Diazepam Tablets USP 10mg Taj Pharma

1.NAME OF THE MEDICINAL PRODUCT
a) Diazepam Tablets USP 2mg Taj Pharma
b) Diazepam Tablets USP 5mg Taj Pharma
c) Diazepam Tablets USP 10mg Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
a) Each tablet contains
Diazepam USP 2mg
Excipients          q.s.

b) Each tablet contains
Diazepam USP 5mg
Excipients           q.s.

c) Each tablet contains
Diazepam USP 10mg
Excipients            q.s.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM
Yellow uncoated tablets.
Yellow, circular, flat, bevelled-edge uncoated tablets

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Adults
1) The short-term relief (2-4 weeks) only, of anxiety which is severe, disabling, or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness.

2) Cerebral palsy.

3) Muscle spasm.

4) As an adjunct to certain types of epilepsy (eg myoclonus).

5) Symptomatic treatment of acute alcohol withdrawal.

6) As oral premedication for the nervous dental patient.

7) For premedication before surgery

Children

1) Control of tension and irritability in cerebral spasticity in selected cases

2) As an adjunct to the control of muscle spasm in tetanus

3) Oral premedication (see section 4.4)

4.2  Posology and method of administration
Posology
As an anxiolytic, the lowest effective dose should be employed; dosage regimes should not exceed beyond 4 weeks and treatment should be gradually withdrawn. Patients who have received benzodiazepines for a long time may require an extended withdrawal period. Long-term chronic use is not recommended.

Adults:
Anxiety states, obsessive-compulsive neuroses, and other psychiatric disorders: 5-30mg daily in divided doses.

Insomnia associated with anxiety: 5-15mg before retiring.

Cerebral palsy: 5-60mg daily in divided doses.

Upper motor neuronic spasticity: 5-60mg daily in divided doses.

Muscle spasm of varied aetiology, fibrositis, cervical spondylosis: 5-15mg daily in divided doses.

Adjunct to the management of some types of epilepsy: 2-60 mg daily in divided doses.

Alcohol withdrawal: 5-20mg, repeated if necessary in 2 to 4 hours.

Oral premedication in dental patients: 5mg the night before, 5mg on waking and 5mg two hours before the appointment.

Oral Premedication before surgery: 5mg-20mg.

Paediatric population:
Alternative presentations of diazepam are recommended for paediatric usage in order to obtain suitable doses of less than 5mg.

Spastic children with minimal brain damage: 5-40mg daily in divided doses.

Oral Premedication before surgery (see section 4.4): 2mg-10mg

Elderly and debilitated patients:
Doses should be half the above recommended doses.

Renal and hepatic impairment (see section 4.4):
The use of diazepam in hepatic impairment may precipitate coma, therefore the dose should be reduced or an alternative drug considered. In severe renal impairment the dose should be reduced.

Method of Administration
For oral administration.

4.3 Contraindications
Diazepam is contra-indicated for patients with:

• Hypersensitivity to the active substance, benzodiazepines or to any of the excipients listed in section 6.1.
• Phobic or obsessional states; chronic psychosis, hyperkinesis (paradoxical reactions may occur)
• Acute pulmonary insufficiency; respiratory depression, acute or chronic severe respiratory insufficiency (ventilatory failure may be exacerbated)
• Myasthenia gravis (condition may be exacerbated)
• Sleep apnoea (condition may be exacerbated)
• Severe hepatic insufficiency (elimination half-life of diazepam may be prolonged)
• Acute porphyria
• Diazepam should not be used as monotherapy in patients with depression or those with anxiety and depression as suicide may be precipitated in such patients.
• Planning a pregnancy (see section 4.6).
• Pregnancy (unless there are compelling reasons – see section 4.6).

4.4 Special Warnings and precautions for use

• The concomitant use of diazepam with alcohol and/or CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of diazepam possibly including severe sedation, clinically relevant respiratory and/or cardio-va
• scular depression (see section 4.5).
• Duration of Treatment – The duration of treatment should be as short as possible depending on the indication. The patient must be evaluated after a period of no more than 4 weeks and then regularly thereafter in order to assess the need for continued treatment, especially if the patient is free of symptoms. In general, treatment must not last any longer than 8-12 weeks, including the tapering off process. Extension beyond these periods should not take place without re-evaluation of the 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 patient should be aware of the possibility of rebound phenomena, thereby minimizing anxiety over such symptoms should they occur while diazepam is being discontinued. There are indications that, in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high.
• When benzodiazepines with a long duration of action are being used it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.
• Dependence and Withdrawal – Withdrawal symptoms occur with benzodiazepines following normal therapeutic doses given for short periods of time.

Use of diazepam may lead to the development of physical and psychic dependence. The risk of dependence increases with the dose and duration of treatment, and in patients with a history of alcoholism and drug abuse or in patients with marked personality disorders. Regular monitoring in such patients is essential, routine repeat prescriptions should be avoided and treatment should be withdrawn gradually.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms (see Section 4.8 Undesirable Effects). These may consist of headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.

Rebound insomnia and anxiety: a transient syndrome whereby the symptoms that led to treatment with diazepam may recur in an enhanced form on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.

As sudden discontinuation of benzodiazepines may result in convulsions, particular care should be taken in patients with epilepsy, other patients who have had a history of seizures or in alcohol or drug dependants.

