Diazepam Injection BP (hameln)

1. Name Of The Medicinal Product

Diazepam Injection BP.

2. Qualitative And Quantitative Composition

Each ml contains 5 mg of Diazepam.

3. Pharmaceutical Form

Sterile injection.

4. Clinical Particulars

4.1 Therapeutic Indications

Diazepam is an anxiolytic, anticonvulsant and central muscle-relaxant. Diazepam is used to relieve anxiety and provide sedation in severe acute anxiety or agitation and for the management of agitation associated with delirium tremens.

Diazepam is used to relieve acute muscle spasm and tetanus.

Acute convulsions including status epilepticus, also convulsions due to poisoning and febrile convulsions. As an adjunct during endoscopy, in dentistry, surgery, radiology. Cardiac catheterisation, cardioversion, used pre-operatively to relieve anxiety, provide sedation, light anaesthesia and anterograde amnesia.

4.2 Posology And Method Of Administration

Diazepam Injection BP may be given IV, IM or by IV infusion.

Adults:

Severe acute anxiety or agitation:

10 mg IV or IM injection

which may be repeated after an interval of not less than 4 hours.

Delirium Tremens:

10 – 20 mg IV or IM.

Higher doses may be needed depending on severity of symptoms.

Acute Muscle Spasm:

10 mg IV or IM injection

which may be repeated after an interval of not less than 4 hours.

Tetanus:

Initially an IV dose of 0.1 - 0.3 mg/kg body weight, repeated at intervals of 1 - 4 hours. Continuous IV infusion of 3 – 10 mg/kg body weight per 24 hours can also be used. The chosen dose should be related to the severity of the case and in extremely severe cases higher doses have been used.

Status epilepticus, convulsions due to poisoning:

10 – 20 mg IV or IM, repeated if necessary 30 - 60 minutes later.

If indicated, this may be followed by slow intravenous infusion (maximum dose 3 mg/kg body weight over 24 hours).

Pre-operative medication or premedication:

0.2 mg/kg body weight. The usual adult dose is 10 – 20 mg but higher doses may be necessary according to the clinical response.

Elderly or Debilitated Patients:

Doses should not exceed half those normally recommended.

Children:

Status epilepticus, convulsions due to poisoning, febrile convulsions:

0.2 - 0.3 mg/kg body weight IV (or IM) or 1 mg per year of life.

Tetanus:

As for adults.

Pre-operative medication or premedication:

0.2 mg/kg body weight. The injection should be given slowly (0.5 ml per minute). Diazepam injection should be given into a large vein of the antecubital fossa, the patient in a supine position throughout the procedure to reduce the possibility of hypotension or apnoea occurring.

4.3 Contraindications

• Known hypersensitivity to diazepam, other benzodiazepines or propylene glycol.

• Acute pulmonary insufficiency or respiratory depression.

• Sleep apnoea syndrome.

• Marked neuromuscular respiratory weakness including unstable myasthenia gravis.

• Severe hepatic impairment.

Diazepam Injection should not be used for the primary treatment of chronic psychosis. It should not be used alone in the treatment of depression or anxiety associated with depression due to the risk of precipitation of suicide in this patient group.

4.4 Special Warnings And Precautions For Use

Except in emergencies, a second person should always be present during the intravenous use of diazepam and facilities for resuscitation should always be available. Patients should ideally remain under medical supervision until at least one hour has elapsed from the time of injection. They should always be accompanied home by a responsible adult, with a warning not to drive or operate machinery for 24 hours.

The IM use of diazepam injection can lead to a rise in serum creatinine phosphokinase activity, with a maximum level occurring between 12 and 24 hours after injection. This fact should be taken into account in the differential diagnosis of myocardial infarction.

The absorption from IM injection of diazepam may be variable, particularly for the gluteal muscles. This route of administration should only be used if IV administration is not possible.

Diazepam Injection BP contains propylene glycol. There have been rare reports of propylene glycol toxicity (e.g. increased anion gap, metabolic acidosis, hyperosmolality, renal impairment) with the potential for organ system failure and circulatory shock, in patients treated with continuous infusions of diazepam. Central nervous system toxicity, including seizures, as well as unresponsiveness, tachypnoea, tachycardia and diaphoresis have also been associated with propylene glycol toxicity. Symptoms may be more likely to develop in patients with renal or hepatic impairment and in paediatric patients.

The elderly, and patients with impaired renal and/or hepatic function may be particularly susceptible to the adverse effects of diazepam listed. Dose reduction may be required.

Extreme care must be taken when administering diazepam injection to very ill patients and to those with limited pulmonary reserve, because of the possibility of respiratory depression or apnoea.

Use with caution in patients with myasthenia gravis, porphyria, known history of drug or alcohol abuse, or organic brain changes, particularly arteriosclerosis. Diazepam injection should be administered with caution to patients in whom a drop in blood pressure might lead to cardiovascular or cerebrovascular complications.

The dependence potential of diazepam increases with dose and duration of treatment and is greater in patients with a history of alcohol or drug abuse. Withdrawal symptoms may occur with benzodiazepines following normal use of therapeutic doses for only short periods and may be associated with physiological and psychological sequelae (see section 4.8 Withdrawal effects). The potential for withdrawal symptoms should be considered when treating patients for more than a few days; abrupt discontinuation should be avoided and the dose reduced gradually.

Abuse of diazepam has been reported.

Diazepam may induce anterograde amnesia. This occurs most often several hours after administration. In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.

