Source: Υπουργείο Υγείας (CY) Revision Year: 2022 Publisher: Remedica Ltd, Aharnon Str., Limassol Industrial Estate, 3056 Limassol, Cyprus
Remedium is contraindicated in patients with:
Benzodiazepines are not recommended as first-line treatment of psychotic disorders.
Benzodiazepines should not be used as monotherapy for the treatment of depression or anxiety associated with depression, due to the risk of suicide in affected patients.
The concomitant use of Remedium with alcohol and/or CNS depressants should be avoided. Such concomitant use may potentiate the clinical effects of diazepam, leading to severe sedation which may result in coma, death or clinically significant respiratory and/or cardiovascular depression (see section 4.5).
Extreme caution should be exercised when prescribing Remedium to patients with a history of alcoholism or drug addiction.
Remedium should be avoided in patients who are dependent on CNS depressants, including alcohol. One exception to the latter is the treatment of acute withdrawal symptoms.
Benzodiazepines may help precipitate episodes of hepatic encephalopathy in patients with severe hepatic impairment. Special caution should be exercised when administering Remedium to patients with mild to moderate hepatic impairment (see section 4.3).
The concomitant use of Remedium with alcohol and/or CNS depressants should be avoided. Such concomitant use may potentiate the clinical effects of diazepam, leading to severe sedation which may result in coma, death or clinically significant respiratory and/or cardiovascular depression (see section 4.5).
Extreme caution should be exercised when prescribing Remedium to patients with a history of alcoholism or drug addiction.
Remedium should be avoided in patients who are dependent on CNS depressants, including alcohol. One exception to the latter is the treatment of acute withdrawal symptoms.
Benzodiazepines may help precipitate episodes of hepatic encephalopathy in patients with severe hepatic impairment. Special caution should be exercised when administering Remedium to patients with mild to moderate hepatic impairment (see section 4.3).
Some loss of response to the effects of benzodiazepines may develop after repeated use of Remedium for a prolonged time.
Treatment with benzodiazepines and benzodiazepine-like drugs may lead to the development of physical and mental dependence (see section 4.8). The risk of dependence increases with the dose and duration of treatment and is also greater in patients with a history of drug addiction and/or alcoholism. Cases of abuse have been reported in polydrug addicts. Remedium should be used with extreme caution in patients with a history of drug and/or alcohol abuse.
Once physical dependence has developed, abrupt discontinuation of treatment may be accompanied by withdrawal symptoms such as headaches, diarrhoea, muscle pain, marked anxiety, tension, restlessness, confusion and irritability. In severe cases, the following symptoms have been described: loss of reality, depersonalisation, hyperacousia, tingling and cramps in the limbs, intolerance to light, sounds and touch, hallucinations or seizures (see section 4.8).
When using benzodiazepines, withdrawal symptoms may develop when switching to a benzodiazepine with a considerably shorter elimination half-life.
A transient syndrome has been described after discontinuation of treatment, which is characterized by the recurrence of the symptoms that led to treatment, but in enhanced form. It may be accompanied by other reactions including mood changes, anxiety or insomnia and restlessness. Since the risk of withdrawal and rebound effect is greater after abrupt discontinuation of treatment, it is recommended that the dosage be decreased gradually until complete discontinuation.
The duration of treatment should be as short as possible (see section 4.2).
Treatment should never be prolonged without a reassessment of the patient’s situation.
It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover it is important that the patients should be aware of the possibility of a rebound effect, thereby minimizing anxiety over such symptoms that may appear after discontinuation of the medication.
It has been shown that with short-acting benzodiazepines, withdrawal syndrome may occur between two doses, especially if the patient is on a high dose.
Because diazepam is a long-acting benzodiazepine, patients should be informed that switching to a short-acting benzodiazepine may lead to withdrawal symptoms.
Note that benzodiazepines can cause anterograde amnesia even at therapeutic doses, and that the risk increases with the dose. Amnesic effects may be associated with behavioral disturbances.
Benzodiazepines can cause reactions such as restlessness, agitation, irritability, aggressiveness, anxiety, delusions, fits of anger, nightmares, hallucinations, psychosis, inappropriate behaviour and other adverse effects on behavior. If this happens, treatment should be discontinued.
These reactions are more common in children and the elderly.
The safety and efficacy of diazepam in children below the age of 6 months have not been established; therefore, it should not be used in this age group. It should only be used if there are no other therapeutic options.
The duration of treatment in children over the age of 6 months should be as short as possible.