• Tolerance – Limits of tolerance in patients with organic cerebral changes (particularly arteriosclerosis) or cardio-respiratory insufficiency may be very wide; care must be taken in adapting the dosage with such patients.

Some loss of efficacy to the hypnotic effects of diazepam may develop after repeated use for a few weeks.

• Alcohol should be avoided during treatment with diazepam (additive CNS depression).
• Amnesia – diazepam may induce anterograde amnesia. The condition occurs most often several hours after ingesting the product and therefore to reduce the risk patients should ensure that they will be able to have uninterrupted sleep of 7-8 hours. Anterograde amnesia may occur using therapeutic doses, the risk increases with higher doses.
• In cases of loss of bereavement, psychological adjustment may be inhibited by benzodiazepines.
• Diazepam should be used with caution in patients with a history of alcohol or drug abuse as these are patients predisposed to habituation and dependence.
• Hypo-albuminaemia may predispose patient to higher incidence of sedative side effects.
• Extreme caution should be used in prescribing diazepam to patients with personality disorders.
• Benzodiazepines should not be used in patients with severe hepatic insufficiency as they may precipitate encephalopathy. In patients with chronic hepatic disease dosage may need to be reduced.
• Cerebral sensitivity is increased in severe renal failure; therefore lower doses should be used (see section 4.2).
• Hypnotics should be avoided in the elderly who are at risk of becoming ataxic and confused and so liable to fall and injure themselves. If, based on clinical need, a decision to treat is nevertheless taken, treatment should be initiated a lower dose (see section 4.2).
• Caution should be exercised when using diazepam peri-operatively in children, as effects and timing of response may be unreliable and paradoxical effects may occur.
• Risk from concomitant use of opioids:

Concomitant use of Diazepam 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 Diazepam with opioids should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Diazepam 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).

Psychiatric and ‘paradoxical’ reactions

• Paradoxical reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. Should this occur, use of the drug should be discontinued. They are more likely to occur in children and the elderly.

Paediatric population
Benzodiazepines should not be given to children without careful assessment of the need to do so; the duration of treatment must be kept to a minimum. Safety and effectiveness of diazepam in paediatric patients below the age of 6 months have not been established.

• Elderly and debilitated patients should be given a reduced dose (see section 4.2). Due to the myorelaxant effect there is a risk of falls and consequently hip fractures in the elderly.
• A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.
• The usual precautions in treating patients with impaired renal function should be observed. In renal failure, the half-life of diazepam is not clinically significantly changed, and dose adjustment is usually not necessary.
• Benzodiazepines are not recommended for the primary treatment of psychotic illness.
• Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients).
• Potentially suicidal individuals should not have access to large amounts of diazepam due to the risk of overdosing.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction
Not recommended

Alcohol
Diazepam should not be used together with alcohol (CNS inhibition enhanced sedative effects: impaired ability to drive/ operate machinery).

Sodium oxybate
Avoid concomitant use (enhanced effects of sodium oxybate).

HIV-protease inhibitors
Avoid concomitant use (increased risk of prolonged sedation) – see below for zidovudine.

Take into account

Pharmacodynamic interactions
If diazepam is used with other centrally acting agents, careful consideration has to be given to the pharmacology of the agents employed, particularly with compounds that may potentiate or be potentiated by the action of diazepam, such as neuroleptics, anxiolytics/sedatives, hypnotics, antidepressants, anticonvulsants, sedating antihistamines, antipsychotics, anaesthetics for general anaesthesia and narcotic analgesics. Such concomitant use may increase sedative effects and cause depression of respiratory and cardiovascular functions. Concomitant use of narcotic analgesics may promote psychic dependency due to enhancement of euphorigenic effects.

Anti-epileptic drugs
Pharmacokinetic studies on potential interactions between diazepam and antiepileptic drugs have produced conflicting results. Both depression and elevation of drug levels, as well as no change, have been reported.

Phenobarbital taken concomitantly may result in an additive CNS effect. Increased risk of sedation and respiratory depression. Phenobarbital is a known inducer of CYP3A4 and increases hepatic metabolism of diazepam. Reduced effect of diazepam.

Special care should be taken in adjusting the dose in the initial stages of treatment.

Side effects may be more evident with hydantoins or barbiturates.

Diazepam has been reported to be displaced from protein-binding sites by sodium valproate (increased serum levels: increased risk of drowsiness).

Narcotic analgesics
Enhancement of the euphoria may lead to increased psychological dependence.

Other drugs enhancing the sedative effect of diazepam
Cisapride, lofexidine, nabilone, disulfiram and the muscle-relaxants – baclofen, Tizanidine, suxamethonium and tubocurarin.

Opioids:
The concomitant use of sedative medicines such as benzodiazepines or related drugs such as Diazepam 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).

Compounds that affect hepatic enzymes (particularly cytochrome P450):

• Inhibitors (eg cimetidine: isoniazid: erythromycin: omeprazole: esomeprazole) reduce clearance and may potentiate the action of benzodiazepines.

Itraconazloe, ketoconazole, and to a lesser extent fluconazole and voriconazole are potent inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma levels of benzodiapines. The effects of benzodiapines may be increased and prolonged by concomitant use. A dose reduction of the benzodiazepine may be required.