Paradoxical reactions and disinhibition have been occasionally reported during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued (see Undesirable Effects). Extreme caution should be used in prescribing diazepam for patients with personality disorders. Suicide may be precipitated in patients who are depressed, as may aggressive behaviour towards self and others.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Particular attention should be paid to the potential effects of drug interactions with diazepam in the elderly.

CNS depressants:

Enhanced sedation, or respiratory or cardiovascular depression may occur when diazepam is administered concomitantly with other CNS depressants including other anticonvulsants, anxiolytics/hypnotics, sedative antihistamines, alcohol, neuroleptics, antidepressants, analgesics and anaesthetics.

Anticonvulsants:

Diazepam may increase or decrease plasma concentrations of phenytoin. Patients should be monitored for signs of increased phenytoin toxicity. Phenytoin and carbamazepine may reduce plasma levels of diazepam. Increased sedation or respiratory depression may occur with concurrent use of barbiturates. Concomitant sodium valproate may increase plasma levels of diazepam, with associated sedation.

Antidepressants:

The plasma levels of some benzodiazepines are increased by fluvoxamine. Concurrent use of selective serotonin receptor antagonists or tricyclic antidepressants may reduce attention and psychomotor performance and affect the ability to perform complex tasks (e.g. driving).

Antipsychotics:

Plasma concentrations of zotepine may be increased. Severe hypotension, collapse, loss of consciousness, respiratory depression, and potentially fatal respiratory arrest have been reported in a few patients taking benzodiazepines and clozapine. Salivary hypersecretion has also occurred. Caution is advised when initiating clozapine therapy in patients taking diazepam. There is an increased risk of hypotension, bradycardia and respiratory depression when parenteral benzodiazepines are given with intramuscular olanzapine.

Sodium oxybate

Concomitant use of sodium oxybate (gamma hydroxybutyrate, GHB) should be avoided as benzodiazepines enhance the effects of this substance.

Antibacterials:

The metabolism of diazepam is inhibited by isoniazid, and to a lesser extent, by erythromycin. The effect of diazepam may be increased and prolonged. Known inducers of hepatic enzymes such as rifampicin may increase the clearance of diazepam.

Antivirals:

Concomitant use of amprenavir and ritonavir should be avoided, as they have been shown to reduce the clearance of benzodiazepines and may prolong their actions, with risk of extreme sedation and respiratory depression.

Alcohol:

The sedative effects of diazepam may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.

Gastric acid suppressants:

The metabolism of diazepam may be inhibited by cimetidine, omeprazole and esomeprazole, resulting in increased plasma concentrations.

Antihypertensive agents:

Enhanced hypotensive effects may occur when diazepam is given with antihypertensive agents. Increased sedation may occur with alpha-blockers or moxonidine.

Disulfiram:

The metabolism of diazepam is inhibited by disulfiram resulting in increased sedation.

Levodopa:

Benzodiazepines may antagonise the effects of levodopa.

Theophylline:

Theophylline may reduce the effects of benzodiazepines.

Skeletal muscle relaxants:

Increased sedation may occur with concurrent use of baclofen or tizanidine and diazepam.

4.6 Pregnancy And Lactation

Pregnancy:

There is no evidence as to drug safety in human pregnancy, nor is there evidence from animal studies, that it is free from hazard. Do not use during pregnancy, especially during the first and last trimesters unless there are compelling reasons.

Results of retrospective studies suggest an increased risk of congenital malformation in infants or mothers who received diazepam during the first trimester of pregnancy.

Infants born to mothers who take benzodiazepines chronically during the later stages of pregnancy may develop physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.

An increase in foetal heart rate has occurred after diazepam use during labour. Hypoactivity, hypotonia, hypothermia, apnoea, feeding problems, hyperbilirubinaemia and kernicterus have been reported in neonates born to mothers who receive large doses of diazepam (generally greater than 30 mg) shortly before delivery.

Lactation:

Diazepam has been detected in breast milk. If possible diazepam should be avoided during breast feeding.

4.7 Effects On Ability To Drive And Use Machines

Sedation, amnesia and impaired muscular function may adversely affect the ability to drive or use machines. If insufficient sleep occurs, the likelihood of impaired alertness may be increased (See also interactions).

4.8 Undesirable Effects

Most frequently reported adverse reactions associated with benzodiazepines include daytime drowsiness, sedation, unsteadiness and ataxia; these are dose-related and may persist to the following day.

Blood and lymphatic system disorders:

Very rare reports of thrombocytopenia, leucopenia, agranulocytosis

Immune system disorders:

Hypersensitivity reactions, including anaphylaxis

Metabolism and nutrition disorders:

Metabolic disorders including metabolic acidosis, increased anion gap and hyperosmolality have been reported as a consequence of propylene glycol toxicity (see section 4.4 Special warnings and precautions for use).

Psychiatric disorders:

Confusion, depression and unmasking of depression, numbed emotions, disinhibition, euphoria, appetite changes, sleep disturbance, change in libido, dependence, suicidal ideation/attempt. Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rage, insomnia, nightmares, hallucinations, psychoses, sexual arousal, and inappropriate behaviour are known to occur with benzodiazepines including diazepam. These are more likely to occur in children and the elderly.

Nervous system disorders:

Daytime drowsiness, sedation, dizziness, ataxia, tremor, headache, reduced alertness, dysarthria/slurred speech, transient anterograde amnesia or memory impairment.

Eye disorders:

Visual disturbance.

Ear and labyrinth disorders:

Vertigo.