The dose should be reduced in elderly patients. Due to the associated risk of respiratory depression, it is also recommended to use lower doses in patients with chronic respiratory failure. Benzodiazepines are not recommended for the first-line treatment of psychotic illness.
Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (risk of suicide).
In epileptic patients receiving long-term treatment with diazepam (or any other benzodiazepine), the use of a benzodiazepine antagonist (flumazenil) is not recommended, because abrupt withdrawal of the protective effect of a benzodiazepine agonist may lead to seizures in epileptic patients, although inherently the mentioned antagonist exerts a slight anticonvulsant effect.
Concomitant use of Remedium and opioids may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs such as Remedium with opioids should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Remedium concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2).
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers (where applicable) to be aware of these symptoms (see section 4.5).
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
The metabolism of diazepam and its major metabolite, DMDZ, is mediated by cytochrome P450 isoenzymes CYP3A4 and CYP2C19. Modulators of these enzymes can produce changes in the disposition and effects of diazepam. Marked interactions have been observed with compounds which simultaneously affect the oxidative metabolic pathways of diazepam; if only one metabolic pathway of diazepam is affected, even potent inhibitors may have only moderate effects. CYP3A4 and CYP2C19 inhibitors decrease the metabolism of diazepam, which may lead to higher concentrations of diazepam and its demethylated metabolite and, in turn, to more prolonged/intense sedation and anxiolytic effects. These changes may be more pronounced in patients who are especially sensitive to the effects of diazepam, for example due to age, hepatic impairment or treatment with other oxidative compounds. Inducers of CYP3A4 and CYP2C19 can lead to lower than expected concentrations and thus to inadequate efficacy.
Grapefruit juice contains potent CYP3A4 inhibitors. Administration of diazepam with grapefruit juice instead of water significantly increased plasma levels of diazepam (3.2-fold increase in the AUC; 1.5-fold increase in Cmax) and the time taken to reach the maximum concentration was delayed.
Azole antifungals inhibit the CYP3A4 and CYP2C19 pathways, leading to increased plasma levels of diazepam (AUC ratio increased 2.5-fold for diazepam-fluconazole and 2.2-fold for diazepam-voriconazole), and prolonged the elimination half-life of diazepam (from 31 to 73 hrs with fluconazole, and from
31 to 61 hrs with voriconazole). The effect of antifungals on plasma levels of diazepam was only observed 4 hrs after administration and thereafter. Itraconazole has a more moderate effect and no clinically significant interaction with diazepam, as determined by psychomotor performance tests.
Fluvoxamine, a serotonin reuptake inhibitor, also inhibits both diazepam degradation pathways, not only increasing plasma levels of diazepam by 180% and prolonging its elimination half-life from 51 to 118 hrs, but also increasing plasma levels and the time to steady state of the demethylated metabolite. Fluoxetine showed a more modest effect on the AUC of diazepam (increase of approximately 50%) and did not affect psychomotor performance, as the combined concentrations of diazepam and its demethylated metabolite were similar with and without fluoxetine.
Combined hormonal contraceptives appear to reduce the clearance of diazepam (by 67%) and prolong its elimination half-life (by 47%). Diazepam-induced psychomotor impairment in women using oral contraceptives may be greater during the 7-day menstrual pause than during use of the contraceptives. There is limited evidence that benzodiazepines may increase the incidence of bleeding in women using hormonal contraceptives.
No drug interaction has been observed that could allow pregnancy to occur.
Administered at a dose of 20 mg daily, omeprazole, a proton pump inhibitor and inhibitor of CYP3A4 and CYP2C19, increased the AUC of diazepam by 40% and its half-life by 36%; at a dose of 40 mg daily, omeprazole increased the AUC of diazepam by 122% and its half-life by 130%. The clearance of the demethylated metabolite of diazepam was also reduced. The effect of omeprazole was only seen in CYP2C19 extensive metabolisers, but not in poor metabolisers. Esomeprazole (but not lansoprazole or pantoprazole) has the potential to inhibit the metabolism of diazepam to a similar degree as omeprazole.
Cimetidine, a histamine H2 receptor antagonist which is an inhibitor of multiple CYP isoenzymes, including CYP3A4 and CYP2C19, reduces the clearance of diazepam and its demethylated metabolite by 40-50%. The effect is the same after one day of treatment with cimetidine as after chronic treatment, resulting in increased plasma levels and a prolonged elimination half-life of diazepam and its main metabolite after a single dose of diazepam, and increased steady-state concentrations after multiple doses. Co-administration of cimetidine has been associated with increased sedation. No other pharmacokinetic interactions have been observed with H2 antagonists such as ranitidine or famotidine.