Rifamycins (rifampicin)
Rifampicin is a potent inducer of CYP3A4 and substantially increases the hepatic metabolism and clearance of diazepam. In a study with healthy subjects administered 600 mg or 1.2 g rifampicin daily for 7 days, the clearance of diazepam was increased by about fourfold. Co-administration with rifampicin gives rise to substantially decreased concentrations of diazepam. Reduced effect of diazepam. The concomitant use of rifampicin and diazepam should be avoided.

Antihypertensives, vasodilators& diuretics:
Enhanced hypotensive effect with ACEinhibitors, alpha-blockers, angiotensin–II receptor antagonists, calcium channel. blockers adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics. Enhanced sedative effect with alpha-blockers or moxonidine.

Dopaminergics
Possible antagonism of the effect of levodopa.

Antacids
Concurrent use may delay absorption of diazepam

Antiviral agents (atazanavir, ritonavir, delavirdine, efavirenz, indinavir, nelfinavir, saquinavir)
Antiviral agents may inhibit the CYP3A4 metabolic pathway for diazepam. Increased risk of sedation and respiratory depression. Therefore, concomitant use should be avoided.Zidivudine

Increased zidovudine clearance by diazepam.

Oral contraceptives
Inhibition of oxidative metabolism of diazepam. Increased effects of diazepam.

Co-administration of diazepam and combined oral contraceptives has been known to cause breakthrough bleeding. The mechanism of this reaction is unknown. Breakthrough bleeding, but no contraceptive failures have been reported.Theophylline

A proposed mechanism is competitive binding of theophylline to adenosine receptors in the brain. Counteraction of the pharmacodynamic effects of diazepam, e.g. reduction of sedation and psychomotor effects.

Caffeine
Concurrent use may result in reduced sedative and anxiolytic effects of diazepam.

Grapefruit juice
Inhibition of CYP3A4 may increase the plasma concentration of diazepam (possible increased sedation and amnesia). C_max is increased by 1.5 times and AUC by 3.2 times. Possible increased effect of diazepam.

This interaction may have little significance in healthy individuals, but it is not clear is if other factors such as old age or liver cirrhosis increase the risk of adverse effects with concurrent use.

Clozapine
Mechanism: Pharmacodynamic synergism.

Effect: Severe hypotension, respiratory depression, unconsciousness and potentially fatal respiratory and/or cardiac arrest. Therefore, concomitant use is not recommended and should be avoided.

Pharmacokinetic interactions
Diazepam is mainly metabolised to the pharmacologically active metabolites N-desmethyldiazepam, temazepam and oxazepam. The oxidative metabolism of diazepam is mediated by CYP3A4 and CYP2C19 isoenzymes. Oxazepam and temazepam are further conjugated to glucuronic acid. Inhibitors of CYP3A4 and/or CYP2C19 can give rise to increased concentrations of diazepam while enzyme inducing drugs such as rifampicin, hypericum perforatum and certain antiepileptics can result in substantially decreased plasma concentrations of diazepam.

Carbamazepine
Carbamazepine is a known inducer of CYP3A4 and increases hepatic metabolism of diazepam. This can result in up to three-fold greater plasma clearance and a shorter half-life of diazepam. Reduced effect of diazepam.

Phenytoin
Phenytoin is a known inducer of CYP3A4 and increases hepatic metabolism of diazepam. Reduced effect of diazepam.

The metabolism of phenytoin may be increased or decreased or remain unaltered by diazepam in an unpredictable way. Increased or decreased serum concentration of phenytoin. Phenytoin concentrations should be monitered more closely when diazepam is added or discontinued.

Azoles (fluconazole, itraconazole, ketoconazole, voriconazole)
Increased plasma concentration of benzodiazepines, due to inhibition of the CYP3A4 and/or CYP2C19 metabolic pathway.

Fluconazole: Co-administration with 400 mg fluconazole on the first day and 200 mg on the second day increased the AUC of a single 5 mg oral dose of diazepam 2.5-fold and prolonged the half-life from 31 hours to 73 hours.

Voriconazole: A study with healthy subjects found that 400 mg voriconazole twice daily on the first day and 200 mg twice daily on the second day increased the AUC of a single 5 mg oral dose of diazepam 2.2-fold and prolonged the half-life from 31 hours to 61 hours.

Increased risk of undesired effects and toxicity of benzodiazepine. Concomitant use should be avoided or the dose of diazepam reduced.

Fluvoxamine
Fluvoxamine inhibits both CYP3A4 and CYP2C19 which leads to inhibition of the oxidative metabolism of diazepam. Co-administration with fluvoxamine results in an increased half-life and an approximately 190% increased plasma concentrations (AUC) of diazepam. Drowsiness, reduced psychomotor performance and memory. Preferably, benzodiazepines that are metabolised via a non-oxidative pathway should be used instead.

Corticosteroids
Chronic use of corticosteroids may cause increased metabolism of diazepam due to induction of cytochrome P450 isoenzyme CYP3A4, or of enzymes responsible for glucuronidation. Reduced effects of diazepam.

Cimetidine
Cimetidine inhibits the hepatic metabolism of diazepam, reducing its clearance and prolonging its half-life. In one stude where 300 mg cimetidine was administered four times daily for 2 weeks, the combined plasma level of diazepam and its active metabolite, desmethyldiazepam,was found to be increased by 57%, but reaction times and other motor and intellectual tests remained unaffected. Increased action of diazepam and increased risk of drowsiness. Reduction of the diazepam dose may be necessary.