Vascular disorders:

Hypotension may occur. The incidence of hypotension may be reduced by not exceeding the recommended rate of administration. Patients should be managed in the supine position and kept there throughout the procedure.

Intravenous injections of diazepam may be associated with local reactions and thrombophlebitis and venous thrombosis may occur.

Respiratory thoracic and mediastinal disorders:

Apnoea, respiratory depression, particularly with high doses (see 4.9 Overdose). Worsening of sleep apnoea, worsening of obstructive pulmonary disease.

Gastrointestinal disorders:

Gastrointestinal disturbances (nausea, salivation changes).

Hepatobiliary disorders:

Raised liver function test values, jaundice.

Skin and subcutaneous tissue disorders:

Rash, allergic dermatitis, urticaria.

Musculoskeletal disorders:

Muscle weakness.

Renal and urinary disorders:

Urinary retention, incontinence

General disorders:

Fatigue, injection site pain or irritation (see Vascular disorders)

Drug withdrawal symptoms:

(See section 4.4 Special warnings and precautions for use).

Symptoms reported following discontinuation of benzodiazepines include headaches, muscle pain, anxiety, depression, insomnia, restlessness, confusion, irritability, sweating, and the occurrence of rebound phenomena.

In severe cases the following symptoms may occur: derealisation, depersonalisation, tinnitus, numbness and tingling of the extremities, hypersensitivity to light, noise, and physical contact, involuntary movements, hyperreflexia, tremor, nausea, vomiting, diarrhoea, abdominal cramps, loss of appetite, agitation, palpitations, tachycardia, panic attacks, vertigo, short-term memory loss, hallucinations/delirium, catatonia, hyperthermia, convulsions. Convulsions may be more common in patients with pre-existing seizure disorders, or those taking other drugs that lower the convulsive threshold such as antidepressants.

4.9 Overdose

Symptoms:

The symptoms of a mild overdose may include confusion, somnolence, lethargy, impairment of consciousness, diminished reflexes or paradoxical excitation. In more serious cases, and especially when other CNS-depressant drugs or alcohol are ingested, symptoms may include ataxia, hypotension, hypotonia, respiratory depression, coma and, very rarely, death.

Rarely, propylene glycol toxicity has been reported following higher than recommended doses (see section 4.4 Special warnings and precautions for use).

Treatment:

Treatment is symptomatic. Respiration, heart rate, blood pressure and body temperature should be monitored and supportive measures taken to maintain cardiovascular and respiratory function. Hypotension may be controlled if necessary by IV administration of adrenaline (epinephrine). Benzodiazepines are poorly dialysable.

The benzodiazepine antagonist, flumazenil, may be useful in hospitalised patients for the management of benzodiazepine overdose. The use of flumazenil is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although flumazenil exerts a slight intrinsic anticonvulsant effect, the abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Diazepam is a benzodiazepine tranquilliser with anticonvulsant, sedative, muscle relaxant and amnesic properties. It is used in the treatment of anxiety and tension states, as a sedative and pre-medicant, in the control of muscle spasm as in tetanus, and in the management of alcohol withdrawal symptoms. It is of value in patients undergoing orthopaedic procedures endoscopy and cardioversion.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

No further information other than that which is included in the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Ethanol

Propylene Glycol

Sodium Hydroxide

Water for Injections

6.2 Incompatibilities

Diazepam injection should not be mixed with other drugs or IV fluids and should not normally be diluted except when given slowly in large intravenous infusions of normal saline or dextrose. Not more than 40 mg of diazepam should be added to 500 mls infusion solution. The solution should be freshly made up and used within six hours.

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Do not store above 25°C.

Keep container in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

Type I clear glass ampoule, 2 ml. Packed in cardboard cartons to contain 10 ampoules x 2 ml.

6.6 Special Precautions For Disposal And Other Handling

Use as directed by a physician.

7. Marketing Authorisation Holder

hameln pharmaceuticals ltd

Gloucester

UK

8. Marketing Authorisation Number(S)

PL 1502/0025

9. Date Of First Authorisation/Renewal Of The Authorisation

9 November 1983

10. Date Of Revision Of The Text

March 2008

Zoladex LA 10.8mg

Zoladex LA 10.8 mg Implant

goserelin

Read all of this leaflet carefully before you start using this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor, nurse or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist.

In this leaflet:

1. What Zoladex LA is and what it is used for

2. Before you are given Zoladex LA

3. How Zoladex LA will be given

4. Possible side effects

5. How to store Zoladex LA

6. Further information

What Zoladex LA is and what it is used for

Zoladex LA contains a medicine called goserelin. This belongs to a group of medicines called ‘LHRH analogues’.

Zoladex LA is used to treat prostate cancer. It works by reducing the amount of ‘testosterone’ (a hormone) that is produced by your body. Zoladex LA is a long-acting form of Zoladex and it is given every 12 weeks.

Before you are given Zoladex LA

Do not have Zoladex LA if:

• You are allergic (hypersensitive) to goserelin or any of the other ingredients of this medicine (listed in Section 6: Further information).


• You are a woman.

Do not have Zoladex LA if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before having Zoladex LA.

Zoladex LA should not be given to children.

Take special care with Zoladex LA

Check with your doctor or nurse before you have Zoladex LA if:

• You have problems passing urine (water) or problems with your back.


• You have diabetes.


• You have high blood pressure.


• You suffer from depression.


• You have any condition that affects the strength of your bones, especially if you are a heavy drinker, a smoker, have a family history of osteoporosis (a condition that affects the strength of your bones) or take anticonvulsants (medicines for epilepsy or fits) or corticosteroids (steroids).