Disulfiram inhibits the metabolism of diazepam (median decrease in clearance 41%, increase in half-life 37%) and probably the further metabolism of its active metabolites. Sedative effects may be increased as a result.
Antituberculosis treatment may alter the disposition of diazepam. In the presence of isoniazid, mean plasma levels (AUC) and the half-life of diazepam were increased (by 33-35% on average), with the greatest changes observed in subjects with the slow acetylator phenotype.
Diltiazem, a calcium channel blocker, substrate for the same isoenzymes as diazepam, and an inhibitor of CYP3A4, increased the AUC of diazepam (by approximately 25%) and prolonged its half-life (by 43% in CYP2C19 extensive metabolisers), with minor differences between subjects with different CYP2C19 phenotypes. The presence of diltiazem was also associated with increased exposure to desmethyldiazepam.
The primary metabolite of idelalisib is a potent CYP3A4 inhibitor which increases plasma concentrations of diazepam, so that a dose adjustment may need to be considered.
The psychostimulants modafinil and armodafinil induce CYP3A4 and inhibit CYP2C19: they can thus prolong the elimination of diazepam and cause excessive sedation.
Rifampicin is a potent inducer of CYP3A4 and also has a significant accelerating effect on the CYP2C19 pathway. When doses of 600 mg daily were administered for 7 days, diazepam clearance increased 4.3-fold and its AUC decreased by approximately 77%. A significant reduction in plasma levels of all diazepam metabolites was observed. Doubling the daily dose of rifampicin did not further increase these effects.
Carbamazepine is a known inducer of CYP3A4 and therefore accelerates the elimination of diazepam 3-fold (increases clearance, reduces half-life), increasing concentrations of desmethyldiazepam.
Food and antacids may slow, but will not reduce the absorption of diazepam from the tablet; this may lead to attenuated effects after a single dose, but does not affect steady-state concentrations during multiple dose treatment.
Prokinetic drugs increase the rate of absorption of diazepam.
Compounds which inhibit certain liver enzymes (particularly cytochrome P450) may potentiate the effects of benzodiazepines. To a lesser extent, this also applies to those benzodiazepines that are metabolised solely by conjugation.
Intravenous (but not oral) metoclopramide increases the absorption rate of diazepam and increases the maximum concentration achieved after oral administration.
Narcotics (morphine, pethidine) decrease the rate of absorption and decrease peak concentrations of oral diazepam.
Diazepam has not been shown to induce or inhibit metabolising enzymes. However, some interactions occur with other drugs which are precipitated by diazepam.
Concomitant use of phenytoin and diazepam has been associated with higher plasma concentrations of phenytoin and increased phenytoin toxicity. However, many authors have found either no interaction or decreased plasma concentrations of phenytoin when co-administered with diazepam.
Alcohol should be avoided in patients receiving Remedium (see section 4.4).
For information on overdose and precautions with other central nervous system depressants, including alcohol, see section 4.9.
Potentiation of adverse effects such as sedation and respiratory depression may also occur when Remedium is co-administered with CNS depressants, including alcohol.
There have been several reports of severe hypotension, respiratory depression and loss of consciousness in patients receiving combination therapy with clozapine and benzodiazepines, including diazepam.
Cumulative CNS depressant effects can be expected when phenothiazines are used in combination with benzodiazepines: sedation, respiratory depression and airway obstruction have been reported with the combined use of levopromazine and diazepam.
Cumulative effects of olanzapine and diazepam with regard to sedation and hypotension have occurred in the absence of pharmacokinetic interaction. Concomitant parenteral use is not recommended.
Diazepam potentiates the subjective opioid effects of methadone. It enhances the effects of methadone on pupil diameter and sedation and also causes a significantly greater impairment in reaction time compared to methadone alone. There is no pharmacokinetic interaction between the two drugs.
Reversible loss of Parkinson’s disease control has been observed in some patients treated with a combination of levodopa and diazepam. This could be caused by decreased levels of striatal dopamine.
The xanthines theophylline and caffeine counteract the sedation caused by diazepam, but possibly also its anxiolytic effects partially through blockade of adenosine receptors.
Premedication with diazepam alters the pharmacodynamics and pharmacokinetics of ketamine, an anaesthetic. The N-demethylation of ketamine is inhibited, resulting in a prolonged half-life and duration of ketamine-induced sleep. In the presence of diazepam, a lower concentration of ketamine is required to achieve adequate anaesthesia.