Omeprazole
Omeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Omeprazole prolongs the elimination half-life of diazepam and increases the plasma concentrations (AUC) of diazepam approximately between 30% – 120%. The effect is seen in CYP2C19 extensive metabolisers but not in slow metabolisers, with a low clearance of diazepam. Increased action of diazepam. Reduction of the diazepam dose may be necessary.

Esomeprazole
Esomeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Co-administration with ezomeprazole results in an extended half-life and an increase in plasma concentrations (AUC) of diazepam by approximately 80%. Increased effect of diazepam. Reduction of the diazepam dose may be necessary.

Isoniazid
Isoniazid inhibits the CYP2C19 and CYP3A4 metabolic pathway for diazepam. Co-administration with 90 mg isoniazid twice daily for 3 days resulted in a a prolonged elimination half-life of diazepam and in a 35% increased plasma concentration (AUC) of diazepam. Increased effect of diazepam.

Itraconazole
Increased plasma concentration of diazepam due to inhibition of the CYP3A4 metabolic pathway. In a study with healthy subject given 200 mg itraconazole daily for 4 days increased the AUC of a single 5 mg oral dose of diazepam by about 15%, but there was no clinically significant interaction as determined by psychomotor performance tests. Possible increased effect of diazepam.

Fluoxetine
Fluoxetine inhibits the metabolism of diazepam via CYP2C19 and other pathways, resulting in elevated plasma concentrations and decreased clearance of diazepam. Increased effect of diazepam. Concomitant use should be monitered closely.

Disulfiram
Reduced metabolism of diazepam leading to prolonged half-life and increased plasma concentration of diazepam. The elimination of the N-desmethyl metabolites of diazepam is slowed down which can give rise to marked sedative effects. Increased risk of CNS inhibition such as sedation.

Cisapride
Accelerated absorption of diazepam. Temporary increase of the sedative effects of orally administered diazepam.

Levodopa
Concomitant use with diazepam resulted in reduced effects of levodopa in a small number of case reports.

Ketamine
Due to similar oxidative processes, diazepam competitively inhibits ketamin metabolism. Pre-medication with diazepam leads to prolonged half-life of ketamine with enhanced effect as a result. Increased sedation.

4.6 Fertility, Pregnancy and lactation
The safety of diazepam in human pregnancy has not been established. It should not be used in the first and third trimesters. There may be a small increase in the risk of congenital malformation, particularly oral cleft with the use of benzodiazepines in the first trimester but a causal relationship has not been established.

If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects that she is pregnant.

Pregnancy
If, for compelling medical reasons, the product is administered during the late phase of pregnancy, or during labour at high doses, effects on the neonate, such as hypothermia, hypotonia (“Floppy Infant Syndrome”), irregularities in the heart rate, poor suckling and moderate respiratory depression, can be expected, due to the pharmacological action of the compound.

Moreover, infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.

Studies in animals have shown reproductive toxicity (see section 5.3).

Breast-feeding
Benzodiazepines are found in the breast milk. Reports have demonstrated milk: plasma concentration ratios to vary between 0.2 and 2.7. There is therefore a risk of accumulation in the breastfeeding child. Benzodiazepines should not be given to breast feeding mothers.

Fertility
Studies in animals have shown a decrease in pregnancy rate and reduced number of surviving offspring in rats at high doses. There are no human data.

4.7 Effects on ability to drive and use machines
Sedation, amnesia and impaired muscular function may adversely effect the ability to drive or use machines. If insufficient sleep occurs, the likelihood of impaired alertness may be increased (see also Interactions).

Impaired function and sedation may occur the following morning and for several days after.

Patients should be warned that effects on the central nervous system may persist into the day after administration even after a single dose.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However, you would not be committing an offence (called ‘statutory defence’) if:

– The medicine has been prescribed to treat a medical or dental problem and

– You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

– It was not affecting your ability to drive safely

4.8 Undesirable Effects
Drowsiness, numbed emotions, reduced alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia or double vision predominantly occur at the start of therapy but usually disappear with repeated administration. Among elderly patients there may be confusion conditions at high dose levels. There is an increased risk of falls and associated fractures in elderly patients using benzodiazepines.

Increased salivary and bronchial secretion has been reported, in particular in children.

Amnesia
Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour (see section 4.4).

Dependence
Chronic use (even at therapeutic doses) may lead to the development of physical and psychic dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena (see section 4.4). Abuse of benzodiazepines has been reported.

The frequencies of adverse events are ranked according to the following:

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)

Not known (cannot be estimated from the available data).

^a Known to occur when using benzodiazepines or benzodiazepine-like agents. These reactions may be quite severe. They are more likely to occur in children and the elderly. Diazepam should be discontinued if such symptoms occur (see section 4.4).

^b Pre-existing depression may be unmasked during benzodiazepine use.

^c May occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour (see section 4.4).

^d The likelihood and degree of severity of withdrawal symptoms is dependent on the duration of treatment, dose level and degree of dependency.

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.

 4.9 Overdose
Features
The symptoms of diazepam overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, bradycardia, nystagmus) or paradoxical excitation. In most cases only observation of vital functions is required.

Extreme overdosage may lead to coma, areflexia, cardio-respiratory depression and apnoea, requiring appropriate countermeasures (ventilation, cardiovascular support). Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease. Severe effects in overdose also include rhabdomyolysis and hypothermia.