Medicines of this type can cause a reduction in bone calcium (thinning of bones).

If you go into hospital, tell the medical staff that you are having Zoladex LA.

Taking other medicines

Please tell your doctor or nurse if you are taking or have recently taken any other medicines. This includes medicines that you buy without a prescription and herbal medicines.

Driving and using machines

Zoladex LA is not likely to affect you being able to drive or use any tools or machines.

How Zoladex LA will be given

• The Zoladex LA 10.8 mg Implant will be injected under the skin on your stomach every 12 weeks. This will be done by your doctor or nurse.


• It is important that you keep having Zoladex LA treatment, even if you are feeling well.


• Keep having this treatment until your doctor decides that it is time for you to stop.

Your next appointment

• You should be given a Zoladex LA injection every 12 weeks.


• Always remind the doctor or nurse to set up an appointment for your next injection.


• If you are given an appointment for your next injection which is earlier or later than 12 weeks from your last injection, tell your doctor or nurse.


• If it has been more than 12 weeks since your last injection, contact your doctor or nurse so that you can receive your injection as soon as possible.

Possible side effects

Like all medicines, Zoladex LA can cause side effects, although not everybody gets them.

Allergic reactions:

These are rare. The symptoms can include sudden onset of:

• Rash, itching or hives on the skin.


• Swelling of the face, lips or tongue or other parts of the body.


• Shortness of breath, wheezing or trouble breathing.

If this happens to you, see a doctor straight away.

Other possible side effects:

• Pain in your lower back or problems passing urine. If this happens, talk to your doctor.


• Bone pain at the beginning of treatment. If this happens, talk to your doctor.


• Hot flushes and sweating.


• A reduced sex drive and impotence.


• Thinning of your bones.


• Rises in blood sugar levels.


• Tingling in your fingers or toes.


• Skin rashes.


• Pain, bruising, bleeding, redness or swelling where Zoladex LA is injected.


• Pain in the joints.


• Reduced heart function.


• Changes in blood pressure.


• Swelling and tenderness of your breasts.


• Changes in your mood (including depression).


• Changes in your blood.


• Liver problems.


• A blood clot in your lungs causing chest pain or shortness of breath.


• Inflammation of the lungs. The symptoms may be like pneumonia (such as feeling short of breath and coughing).


• Psychiatric problems called psychotic disorders which may include hallucinations (seeing, feeling or hearing things that are not there), disordered thoughts and personality changes. This is very rare.


• The development of a tumour of the pituitary gland in your head or, if you already have a tumour in your pituitary gland, Zoladex LA may make the tumour bleed or collapse. These effects are very rare. Pituitary tumours can cause severe headaches, feeling or being sick, loss of eyesight and becoming unconscious.

Do not be concerned by this list of possible side effects. You may not get any of them.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist.

How to store Zoladex LA

• Your doctor may give you a prescription so that you can get your medicine from the pharmacy and give it to your doctor when you see him or her again.


• Keep it in its original package and do not break the seal.


• Do not store it above 25°C.


• Keep it in a safe place where children cannot see it or reach it.


• Your medicine should not be used after the expiry date on the carton.


• If your medicine is not used, take it back to your pharmacist.

Further information

What Zoladex LA 10.8 mg Implant contains

The active substance is goserelin. Each Zoladex LA 10.8 mg Implant contains 10.8 mg of goserelin.

The other ingredient is lactide/glycolide copolymer which is an inactive substance.

What Zoladex LA 10.8 mg Implant looks like and contents of the pack

Zoladex LA 10.8 mg Implant comes as an implant (a very small pellet) in a pre-filled syringe, ready to be used by the doctor or nurse.

Zoladex LA 10.8 mg Implant is produced in packs of one implant (injection).

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisation for Zoladex LA 10.8 mg Implant is held by

AstraZeneca UK Limited

600 Capability Green

Luton

LU1 3LU

UK

Zoladex LA 10.8 mg Implant is manufactured by

AstraZeneca UK Limited

Silk Road Business Park

Macclesfield

Cheshire

SK10 2NA

UK

To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge:

0800 198 5000 (UK only)

Please be ready to give the following information:

Product name Zoladex LA 10.8 mg Implant

Reference number 17901/0065

This is a service provided by the Royal National Institute of Blind People.

Leaflet updated: February 2010

© AstraZeneca 2010

Zoladex is a trade mark of the AstraZeneca group of companies.

ONC 10 0008

P027718

Zonegran capsules

Zonegran 25 mg hard capsules

Zonegran 50 mg hard capsules

Zonegran 100 mg hard capsules

zonisamide

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or your pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms 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 or pharmacist.

In this leaflet:

• 1. What Zonegran is and what it is used for


• 2. Before you take Zonegran


• 3. How to take Zonegran


• 4. Possible side effects


• 5. How to store Zonegran


• 6. Further information

What Zonegran Is And What It Is Used For

Zonegran is an antiepileptic medicine.

Zonegran is used to treat adults who are already taking other antiepileptic medicines but are still experiencing seizures that affect one part of the brain (partial seizure), which may or may not be followed by a seizure affecting all of the brain (secondary generalisation).

Before You Take Zonegran

Do not take Zonegran:

If you:

• are allergic to any of the ingredients in Zonegran (see section 6. Further information),


• are allergic to other sulphonamide medicines.

