Patients should be advised that their tolerance for alcohol and other CNS depressants will be diminished and that these medications should either be eliminated or given in reduced dosage in the presence of Valium. Such concomitant use has the potential to increase the clinical effects of Valium, possibly including severe sedation, clinically relevant respiratory and/or cardiovascular depression (see Interactions with Other Medicines).
In general, benzodiazepines should be prescribed for short periods only (e.g. 2-4 weeks). Continuous long-term use of Valium is not recommended. There is evidence that tolerance develops to the sedative effects of benzodiazepines. After as little as one week of therapy, withdrawal symptoms can appear following the cessation of recommended doses (e.g. rebound insomnia following cessation of a hypnotic benzodiazepine).
Following the prolonged use of Valium at therapeutic doses, withdrawal from medication should be gradual. An individualised withdrawal timetable needs to be planned for each patient in whom dependence is known or suspected. Periods from 4 weeks to 4 months have been suggested. As with other benzodiazepines, when treatment is suddenly withdrawn, a temporary increase in sleep disturbance can occur after use of Valium (see Precautions, Dependence).
Since Valium contains lactose, patients with rare hereditary problems of galactose intolerance (the Lapp lactase deficiency or glucose/ galactose malabsorption) should not take this medicine.
Hypotension.
Although hypotension has occurred rarely, Valium should be administered with caution to patients in whom a drop in blood pressure might lead to cardiac or cerebral complications. This is particularly important in elderly patients.
Amnesia.
Transient amnesia or memory impairment has been reported in association with the use of benzodiazepines. Anterograde amnesia may occur using therapeutic doses, the risk increasing at higher doses. Amnestic effects may be associated with inappropriate behaviour.
Acute narrow angle glaucoma.
Caution should be used in the treatment of patients with acute narrow angle glaucoma (because of atropine-like side effects).
Impairment of fertility.
Reproductive studies in rats showed decreases in the number of pregnancies and in the number of surviving offspring following administration of oral doses of 100 mg/kg/day (22-fold the MRHD on a body surface area basis) to both males and females prior to and during mating and throughout gestation and lactation. No adverse effects were observed at 10 mg/kg/day (60 mg/m2/day, twice the MRHD).
Use in pregnancy
(Category C)
The safety of Valium for use in human pregnancy has not been established. Diazepam and its metabolites readily cross the placenta. An increased risk of congenital malformation associated with the use of benzodiazepines during the first trimester of pregnancy has been suggested. Benzodiazepines should be avoided during pregnancy unless there is no safer alternative. Benzodiazepines cross the placenta and may cause hypotension, hypotonia, reduced respiratory function and hypothermia in the newborn infant. Continuous treatment during pregnancy and administration of high doses in connection with delivery should be avoided. Withdrawal symptoms in newborn infants have been reported with this class of drugs. Special care must be taken when Valium is used during labour and delivery, as single high doses may produce irregularities in the foetal heart rate and hypotonia, poor sucking, hypothermia and moderate respiratory depression (floppy infant syndrome) in the neonate. With newborn infants it must be remembered that the enzyme system involved in the breakdown of the drug is not yet fully developed (especially in premature infants).
Teratogenicity.
Diazepam was found to be teratogenic in mice at intravenous doses of 45 mg/kg or greater and oral doses of 100 mg/kg or greater (both 10-fold the MRHD on a body surface area basis), as well as in hamsters at 280 mg/kg (41-fold the MRHD). The respective no effect doses were 50 mg/kg (5-fold the MRHD) in mice and 200 mg/kg (30-fold the MRHD) in hamsters. Malformations included exencephaly, cranioschisis, kinking of the spinal cord, and cleft palate with and without cleft lip. Malformations were not observed in rats or rabbits at respective doses of up to 300 and 50 mg/kg/day (greater than 20-fold the MRHD). Delayed development has been reported in offspring from several animal species treated with diazepam during pregnancy or during pregnancy and lactation.
Use in lactation
Valium is excreted in human breast milk, and may cause drowsiness and feeding difficulties in the infant. Breastfeeding is not recommended in patients receiving oral Valium.
Paediatric use
Prolonged CNS depression has been observed in neonates due to inability to transform the drug. In view of lack of adequate clinical experience, oral use is not recommended in children younger than 6 months.
Use in the elderly.
There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.
Elderly or debilitated patients may be particularly susceptible to the sedative effects of benzodiazepines and associated giddiness, ataxia and confusion, which may increase the risk of a fall.
Lower doses should be used for elderly and debilitated patients.
Impaired renal/ liver function and blood dyscrasias.
Patients with impaired renal or hepatic function should use benzodiazepine medication with caution and dosage reduction may be advisable. In rare instances some patients taking benzodiazepines have developed blood dyscrasias, and some have had elevation of liver enzymes. As with other benzodiazepines, periodic blood counts and liver function tests are recommended.