Management
Maintain a clear airway and adequate ventilation.

Consider activated charcoal (50g for an adult, 1g/kg for a child) in adults who have taken more than 100mg or children who have taken more than 1mg/kg within one hour, provided they are not too drowsy.

Monitoring level of consciousness, respiratory rate, pulse oximetry and blood pressure in symptomatic patients.

Consider arterial blood gas analysis in patients who have a reduced level of consciousness (GCS < 8; AVPU scale P or U) or have reduced oxygen saturations on pulse oximetry.

Correct hypotension by raising the foot of the bed and by giving an appropriate fluid challenge. Where hypotension is thought mainly due to decreased systemic vascular resistance, drugs with alpha-adrenergic activity such as noradrenaline or high dose dopamine (10-30 micrograms/kg/min) may be beneficial. The dose of inotrope should be titrated against blood pressure.

If severe hypotension persists despite the above measures, then central venous pressure monitoring should be considered.

Supportive measures are indicated depending on the patient’s clinical state.

Benzodiazepines are not significantly removed from the body by dialysis.

Flumazenil, a benzodiazepine antagonist, is not advised as a routine diagnostic test in patients with reduced conscious level. It may sometimes be used as an alternative to ventilation in children who are naive to benzodiazepines, or in patients with COPD to avoid the need for ventilation. It is not necessary or appropriate in cases of poisoning to fully reverse the benzodiazepine effect. Flumazenil has a short half-life (about an hour) and in this situation an infusion may therefore be required. Flumazenil is contraindicated when patients have ingested multiple medicines, especially after co-ingestion of a benzodiazepine and a tricyclic antidepressant or any other drug that causes seizures. This is because the benzodiazepine may be suppressing seizures induced by the second drug; its antagonism by flumazenil can reveal severe status epilepticus that is very difficult to control.

Contraindications to the use of flumazenil include features suggestive of a tricyclic antidepressant ingestion including a wide QRS, or large pupils. Use in patients post-cardiac arrest is also contraindicated.

It should be used with caution in patients with a history of seizures, head injury, or chronic benzodiazepine use.

Occasionally a respirator may be required but generally few problems are encountered, although behavioural changes are likely in children.

If excitation occurs, barbiturates should not be used.

Effects of overdose are more severe when taken with centrally-acting drugs, especially alcohol, and in the absence of supportive measures, may prove fatal.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Benzodiazepine derivatives

Diazepam is a benzodiazepine tranquilliser with anticonvulsant, sedative, muscle relaxant and amnesic properties.

Benzodiazepines, such as diazepam, bind to receptors in various regions of the brain and spinal cord. This binding increases the inhibitory effects of gamma-aminobutyric acid (GABA). GABAs functions include CNS involvement in sleep induction. Also involved in the control of hypnosis, memory, anxiety, epilepsy and neuronal excitability.

5.2 Pharmacokinetic properties
Absorption
Diazepam is readily and completely absorbed from the GI tract. Peak plasma concentrations occurring within about 30-90 minutes of oral administration, a steady plasma concentration is reached after 5-6 days and is directly related to dose.

Disribution
Diazepam crosses the blood-brain barrier and is highly lipid soluble, this causes the initial effects to decrease rapidly as it is redistributed into fat deposits and tissues Diazepam is very extensively bound to plasma proteins (98-99%). Diazepam and its metabolites also enters breast milk and crosses the placenta freely, this may lead to accumulation in the infant or foetus.

Biotransformation
Diazepam is extensively metabolised in the liver and, in addition to desmethyldiazepam, its active metabolites include oxazepam and temazepam. Diazepam has a biphasic half-life with an initial rapid distribution phase followed by a prolonged terminal elimination phase of 1 or 2 days; its action is further prolonged by the even longer half-life of 2-5 days of its principle active metabolite, desmethyldiazepam (nordiazepam), the relative proportion of which increases in the body on long-term administration. The plasma half-life of diazepam is prolonged in neonates, in the elderly, and in patients with kidney or liver disease.

Elimination
It is excreted in the urine, mainly in the form of its metabolites, either free or in conjugated form.

5.3 Preclinical safety data
Not applicable.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Also contains: lactose, magnesium stearate, maize starch, stearic acid, E104.

6.2 Incompatibilities
None known

6.3  Shelf life
Shelf-life
Three years from the date of manufacture.
Shelf-life after dilution/reconstitution
Not applicable.
Shelf-life after first opening
Not applicable.

6.4 Special precautions for storage
Do not store above 25°C.

6.5 Nature and contents of container
The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps.

The product may also be supplied in blister packs in cartons:
a) Carton: Printed carton manufactured from white folding box board.
b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-6g/M²PVC and PVdC compatible heat seal lacquer on the reverse side.

The product may be contained in blister packs which enhances security of the pack increasing resistance to deliberate contamination, pilfering, etc.

Pack size: 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 168, 180, 250, 500, 1000.

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 50,000.

6.6 Special precautions for disposal and other handling
Not applicable.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Diazepam Tablets USP 10mg Taj Pharma

Package leaflet: Information for the patient

a) Diazepam Tablets USP 2mg Taj Pharma
b) Diazepam Tablets USP 5mg Taj Pharma
c) Diazepam Tablets USP 10mg Taj Pharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
 – If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

What is in this leaflet
1. What  Diazepam tablets is and what it is used for
2. Before you are given Diazepam tablets
3. How you will be given  Diazepam tablets
4. Possible side effects
5. How Diazepam tablets is stored
6. Further Information

1. What Diazepam tablets is and what it is used for
Diazepam belongs to a group of medicines called benzodiazepines. Diazepam helps in the treatment of anxiety, muscle spasms and convulsions (fits).