Take special care with Zonegran:

Zonegran belongs to a group of medicines (sulphonamides) which can cause severe allergic reactions, severe skin rashes, and blood disorders, which very rarely can be fatal (see section 4. Possible Side Effects).

Before you take Zonegran, tell your doctor if you:

• are younger than 18 years old. Zonegran is not recommended for you.


• are elderly, as your dose of Zonegran may need adjusting, and you may be more likely to develop an allergic reaction or severe skin rash when taking Zonegran (see section 4 Possible Side Effects).


• suffer from liver problems, as your dose of Zonegran may need adjusting.


• suffer from kidney problems as your dose of Zonegran may need adjusting.


• have previously suffered from kidney stones, as you may be at increased risk of developing more kidney stones. Reduce the risk of kidney stones by drinking sufficient water.


• live in a place or are on holiday in a place where the weather is warm. Zonegran can make you perspire less, which can cause your body temperature to increase. Reduce the risk of overheating by drinking sufficient water and keeping cool.


• weigh less than 40 kg, or have lost a lot of weight as Zonegran can cause you to lose more weight.
  
  Tell your doctor as this may need to be monitored.

If any of these applies to you, tell your doctor before you take Zonegran.

Taking other medicines

Please tell your doctor or pharmacist if you are taking, or have recently taken, any other medicines, including medicines obtained without a prescription.

• Zonegran should be used carefully when taken with medicines that can cause kidney stones, like topiramate.


• Zonegran could possibly increase your blood levels of medicines like digoxin and quinidine, and so a reduction in their dose may be required.


• Other medicines like phenytoin, carbamazepine, phenobarbitone and rifampicin can decrease your blood levels of Zonegran, which may require an adjustment of your dose of Zonegran.

Taking Zonegran with food and drink

Zonegran can be taken with or without food.

Pregnancy and breastfeeding

If you are a woman of childbearing age you must use adequate contraception while taking and for one month after stopping Zonegran.

Tell your doctor immediately if you might be, or are pregnant, or are planning to get pregnant.

You must only take Zonegran during your pregnancy if your doctor tells you to. Research has shown an increased risk of birth defects in children of women taking anti-epileptic medicines.

Do not breastfeed whilst taking, or for one month after stopping Zonegran.

Driving and using machines

Zonegran may affect your concentration, ability to react/respond, and may make you feel sleepy, particularly at the beginning of your treatment or after your dose is increased. Be especially careful while driving or operating machinery, if Zonegran affects you in this way.

Important information about some of the ingredients of Zonegran

Zonegran 100 mg hard capsules contain a yellow colour called sunset yellow FCF (E110) and a red colour called allura red AC (E129), which may cause allergic reactions (see section 6 – Further Information).

How To Take Zonegran

Always take Zonegran exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

The usual adult dose

• The starting dose is 50 mg daily taken in two equal doses of 25 mg.


• This may be increased by up to 100 mg at intervals of one to two weeks.


• The usual daily dose is between 300 mg and 500 mg.


• Some people respond to lower doses. The dose may be increased more slowly if you experience side effects, are elderly or if you suffer from kidney or liver problems.

If you feel that the effect of Zonegran is too strong or too weak, talk to your doctor or pharmacist.

• Zonegran capsules must be swallowed whole with water.


• Do not chew the capsules.


• Zonegran can be taken once or twice daily, as instructed by your doctor.


• It you take Zonegran twice a day, take half the daily dose in the morning and half in the evening.

If you take more Zonegran than you should

If you may have taken more Zonegran than you should, tell a carer (relative or friend), your doctor or pharmacist immediately, or contact your nearest hospital casualty department, taking your medicine with you. You may become sleepy and could lose consciousness. You might also feel sick, have a sore stomach, muscle twitches, eye movement, feel faint, have a slowed heart beat, and reduced breathing and kidney function. Do not try to drive.

If you forget to take Zonegran

• If you forget to take a dose, don’t worry: take the next dose when it is due.


• 
  Do not take double the dose to make up for the forgotten dose.

If you stop taking Zonegran

• Zonegran is meant to be taken as a long-term medicine. Do not reduce your dose or stop your medicine unless your doctor tells you to.


• If your doctor advises you to stop taking Zonegran your dose will be reduced gradually to lower the risk of more seizures.

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

Zonegran capsules Side Effects

Like all medicines, Zonegran can cause side effects, although not everybody gets them.

Zonegran belongs to a group of medicines (sulphonamides) that can cause severe allergic reactions, severe skin rashes, and blood disorders, which very rarely can be fatal.

Contact your doctor immediately if you:

• have difficulty breathing, a swollen face, lips or tongue, or a severe skin rash as these symptoms may indicate that you are having a severe allergic reaction.


• have thoughts of harming or killing yourself. A small number of people being treated with antiepileptics such as Zonegran have had thoughts of harming or killing themselves.


• have pain in your muscles or a feeling of weakness, as this may be a sign of abnormal muscle breakdown which can lead to kidney problems.


• get a sudden pain in your back or stomach, have pain on urinating (passing water) or notice blood in your urine, as this may be a sign of kidney stones.

Contact your doctor as soon as possible if you:

• have an unexplained skin rash, as this could develop into a more severe skin rash or skin peeling.


• feel unusually tired or feverish, have a sore throat, swollen glands, or find that you bruise more easily, as this may mean you have a blood disorder.


• have headaches, drowsiness, shortness of breath and loss of appetite as this could be a sign that your blood level of bicarbonate is too low, which your doctor may need to monitor or treat.

Your doctor may decide that you should stop using Zonegran.