In the case of narcotic analgesics, the sensation of euphoria may be enhanced, which may increase psychological dependence.
The concomitant use of sedative medicines such as benzodiazepines or related drugs such as Remedium with opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited (see section 4.4).
If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuation of treatment if she is planning to have a baby or discovers that she is pregnant during treatment.
The safety of diazepam in pregnant women has not been established. It has been suggested that the use of benzodiazepines during the first trimester is associated with an increased risk of congenital malformations.
A review of spontaneous adverse event reports did not show a higher incidence than expected in a similar untreated population. Benzodiazepines should be avoided during pregnancy unless there is no safer alternative. Before administering Remedium during pregnancy, especially during the first trimester, the potential risks to the fetus should be weighed against the expected therapeutic benefit to the mother.
If the administration of diazepam either continuously during pregnancy or at high doses during delivery is strictly medically necessary, effects such as hypothermia, hypotonia, hypotension and respiratory depression should be expected in the newborn infant (see section 5.2). Withdrawal symptoms in the newborn have been reported occasionally with this drug class.
Infants born to mothers taking benzodiazepines chronically in late pregnancy may develop physical dependence, with the potential for withdrawal syndrome in the postnatal period. Therefore, special precautions are necessary before using Remedium during childbirth, as high single doses can cause irregular fetal heart rate and hypotonia, reduced sucking, hypothermia and moderate respiratory depression in the newborn infant. Note that the enzyme system responsible for the metabolism of diazepam is not fully developed in newborn infants (especial preterm).
Benzodiazepines are excreted in human milk; therefore, their use is contraindicated during breast-feeding.
The ability to drive vehicles and operate machinery may be adversely affected by the sedation, amnesia, difficulty concentrating and impaired muscle function that can occur as a result of treatment. Before receiving Remedium, patients should be advised not to drive or operate machinery until fully recovered. It is at the discretion of the physician to decide when these activities can be resumed.
In addition, insufficient sleep duration or alcohol consumption may exacerbate impairment of alertness (see section 4.5).
Note also that alcohol enhances these effects.
The most common adverse reactions are fatigue, drowsiness and muscle weakness, which generally occur in a dose-dependent manner. These symptoms are most common at the start of treatment and generally disappear with continued use.
Nervous system disorders:
Ataxia, dysarthria, slurred speech, headache, tremor, dizziness, decreased alertness. Anterograde amnesia may occur at therapeutic doses, increasing the risk of occurrence of this reaction at higher doses. These amnesic effects can be associated with inappropriate behaviour.
Psychiatric disorders:
Paradoxical reactions such as s restlessness, agitation, irritability, disorientation, aggressiveness, nervousness, hostility, anxiety, delirium, fits of anger, nightmares, abnormal dreams, hallucinations, psychosis, hyperactivity, inappropriate behaviour, and other behavioural disturbances have been described. If this happens, treatment should be discontinued. These reactions are more common in children and the elderly.
Confusional state, emotional and mood disturbances, depression and changes in libido have also been observed.
Dependence:
Continued administration of the medicinal product (even at therapeutic doses) can lead to the development of physical dependence: discontinuation of treatment can lead to the development of withdrawal or rebound effect. Cases of benzodiazepine abuse have also been reported in polydrug addicts (see section 4.4).
Injury, poisoning and procedural complications:
Falls and fractures have been reported in patients taking benzodiazepines. The risk of this adverse reaction is increased in patients concomitantly using other sedative substances (including alcohol) and in the elderly.
Gastrointestinal disorders:
Nausea, dry mouth or hypersalivation, constipation and other gastrointestinal disturbances.
Eye disorders:
Diplopia, blurred vision.
Vascular disorders:
Hypotension, circulatory depression.
Investigations:
Irregular heart rate, very rarely increased serum alkaline phosphatase.
Renal and urinary disorders:
Incontinence, urinary retention.
Skin and subcutaneous tissue disorders:
The most common skin reactions are rash, urticaria, pruritus and erythematous rash. Most of the cases reported were not serious.
In the majority of cases of serious skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme), concomitant medications and impaired general condition were considered important confounders.
Ear and labyrinth disorders:
Dizziness.
Cardiac disorders:
Heart failure, including cardiac arrest.
Hepatobiliary disorders:
Very rare cases of jaundice.
Respiratory, thoracic and mediastinal disorders:
Respiratory depression, including respiratory failure.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: Cyprus, Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, Tel: +357 22608607, Fax: +357 22608669, Website: www.moh.gov.cy/phs.
Not applicable.
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