Diazepam tablets are used to treat a number of conditions, including:
In adults
• short term relief (2-4 weeks only) of severe anxiety, which is an emotional state where you may sweat, tremble, feel anxious and have a fast heart beat and may occur alone or with insomnia (trouble sleeping) or mental health problems
• helping muscles relax and for muscle spasm and cerebral palsy (a condition affecting the brain which causes movement problems and rigidity or stiffness)
• epilepsy (when taken with other medicines)
• patients with the symptoms of alcohol withdrawal
• helping to relax nervous dental patients.

In children
• helping to treat tension and irritability caused by cerebral spasticity (a condition associated with a disease or trauma affecting the brain or spinal cord which causes weakness, un-coordinated movements, rigidity and stiffness)
• helping to treat muscle spasm caused by tetanus (when taken with other medicines).

Both adults and children can take Diazepam tablets before an operation to help with relaxation and to cause sleepiness.

This medicine should be used for as short a time as possible and should not be used for more than four weeks. If used for too long without a break, there is a risk of becoming dependent or of having problems when you stop taking it.

When taking this medicine there is a risk of dependence (a need to keep taking the medicine). The risk increases with the dose and length of treatment period. The risk is greater if you have ever had a history of alcohol or drug abuse.

2. Before you are given Diazepam tablets
Do not take Diazepam tablets and tell your doctor if you
• are allergic (hypersensitive) to diazepam or to other benzodiazepine medicines or to any of the other ingredients in your tablets (see section 6)
• breathing problems, which may be severe, including slow and/or shallow breathing
• suffer from depression (with or without anxiety) or hyperactivity
• have a phobia (a fear of a particular object or situation) or other mental illness
• have myasthenia gravis (a condition which causes muscles to weaken and tire easily)
• suffer from sleep apnoea (a sleep disorder where you have abnormal pauses in breathing during sleep)
• have severe liver disorders
• have porphyria (an inherited condition causing skin blisters, abdominal pain and brain or nervous system disorders)
• planning a pregnancy or are pregnant (see below Pregnancy and breast-feeding).

Warnings and precautions
Talk to your doctor or pharmacist before taking Diazepam tablets if you
• have a history of alcoholism or drug abuse
• have problems with your heart and lungs or have severe kidney failure
• have someone close to you that has recently died
• have low blood levels of a protein called albumin
• have a personality disorder
• have a poor blood supply to the brain (arteriosclerosis)
• are elderly. Diazepam tablets can cause confusion and have effects on muscles causing falls and injuries.
• have breathing difficulties
• smoke
• suffer from depression
• have suicidal thoughts
• have epilepsy or a history of seizures

Other considerations
• Mental side effects – contact your doctor if you experience side effects such as agitation, hyperactivity, restlessness, aggressiveness, nightmares or hallucinations. These side effects are more likely to occur in children or the elderly.
• Amnesia (Total or partial memory loss) – you could experience amnesia when taking this medicine. Amnesia is more likely to occur when taking high doses of diazepam.
• Dependence – when taking this medicine there is a risk of dependence, which increases with the dose and duration of treatment and also in patients with a history of alcoholism and drug abuse. Therefore, you should take Diazepam tablets for as short a period of time as possible.
• Tolerance – if after a few weeks you notice that the tablets are not working as well as they did when first starting treatment, you should speak to your doctor.
• Withdrawal – treatment should be gradually withdrawn. Withdrawal symptoms occur with Diazepam tablets even when normal doses are given for short periods of time. See Section 3, ‘If you stop taking Diazepam tablets.’

Other medicines and Diazepam tablets
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Especially:
• sodium oxybate (used to prevent episodes of sudden onset of sleep (narcolepsy) with muscle weakness)
• antidepressants (e.g. fluvoxamine, fluoxetine)
• antipsychotics such as clozapine (to treat mental problems)
• antihistamines (to treat allergies)
• general anaesthetics
• sedatives (used to give calming effects)
• hypnotics (to help you sleep)
• erythromycin (an antibiotic)
• muscle relaxants (e.g. suxamethonium, tubocurarin)
• some strong pain killers such as morphine (opioids) may give you a heightened sense of well being when taken with diazepam, which can increase your desire to continue taking these medicines (dependency) or can make you very sleepy.
• barbiturates such as phenobarbital (to treat epilepsy and mental disorders)
• medicines to lower high blood pressure, diuretics (water tablets), nitrates (for heart conditions) as these could lower your blood pressure too much.
• antacids (reduces stomach acid) may slow down absorption of diazepam in the body.