The most common side effects of Zonegran are mild. They occur during the first month of treatment and usually decrease with continued treatment. The frequency of possible side effects listed below is defined using the following convention:

• very common (affects more than 1 user in 10)


• common (affects 1 to 10 users in 100)


• uncommon (affects 1 to 10 users in 1,000)


• rare (affects 1 to 10 users in 10,000)


• very rare (affects less than 1 user in 10,000)


• not known (frequency cannot be estimated from the available data).”

Very common side effects (affects more than 1 user in 10)

• agitation, irritability, confusion, depression


• poor muscle coordination, dizziness, poor memory, sleepiness, double vision


• loss of appetite, decreased blood levels of bicarbonate (a substance that prevents your blood from becoming acidic)

Common side effects (affects 1 to 10 users in 100)

• difficulty sleeping, strange or unusual thoughts, feeling anxious or emotional.


• slowed thoughts, loss of concentration, speech abnormalities, abnormal skin sensation (pins and needles), tremor, involuntary movement of the eyes.


• kidney stones.


• skin rashes, allergic reactions, fever, tiredness, flu-like symptoms.


• ecchymosis (a small bruise caused by blood leaking from broken blood vessels in the skin).


• loss of weight, nausea, indigestion, stomach pains, diarrhoea (loose stools), constipation.

Uncommon side effects (affects 1 to 10 users in 1000 patients)

• anger, aggression, thoughts of suicide, suicide attempt.


• vomiting.


• gall bladder inflammation, gallstones.


• urinary stones.


• lung infection / inflammation, urinary tract infections.


• low blood potassium levels, convulsions/seizures.

Very rare side effects (affects less than 1 user in 10,000 patients):

• hallucinations, memory loss, coma, neuroleptic malignant syndrome (inability to move, sweating, fever, incontinence), status epilepticus (prolonged or repeated seizures).


• breathing disorders, shortness of breath, inflammation of the lungs.


• inflammations of the pancreas (severe pain in the stomach or back)


• liver problems, kidney failure, increased blood levels of creatinine (a waste product that your kidneys should normally remove). .


• severe rashes or skin peeling (at the same time you may feel unwell or develop a fever), itching.


• abnormal muscle breakdown (you may feel pain or weakness in your muscles) which can lead to kidney problems.


• swollen glands, blood disorders (reduction in the number of blood cells, which can make infection more likely and can make you look pale, feel tired and feverish, and bruise more easily).


• decreased sweating, overheating.

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.

How To Store Zonegran

Keep Zonegran out of the reach and sight of children.

Do not use Zonegran after the expiry date stated on the blister and the carton after EXP. The expiry date refers to the last day of that month.

Do not store above 30°C.

Do not use if you notice any damage to the capsules, blister or carton or any visible signs of deterioration in the medicine. Return the pack to your pharmacist.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What Zonegran contains

The active substance in Zonegran is zonisamide. Zonegran 25 mg hard capsules contain 25 mg of zonisamide. Zonegran 50 mg hard capsules contain 50 mg zonisamide. Zonegran 100 mg hard capsules contain 100 mg zonisamide.

• The other ingredients that are present in the capsule contents are: microcrystalline cellulose, hydrogenated vegetable oil and sodium laurilsulfate.


• The capsule shell contains: gelatin, titanium dioxide (E171), shellac, propylene glycol, potassium hydroxide, black iron oxide (E172). Additionally the 100 mg capsule shell contains sunset yellow FCF (E110) and allura red (E129).

See Section 2 for important information about the ingredients: sunset yellow FCF (E110) and allura red AC (E129).

What Zonegran looks like and contents of the pack

• Zonegran 25 mg hard capsules have a white opaque body and a white opaque cap and are printed with a logo and “ZONEGRAN 25” in black.


• Zonegran 50 mg hard capsules have a white opaque body and a grey opaque cap and are printed with a logo and “ZONEGRAN 50” in black.


• Zonegran 100 mg hard capsules have a white opaque body and a red opaque cap and are printed with a logo and “ZONEGRAN 100” in black.

Zonegran capsules are packaged in blister packs supplied in boxes containing:

• 25 mg: 14, 28, 56 and 84 capsules


• 50 mg: 14, 28, 56 and 84 capsules


• 100 mg: 28, 56, 84, 98 and 196 capsules.

Not all pack sizes may be available.

Marketing Authorisation Holder

Eisai Ltd.

Mosquito Way

Hatfield

Herts

AL10 9SN

United Kingdom

Manufacturer

Eisai Manufacturing Ltd

Mosquito Way

Hatfield

Herts

AL10 9SN

United Kingdom

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

United Kingdom

Eisai Ltd.

Tel:+ 44 (0) 208 600 1400

This leaflet was last approved in December 2009

Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site: http://www.emea.europa.eu/.

Diamorphine Hydrochloride Injection BP 100mg

1. Name Of The Medicinal Product

Diamorphine Hydrochloride BP 100 mg Lyophilisate for Solution for Injection.

2. Qualitative And Quantitative Composition

Each ampoule contains 100 mg of Diamorphine Hydrochloride BP.

3. Pharmaceutical Form

Lyophilisate for solution for injection.

A white to off-white, sterile, freeze dried powder of Diamorphine Hydrochloride BP for reconstitution for injection.

4. Clinical Particulars

4.1 Therapeutic Indications

Diamorphine may be used in the treatment of severe pain associated with surgical procedures, myocardial infarction or pain in the terminally ill and for the relief of dyspnoea in acute pulmonary oedema.