Depression, psychosis and schizophrenia.
Valium is not recommended as primary therapy in patients with depression and/or psychosis. In such conditions, psychiatric assessment and supervision are necessary if benzodiazepines are indicated. Benzodiazepines may increase depression in some patients, and may contribute to deterioration in severely disturbed schizophrenic patients with confusion and withdrawal. Suicidal tendencies may be present or uncovered, and protective measures may be required.
Paradoxical reactions.
Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects, acute rage, stimulation or excitement may occur. Should such reactions occur, Valium should be discontinued. They are more likely to occur in children and the elderly.
Carcinogenicity.
The carcinogenic potential of oral diazepam has been studied in several rodent species. An increase in the incidence of malignant hepatocellular tumours occurred in male rats and mice following lifetime dietary administration of diazepam at 75 mg/kg/day (17-fold and 8-fold the maximum recommended human dose (MRHD) on a body surface area basis, respectively). This was not observed in female rats and mice treated with 75 mg/kg/day or hamsters treated with 120 mg/kg/day (18-fold the MRHD).
Genotoxicity.
Limited data from a number of studies have provided weak evidence of a genotoxic potential. Diazepam has been shown to induce aneuploidy in sperm obtained from both mice and humans treated with approximately 10 mg/m2/day (less than the MRHD).
Impaired respiratory function.
Caution in the use of Valium is recommended in patients with respiratory depression. In patients with chronic obstructive pulmonary disease, benzodiazepines can cause increased arterial carbon dioxide tension and decreased oxygen tension. A lower dose is recommended for patients with chronic respiratory insufficiency, due to the risk of respiratory depression.
Epilepsy.
When Valium is administered to persons with convulsive disorders, an increase in the frequency and/or severity of grand mal seizures may occur, necessitating increased anticonvulsant medication. Abrupt withdrawal of benzodiazepines in persons with convulsive disorders may be associated with a temporary increase in the frequency and/or severity of seizures.
Abuse.
Extreme caution must be exercised in administering Valium to individuals with a history of alcohol or drug abuse, dependence on CNS depressants, those known to be addiction prone or those whose history suggests they may increase the dosage on their own initiative. It is desirable to limit repeat prescriptions without adequate medical supervision.
Dependence.
The use of benzodiazepines and benzodiazepine-like agents may lead to the development of physical and psychic dependence (see Adverse Effects), as defined by the presence of a withdrawal syndrome on discontinuation of the drug. The risk of dependence increases with dose and duration of treatment. It is more pronounced in patients on long-term therapy and/or high dosage and particularly so in predisposed patients with a history of alcohol or drug abuse. Tolerance, as defined by a need to increase the dose in order to achieve the same therapeutic effect, seldom occurs in patients receiving recommended doses under medical supervision. Tolerance to sedation may occur with benzodiazepines, especially in patients with drug seeking behaviour.
Withdrawal symptoms similar in character to those noted with barbiturates and alcohol have occurred once physical dependence to benzodiazepines has developed or following abrupt discontinuation of benzodiazepines. These symptoms range from insomnia, anxiety, dysphoria, palpitations, panic attacks, vertigo, myoclonus, akinesia, hypersensitivity to light, sound and touch, abnormal body sensations (e.g. feeling of motion, metallic taste), depersonalisation, derealisation, delusional beliefs, hyper-reflexia and loss of short-term memory, to a major syndrome which may include convulsions, tremor, abdominal and muscle cramps, confusional state, delirium, hallucinations, hyperthermia, psychosis, vomiting and sweating. Such manifestations of withdrawal, especially the more serious ones, are more common in those patients who have received excessive doses over a prolonged period. However, withdrawal symptoms have been reported following abrupt discontinuation of benzodiazepines taken continuously at therapeutic levels. Accordingly, Valium should be terminated by tapering the dose to minimise occurrence of withdrawal symptoms. Patients should be advised to consult with their doctor before either increasing the dose or abruptly discontinuing the medication.
Rebound phenomena have been described in the context of benzodiazepine use. Rebound insomnia and anxiety mean an increase in the severity of these symptoms beyond pretreatment levels following cessation of benzodiazepines. Rebound phenomena, in general, possibly reflect re-emergence of pre-existing symptoms combined with withdrawal symptoms described earlier. Some patients prescribed benzodiazepines with very short half-lives (in the order of 2 to 4 hours) may experience relatively mild rebound symptoms in between their regular doses. Withdrawal/ rebound symptoms may follow high doses for relatively short periods.
Ability to drive and use machines.
Sedation, amnesia, impaired concentration and impaired muscle function may adversely affect the ability to drive or operate machinery. As with all patients taking CNS depressant medications, patients receiving Valium should be warned not to operate dangerous machinery or motor vehicles until it is known that they do not become drowsy or dizzy from Valium therapy. Abilities may be impaired on the day following use.