Taking these medicines with diazepam could affect your mental status, make you very sleepy and suppress your breathing and blood pressure.
• disulfiram (to treat alcohol addiction). Taking this medicine with diazepam could make you very sleepy and can cause diazepam to be removed from the body more slowly than usual.
• medicines for epilepsy e.g. phenobarbital, phenytoin and carbamazepine, sodium valproate, (diazepam can affect the blood levels of these medicines). Diazepam can furthermore affect how phenytoin works.
• theophylline (to treat asthma and other breathing disorders), as it can weaken the effect of diazepam. As this can cause diazepam to be removed from the body more quickly than usual.
• cimetidine, omeprazole or esomeprazole (stomach acid reducing medicines), as these can cause diazepam to be removed from the body more slowly than usual.
• rifampicin, to treat infections (an antibiotic) as this can cause diazepam to be removed from the body more quickly than usual. The effect of diazepam can be weakened.
• hypericum perforatum (Perforate St John’s wort, a herbal remedy)
• amrenavir, atazanavir,ritonavir, delavirdine, efavirenz, indinavir, nelfinavir, zidovudine or saquinavir (antivirals), fluconazole, itraconazole, ketoconazole or voriconazole (anti-fungal medicines) as these can cause diazepam to be removed from the body more slowly than usual and therefore increase the risk of side effects. As these can make you feel sleepy for longer or cause difficulty breathing.
• isoniazid (used to treat tuberculosis), as it can cause diazepam to be removed from the body more slowly than usual.
• oral contraceptives, as they can slow down the removal of diazepam from the body and increase its effect. Breakthrough bleeding can occur when taking diazepam and oral contraceptives together, but the contraceptive protection is not reduced.
• cisapride (used to treat stomach problems), as it can cause diazepam to be removed from the body more slowly than usual.
• corticosteroids (medicines used to treat inflammation in the body) as they can weaken the effect of diazepam.
• levodopa (used to treat Parkinson’s disease). Diazepam can reduct the effect of levodopa.
• valproic acid (used to treat epilepsy and mental disorders) as it can slow down the removal of diazepam from the body and increase its effect.
• ketamine (an anaesthetic) as diazepam increases the effect of ketamine.
• lofexidine (to help relieve symptoms when you stop taking opioids)
• nabilone (to treat nausea and vomiting)
• alpha blockers, beta blockers or moxonidine (to lower high blood pressure)

Concomitant use of Diazepam tablets and opioids (strong pain killers, medicines for substitution therapy and some cough medicines) increases the risk of drowsiness, difficulties in breathing (respiratory depression), coma and may be lifethreatening. Because of this, concomitant use should only be considered when other treatment options are not possible. However if your doctor does prescribe Diazepam tablets together with opioids the dose and duration of concomitant treatment should be limited by your doctor. Please tell your doctor about all opioid medicines you are taking, and follow your doctor’s dose recommendation closely. It could be helpful to inform friends or relatives to be aware of the signs and symptoms stated above. Contact your doctor when experiencing such symptoms.

Diazepam tablets with food and drink
Do not drink alcohol while you are taking Diazepam tablets. Alcohol may increase the sedative effects of Diazepam tablets and make you very sleepy.
Grapefruit juice may increase the amount of diazepam in your blood. If you are elderly, suffer from cirrhosis or any of the conditions listed in section 2, this could possibly increase the sedative effects of Diazepam tablets and you should speak to your doctor or pharmacist.
Drinks containing caffeine may reduce the effects of diazepam.

Pregnancy, breast-feeding and fertility
Do not take Diazepam tablets if you are pregnant, might become pregnant or breastfeeding. If you and your doctor decide that you should take this medicine towards the end of your pregnancy (or during labour) this may harm your baby. The baby may have a low temperature, be listless, have breathing problems or difficulty in feeding. Also, if you take this medicine regularly during your pregnancy your baby may get withdrawal symptoms. If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines
Diazepam tablets can make you sleepy, forgetful, have poor co-ordination along with other side effects that can affect everyday activities (see Possible side effects). You should not drive, operate machinery or take part in such activities where, if affected, you could put yourself or others at risk.

The medicine can affect your ability to drive as it may make you sleepy or dizzy.
• Do not drive while taking this medicine until you know how it affects you.
• It is an offence to drive if this medicine affects your ability to drive.
• However, you would not be committing an offence if:
– The medicine has been prescribed to treat a medical or dental problem and
– You have taken it according to the instructions given by the prescriber or in the information provided with the medicine and
– It was not affecting your ability to drive safely
Talk to your doctor or pharmacist if you are not sure whether it is safe for you to drive while taking this medicine.

Diazepam tablets contain lactose
Diazepam tablets contain lactose (a type of sugar). If you have been told that you have intolerance to some sugars contact your doctor before taking this medicine.

3. How you will be given Diazepam tablets
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.
You should not take Diazepam tablets for longer than 4 weeks.

Swallow the tablets whole, with a glass of water.

The recommended dose is:
Adults
• Anxiety or mental health problems: 5mg30mg each day, in divided doses.
• To help you sleep: 5mg-15mg at bedtime.
• To help cerebral palsy or other spasticities: 5mg-60mg each day, in divided doses.
• To help control muscle spasm: 5mg-15mg each day, in divided doses.
• To help epilepsy: 2mg-60mg each day, in divided doses.
• To help with alcohol withdrawal symptoms: 5mg-20mg, which may be repeated after 2 to 4 hours if necessary.
• Before dental treatment: 5mg the night before treatment, 5mg on waking and 5mg two hours before the appointment.
• Before an operation: 5mg-20mg

Use in children
For tension and irritability in cerebral spasticity: 5mg-40mg each day, in divided doses.
If your doctor has given your child Diazepam tablets to take before an operation, the usual dose is 2mg-10mg.