4.2 Posology And Method Of Administration

Diamorphine may be given by the intramuscular, intravenous or subcutaneous routes. Glucose intravenous infusion is the preferred diluent, particularly when the drug is administered by a continuous infusion pump over 24 to 48 hours, although it is also compatible with sodium chloride intravenous infusion.

The dose should be suited to the individual patient.

Adults:

Acute pain, 5 mg repeated every four hours if necessary (up to 10 mg for heavier, well muscled patients) by subcutaneous or intramuscular injection. By slow intravenous injection, one quarter to one half the corresponding intramuscular dose.

Chronic pain, 5-10 mg regularly every four hours by subcutaneous or intramuscular injection. The dose may be increased according to individual needs.

Myocardial infarction, 5 mg by slow intravenous injection (1 mg/minute) followed by a further 2.5 mg to 5 mg if necessary.

Acute pulmonary oedema, 2.5 mg to 5 mg by slow intravenous injection (1mg/minute).

If breakthrough pain occurs give a subcutaneous (preferable) or intramuscular injection of diamorphine equivalent to one-sixth of the total 24-hour subcutaneous infusion dose. It is kinder to give an intermittent bolus injection subcutaneously—absorption is smoother so that the risk of adverse effects at peak absorption is avoided (an even better method is to use a subcutaneous butterfly needle).

To minimise the risk of infection no individual subcutaneous infusion solution should be used for longer than 24 hours.

If treatment continues for more than 24 hours it may be appropriate to use a syringe driver (Burne R, Hunt A, Palliative Medicine 1987, 1, 27-30)

Children and Elderly:

Diamorphine has been used in the treatment of terminally ill children. Diamorphine has been administered in reduced doses to children with neoplastic disease when it becomes difficult to give treatment orally. The starting dose should be selected according to age, size, symptoms and previous analgesic requirements and administered 4 hourly; the dose being titrated according to the degree of pain.

As diamorphine has a respiratory depressant effect, care should be taken when giving the drug to the very young and the elderly and a lower starting dose than normal is recommended.

Patients with hepatic or renal dysfunction:

Diamorphine undergoes biotransformation to an active metabolite, morphine-6-glucuronide (M6G). This metabolite can accumulate and result in greater pharmacological effect, because it is more active than morphine. Less diamorphine will therefore be needed. Care needs to be taken with unconscious intensive care patients on fixed dose schedules where their renal function is impaired.

A wide range of doses of diamorphine can be given intravenously or subcutaneously starting with the “standard” 5-10mg regularly every four hours recommended in the SmPC. Lower starting doses are recommended for patients with hepatic or renal impairment. Ultimately, the dose given to the individual is arrived at by “titrating to therapeutic effect”.

Instructions for use and handling

Instructions for preparation: see Section 6.6.

Further advice on use and handling can be found in the current British National Formulary (BNF/BNFC) (Prescribing in Palliative Care and Syringe Drivers).

4.3 Contraindications

Respiratory depression and obstructive airways disease.

Phaeochromocytoma (endogenous release of histamine may stimulate catecholamine release).

Raised intracranial pressure.

Concurrent use of monoamine oxidase inhibitors or within two weeks of their discontinuation.

4.4 Special Warnings And Precautions For Use

Diamorphine should be administered with care to patients with head injuries as there is an increased risk of respiratory depression which may lead to elevation of CSF pressure. The sedation and pupillary changes produced may interfere with accurate monitoring of the patient.

Repeated administration of diamorphine may lead to dependence and tolerance developing. Abrupt withdrawal in patients who have developed dependence may precipitate a withdrawal syndrome. Great caution should be exercised in patients with a known tendency or history of drug abuse.

Use with caution in patients with toxic psychosis, CNS depression, myxoedema, prostatic hypertrophy or urethral stricture, kyphoscoliosis, acute alcoholism, delirium tremens, severe inflammatory or obstructive bowel disorders, adrenal insufficiency or severe diarrhoea. Care should be exercised in treating the elderly or debilitated patients and those with hepatic or renal impairment.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The depressant effects of diamorphine may be exaggerated and prolonged by phenothiazines, monoamine oxidase inhibitors, tricyclic antidepressants, anxiolytics and hypnotics. There may be antagonism of the gastrointestinal effects of cisapride, domperidone and metoclopramide. The risk of severe constipation and/or urinary retention is increased by administration of antimuscarinic drugs (e.g. atropine). There may be increased risk of toxicity with 4-quinolone antibacterials.

Alcohol may enhance the sedative and hypotensive effects of diamorphine.

Cimetidine inhibits metabolism of opioid analgesics.

Hyperpyrexia and CNS toxicity have been reported when opioid analgesics are used with selegiline.

4.6 Pregnancy And Lactation

Safety has not been established in pregnancy.

Administration during labour may cause respiratory depression in the neonate and gastric stasis during labour, increasing the risk of inhalation pneumonia.

Diamorphine should not be given to women who are breast-feeding as there is limited information available on diamorphine in breast milk.

4.7 Effects On Ability To Drive And Use Machines

Diamorphine causes drowsiness and mental clouding. If affected patients should not drive or use machines.

4.8 Undesirable Effects

The most serious hazard of therapy is respiratory depression although circulatory depression is also possible. The most common side effects are sedation, nausea and vomiting, constipation and sweating. Other side effects include dizziness, miosis, confusion, urinary retention, biliary spasm, orthostatic hypotension, facial flushing, vertigo, palpitations, mood changes, dry mouth, dependence, urticaria, pruritus and raised intracranial pressure.

