Special Warning : אזהרת שימוש

4.4    Special warnings and precautions for use

Risks due to simultaneous use with opioids:
The simultaneous use of Assival Teva 10 mg/2 ml solution for injection and opioids can cause sedation, respiratory depression, coma and death. Due to these risks, sedatives such as benzodiazepine or related drugs such as Assival Teva 10 mg/2 ml solution for injection should only be prescribed together with opioids in patients for whom there are no alternative treatment options. If, however, a simultaneous prescription for Assival Teva 10 mg/2 ml solution for injection together with opioids is deemed necessary, then the lowest effective dose should be used and the treatment duration should be as short as possible (see also the general dosage recommendation in section 4.2).
Patients should be closely monitored for signs and symptoms of respiratory depression and sedation. In this regard it is strongly recommended that patients and their caregivers (where applicable) be informed about these symptoms (see section 4.5).

At the beginning of therapy, patient's individual response to the drug should be monitored, in order to identify as soon as possible any relative overdose due to accumulation. This applies in particular to elderly and debilitated patients, children and adolescents, as well as patients with organic brain changes, circulatory or respiratory failure or with impaired hepatic or renal function. Furthermore, patients should be instructed about conduct in relation to everyday activities, while taking into account their specific situation (e.g. professional activity).

After ambulatory administration for diagnostic purposes, the patient should be discharged home only after 1 hour and only if accompanied by another person.
Moreover, the patient should be advised not to consume alcohol.


Diazepam should not be taken concomitantly with alcohol and/or drugs with a depressant action on the central nervous system. Concomitant use can enhance the effects of diazepam and possibly lead to deep sedation and clinically relevant cardiovascular and/or respiratory depression (see Section 4.5).

In elderly patients, caution is required because of the risk of falls, particularly when getting up at night.

High-risk patients
Benzodiazepines are not recommended for the primary treatment of psychoses.

Benzodiazepines should not be used as the sole means of treatment of depressions or anxiety states accompanied by depression. In some circumstances, the depressive symptoms can be exacerbated in the absence of appropriate treatment of the underlying disease with antidepressants (danger of suicide).

In epileptic patients, the sudden discontinuation of diazepam can cause seizures.

In elderly and debilitated patients, as well as in patients with heart failure and/or hypotension, whose response to benzodiazepines is often stronger than desired, and in patients with organic brain changes, the prescription should be carefully considered.
This also applies to patients with impaired renal function. If necessary, the dose should be reduced or diazepam should be discontinued (see Section 4.2).

A lower dose is also recommended for patients with chronic respiratory failure because of the risk of respiratory depression (see Section 4.2).

Although a fall in blood pressure does not occur often, diazepam should be used with caution in patients in whom a fall in blood pressure could cause cardiac complications.
This applies in particular to elderly patients.

Patients with severe hepatic impairment must not be treated with benzodiazepines, because of the risk of encephalopathy (see Section 4.3).

Patients with dependency on medicines with a depressant action on the central nervous system, including alcohol, should not be treated with diazepam, except in cases of acute withdrawal reactions.

Patients with hypovolemic shock may be treated with the injection form only if measures to compensate for the volume deficiency are taken simultaneously.

Patients in a coma may be treated with the injection form only in case of severe restlessness or convulsive states provided the coma has not been caused by intoxication.

In patients with allergic skin disease, increased vascular permeability, or hematopoietic disorders, the solution for injection should be administered with particular care.

Development of tolerance
After repeated use of benzodiazepines over a few weeks, a loss of effectiveness (tolerance) is possible.
In pre-existing alcohol or barbiturate dependency, cross tolerance is possible.

Development of dependency
The use of benzodiazepines can lead to the development of psychological and physical dependency. This is true not only for inappropriate use of particularly high doses, but also for the therapeutic dosage range. The risk of dependency increases with the dose and with the duration of the treatment. This risk is also increased in patients with a history of alcohol, medicine or drugs dependency.

Uninterrupted use for a period longer than 4 weeks should be avoided, as it can lead to dependency.

If physical dependency has developed, withdrawal symptoms occur in case of sudden discontinuation (see below).

Discontinuation withdrawal symptoms
Withdrawal symptoms are possible especially when discontinuing longer-term treatment.
These symptoms are manifested as sleeping disorders, increased dreaming, headaches, muscular pain, anxiety, states of tension, inner restlessness, sweating, shaking, mood changes, confusion and irritability.