Elderly or Frail
If you are elderly or frail you are likely to be more sensitive to the effects of Diazepam tablets, such as confusion, and your doctor will give you much lower doses. The dose should not be more than half the adult dose.

Kidney or liver impairment
If you have liver or kidney problems you may also be given a lower dose.

If you take more Diazepam tablets than you should
If you (or someone else) swallow a lot of tablets at the same time, or you think a child may have swallowed any, contact your nearest hospital casualty department or tell your doctor immediately. Signs of an overdose include clumsiness and loss of coordination, feeling sleepy or deep sleep, speech problems, irregular or slow heartbeat, uncontrolled eye movement, muscle weakness or excitement. An extreme overdose may lead to coma (unrousable unconsciousness), reflex problems and breathing difficulties.

If you forget to take Diazepam tablets
Do not take a double dose to make up for a forgotten dose. If you forget to take a dose, take it as soon as you remember it and then take the next dose at the right time.

Stopping Diazepam tablets and Withdrawal Effects
This medicine should not be stopped suddenly; keep taking it until your doctor tells you how to reduce the dose slowly. If you stop taking the tablets suddenly you may experience the following withdrawal effects:
• depression,
• nervousness,
• difficulty in sleeping,
• irritability,
• sweating,
• upset stomach/diarrhoea,

• or the symptoms you are being treated for can come back worse than before.
  You may also experience mood changes, anxiety, restlessness and changes in sleep patterns. These effects may occur even after taking low doses for a short period of time. If you stop taking these tablets suddenly after being treated with high doses of Diazepam tablets, you may experience confusion, hallucinations, shaking, faster heartbeat or fits. Withdrawal may also cause unusual behaviour including aggressive outbursts, excitement or depression with suicidal thoughts or actions.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Side Effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor if you notice any of the following side effects or notice any other effects not listed:

Some side effects can be serious and may require immediate medical treatment:

Uncommon (may affect up to 1 to 100 people)
• Respiratory depression (very slow and/or shallow breathing)

Rare (may affect up to 1 in 1,000 people)
• Respiratory arrest (cessation of breathing)
• Unconsciousness
• Jaundice (yellowing of your skin or the white of your eyes)

Very rare (may affect up to 1 in 10,000 people)
• Anaphylaxis (severe allergic reaction) with symptoms such as sudden wheezing, swelling of your lips, tongue and throat or body, rash, fainting or difficulties to swallow

Other side effects:

Very common (may affect more than 1 in 10 people)
• Drowsiness

Common (may affect up to 1 in 10 people) • Fatigue
• Withdrawal symptoms (for possible symptoms please see ‘If you stop taking Diazepam tablets’ in Section 3)
• Confusion
• Loss of coordination of muscle movements (ataxia) and other movement disorders, tremor

Uncommon (may affect up to 1 in 100 people)
• Muscle weakness
• Memory loss
• Difficulty in concentrating
• Balance disorders
• Dizziness
• Headache
• Slurred speech
• Stomach and intestinal problems such as nausea, vomiting, constipation, diarrhoea
• Increased salivation
• Allergic skin reactions in the form of itching, skin redness and swelling and skin rash.

Rare (may affect up to 1 in 1,000 people)
• Mental side effects such as excitation, agitation, restlessness, irritability, aggressiveness, memory loss, inappropriate behaviour, delusion, rages, psychoses, nightmares or hallucinations. May be or become serious. These side effects are more likely to occur in children or the elderly. Talk to your doctor.
• Decreased alertness
• Depression
• Emotional withdrawal
• Insomnia (problems sleeping)
• Heart problems such as slow heartbeat (bradycardia), heart failure and cessation of heartbeat (cardiac arrest).
• Low blood pressure, fainting (syncope)
Increased mucus in the lungs
• Dry mouth
• Increased appetite
• Changes in certain liver enzymes as seen in blood tests
• Lack of ability to urinate, loss of bladder control (leakage of urine)
• Breast enlargment in men
• Impotence, changes in sexual drive (libido)
• Blood disorders (you may develop sore throats, nose bleeds or infections)

Very rare (may affect up to 1 in 10,000 people)
• Low levels of white blood cells (leukopenia)
• Higher level of a certain enzyme in the blood (transaminase)

Not known (frequency cannot be estimated from the available data)
• Blurred vision, double vision and involuntary eye movements (these side effects disappear after you have stopped taking diazepam) Withdrawal symptoms: see Section 3, ‘If you stop taking Diazepam tablets.’ If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

5. How Diazepam tablets is stored
Keep this medicine out of the sight and reach of children.
Do not store above 25°C.
Do not use this medicine after the expiry date which is stated on the label/carton/bottle.
The expiry date refers to the last day of that month.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

6. Further information

What Diazepam tablets contains
• The active substance (the ingredient that makes the tablet work) is diazepam.
a) Each tablet contains: Diazepam USP 2mg
b) Each tablet contains: Diazepam USP 5mg
c) Each tablet contains: Diazepam USP 10mg
The other ingredients are lactose, magnesium stearate, maize starch and stearic acid.
• The 5mg tablets also contain quinoline yellow (E104).
• The 10mg tablets also contain HT Lake (E132).

What Diazepam tablets looks like and contents of the pack
Diazepam tablets are uncoated tablets in the following colours: 2mg-white, 5mg-yellow, 10mg-blue.
Pack size: 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 168, 180, 250, 500, 1000.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com