodiazepine in plasma and, if necessary, dosage adaptation.
Morphine derivatives (analgesics, antitussives and substitution therapies other than buprenorphine), neuroleptics, barbiturates; other anxiolytics; hypnotics; sedative antidepressants, sedative H1-antihistames; central antihypertensives; baclofen; thalidomide; pizotifen. Potentiation of central depression. A decrease in vigilance may impair the ability to drive vehicles and operate machinery safely. Impaired alertness may render driving or machine operation dangerous.
Furthermore, concomitant use with morphine derivatives (analgesics, antitussives and substitution therapies); barbiturates increases the risk of respiratory depression, which may be fatal in the event of an overdose.
Increased risk of respiratory depression, which may be fatal.
The benefit/risk ratio of this combination must be carefully weighted. The patient must be informed of the need to strictly follow the prescribed dose.
Risk of increased buspirone adverse effects.
Transient increase of sedative effects of diazepam due to a faster speed of absorption. Impaired alertness may render driving or machine operation dangerous.
To date, no malformative effect has been attributed to exposure to benzodiazepines during the first trimester of pregnancy.
A reduction in active foetal movements and foetal heart rate variability may occur when benzodiazepines are taken at high doses during the second and/or third trimesters of pregnancy.
Treatment with benzodiazepine at the term of pregnancy even at low doses may cause signs of absorption in the neonate, such as axial hypotonia and sucking disorders resulting in poor weight gain. These signs are reversible, but may persist for 1 to 3 weeks depending on the half-life of the benzodiazepine prescribed. At high doses, respiratory depression or apnea and hypothermia, all of which are reversible, may occur in the neonate. Furthermore, neonatal withdrawal syndrome is possible, even if no signs of absorption are observed. This is characterized by symptoms including particularly hyperexcitability, agitation and tremor in the neonate, observed after a certain period of time after birth. The time to onset is dependent on the elimination half-life of the medicinal product and may increase in duration when the half-life is long.
In view of these data, use of diazepam may be contemplated during pregnancy; irrespective of the trimester, with strict adherence to indications and dosages.
If initiation of treatment with diazepam proves necessary at the term of pregnancy, avoid prescribing high doses and take into account the above-mentioned effects when monitoring the neonate.
Use of this drug is not recommended in breast-feeding women.
Patients who drive and use machines should be informed of the risk of drowsiness.
Patients should be advised against using the drug concomitantly with other sedative drugs and should take this into account when driving or using machines (see section 4.5).
The risk of impaired alertness is further enhanced if sleep duration is insufficient.
Adverse effects are dose-dependent and depend on individual patient sensitivity.
Vascular disorders: Not known (cannot be estimated from the available data)
General disorders and administration site conditions: Not known (cannot be estimated from the available data)
Immune system disorders: Not known (cannot be estimated from the available data)
Hepatobiliary disorders: Not known (cannot be estimated from the available data)
Psychiatric disorders (see section 4.4): Not known (cannot be estimated from the available data)
Nervous system disorders: Not known (cannot be estimated from the available data)
Eye disorders: Not known (cannot be estimated from the available data)
Skin and subcutaneous tissue disorders: Not known (cannot be estimated from the available data)
Hepatobiliary disorders: Very rare (<1/10,000)
Musculoskeletal and connective tissue disorders: Not known (cannot be estimated from the available data)
General disorders and administration site conditions: Not known (cannot be estimated from the available data)
Investigations: Not known (cannot be estimated from the available data)
Reporting suspected adverse reactions is an important way to gather more information to continuously monitor the benefit/risk balance of the medicinal product. Any suspected adverse reactions should be reported to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy / phs Fax: +357 22608649.
Mixing with other products in the same syringe should be avoided.
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