In severe cases, the following symptoms can also appear: states of confusion, depersonalization, derealization, hypersensitivity to light, noise and body contact, numbness and paraesthesia in the extremities, epileptic seizures, hallucinations and symptomatic psychoses (e.g. withdrawal delirium).

The sudden discontinuation of a shorter treatment can also cause transient withdrawal signs (rebound phenomena), in which the symptoms that had led to the treatment with diazepam reappear in a more severe form. Accompanying reactions such as mood changes, states of anxiety and restlessness are possible.

As the risk of withdrawal or discontinuation phenomena is higher after sudden treatment discontinuation, it is recommended that the therapy be discontinues by gradual reduction of the dose.

It is recommended that at the beginning of the therapy the patient be advised on the limited treatment period and be explained in detail about the gradual reduction of the dose. Moreover, it is important that the patient be aware of the possibility of rebound phenomena, as a result of which the fear of such symptoms – should they appear upon discontinuation of the drug – can be minimized.

Amnesia
Benzodiazepines can cause anterograde amnesias. This means that (in most cases a few hours) after use of the medicinal product the patient may carry out actions which will not be remembered by him subsequently.

This risk increases with the dose and can be diminished by a sufficiently long uninterrupted period of sleep (7-8 hours).

Mental and "paradoxical" reactions
The use of benzodiazepines can cause, especially in elderly patients or in children, mental as well as so-called "paradoxical" reactions (see Section 4.8). In such cases, the treatment with this preparation should be stopped.

Children and adolescents
Treatment of children or adolescents with Assival Teva 10 mg/2 ml solution for injection should take place only if there is an urgent indication (see Section 4.2).

The safety and the effectiveness of diazepam in children of less than 6 months of age were not studied. In this age group, Assival Teva 10 mg/2 ml solution for injection should be used with outmost care and only if no other therapeutic alternatives are available.

In the newborn and especially in premature babies, the benzyl alcohol contained in Assival Teva 10 mg/2 ml solution for injection can lead to irreversible damage. For this reason, Assival Teva 10 mg/2 ml solution for injection must not be used in newborn and in premature babies (see Section 4.3).


Excipients
-      This medicine contains 15 mg benzyl alcohol per ml.
Benzyl alcohol has been linked to serious side effects (“gasping syndrome”) in neonates and small children.
In small children (under the age of 3 years), the medicine is not to be used for longer than 1 week due to accumulation.
Due to the risk of accumulation and toxicity (metabolic acidosis), large quantities of benzyl alcohol should be used with caution and only when absolutely necessary, particularly in patients with impaired hepatic or renal function or during pregnancy and breast-feeding (see Contraindications 4.3)

-      This drug contains 1 mg benzoic acid and 49 mg sodium benzoate per ml of solution for injection.

-      This drug contains less than 1 mmol sodium (23 mg) per ml of solution for injection, that is to say essentially “sodium-free”.

-      This drug contains 400 mg propylene glycol per ml of solution for injection.
Simultaneous use with an alcohol dehydrogenase substrate, such as ethanol, can cause serious side effects in children under the age of 5 years.
Reproductive or developmental toxicity have not been demonstrated for propylene glycol; however, it can reach the fetus and has been detected in breast milk. The use of propylene glycol in pregnant and breast-feeding patients should be assessed on a case-by-case basis (see Contraindications 4.3).
Medical monitoring is required in patients with impaired renal or hepatic function, as various undesirable effects have been reported that are associated with propylene glycol, e.g. renal dysfunction (acute tubular necrosis), acute kidney injury and hepatic dysfunction.


-      This drug contains 13.12% alcohol by volume.
Because of the alcohol content, the use of Assival Teva 10 mg/2 ml solution for injection can lead to positive results in doping tests.

Effects on Driving

4.7    Effects on ability to drive and use machines
Even in case of appropriate administration, this drug can alter the ability to reactto such an extent that the fitness to drive and the capacity to operate machines are affected. This applies even more so in combination with alcohol.
In the course of the treatment with the solution for injection as well as 24 hours after the last injection, the patient must not drive or undertake any activity through which the patient can put himself/herself or others in danger. If the solution for injection has been used for diagnostic purposes, the patient should return home only if accompanied by another person.
Consumption of alcohol during concomitant use of Assival Teva 10 mg/2 ml solution for injection still causes increased impairment of motor functions and of usual behaviour even 10 hours after the last dose. This can represent a considerable risk for work and traffic accidents.