4.9 Overdose

a) Symptoms

Respiratory depression, pulmonary oedema, muscle flaccidity, coma or stupor, constricted pupils, cold, clammy skin and occasionally bradycardia and hypotension.

b) Treatment

Respiration and circulation should be maintained and naloxone is indicated if coma or bradypnoea are present. A dose of 0.4 to 2 mg repeated at intervals of two to three minutes (up to 10 mg) may be given by subcutaneous, intramuscular or intravenous injection. The usual initial dosage for children is 10 micrograms per kg body weight. Naloxone may also be given by continuous intravenous infusion, 2 mg diluted in 500 ml, at a rate adjusted to the patient's response. Oxygen and assisted ventilation should be administered if necessary.

5. Pharmacological Properties

ATC code: NO2AA09

5.1 Pharmacodynamic Properties

Diamorphine is a narcotic analgesic which acts primarily on the central nervous system and smooth muscle. It is predominantly a central nervous system depressant but it has stimulant actions resulting in nausea, vomiting and miosis.

5.2 Pharmacokinetic Properties

Diamorphine is a potent opiate analgesic which has a more rapid onset of activity than morphine as the first metabolite, monoacetylmorphine, more readily crosses the blood brain barrier. In man, diamorphine has a half life of two to three minutes. Its first metabolite, monoacetylmorphine, is more slowly hydrolysed in the blood to be concentrated mainly in skeletal muscle, kidney, lung, liver and spleen. Monoacetylmorphine is metabolised to morphine. Morphine forms conjugates with glucuronic acid. The majority of the drug is excreted via the kidney as glucuronides and to a much lesser extent as morphine. About 7-10 % is eliminated via the biliary system into the faeces.

Diamorphine does not bind to protein. However, morphine is about 35 % bound to human plasma proteins, mainly to albumin. The analgesic effect lasts approximately three to four hours.

5.3 Preclinical Safety Data

There are no additional pre-clinical data of relevance to the prescriber.

6. Pharmaceutical Particulars

6.1 List Of Excipients

None.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

3 years.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 – 8 °C, unless reconstitution/dilution (etc.) has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Store below 25ºC. Protect from light.

Keep container in the outer carton.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

5 ml clear Ph. Eur. Class 1 glass ampoules containing 100 mg Diamorphine Hydrochloride BP lyophilisate each.

The ampoules are packed into a carton of 5.

6.6 Special Precautions For Disposal And Other Handling

The product is prepared by dissolving Diamorphine Hydrochloride Lyophilisate for Solution for Injection in the requisite amount of water for injection immediately before use.

The reconstituted lyophilisate is a clear solution.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Continuous subcutaneous infusion should be monitored regularly both to check for precipitation (and discoloration) and to ensure that the infusion is running at the correct rate.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Auralis

Daresbury Innovation Centre,

Keckwick Lane, Daresbury, Halton WA4 4FS

United Kingdom

8. Marketing Authorisation Number(S)

PL 30956/0001

9. Date Of First Authorisation/Renewal Of The Authorisation

12/02/2008

10. Date Of Revision Of The Text

03/09/2008

11 DOSIMETRY (IF APPLICABLE)

Not applicable.

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

Not applicable.

Diazepam RecTubes 10mg

1. Name Of The Medicinal Product

Diazepam RecTubes 10mg Rectal Solution

2. Qualitative And Quantitative Composition

Diazepam Ph Eur 10mg in 2.5ml

(4mg/ml)

For excipients, see 6.1

3. Pharmaceutical Form

Rectal solution

A clear, colourless or almost yellow solution

4. Clinical Particulars

4.1 Therapeutic Indications

Diazepam rectal tubes may be used in severe or disabling anxiety and agitation; epileptic and febrile convulsions; to relieve muscle spasm caused by tetanus; as a sedative in minor surgical and dental procedures, or other circumstances in which a rapid effect is required but where intravenous injection is impracticable or undesirable.

Diazepam rectal tubes may be of particular value for the immediate treatment of convulsions in children.

4.2 Posology And Method Of Administration

Dosage depends on age and weight.

Children:

0.5mg/kg

(not recommended for use in children less than one year old)

Adults:

0.5mg/kg

If convulsions are not controlled other anticonvulsive measures should be instituted.

The dose can be repeated every 12 hours.

Elderly and debilitated patients should be given not more than one half the appropriate adult dose.

Dosage reduction may also be required in patients with liver or kidney dysfunction.

The solution is administered rectally. Adults should be in the lateral position; children should be in the prone or lateral position.

a) Tear open the foil pack. Remove the cap.

b) Insert the tube nozzle completely into the rectum. For children under 15kg, insert only half way. Hold the tube with the spout downwards. The contents of the tube should be completely emptied by using firm pressure with the index finger and thumb.

c) To avoid suction, maintain pressure on the tube until it is withdrawn from the rectum. Press together the patient's buttocks for a short time.

In anxiety, the duration of treatment should be as short as possible and generally not more than 8-12 weeks, including a tapering off process (see 4.4 Special Warnings and Special Precautions for Use).

Patients requiring chronic dosing should be checked regularly at the start of treatment in order to decrease, if necessary, the dose or frequency of administration, to prevent overdose due to accumulation.

4.3 Contraindications

Known hypersensitivity to benzodiazepines or any of the ingredients.

Severe or acute respiratory insufficiency/depression

Sleep apnoea syndrome

Severe hepatic insufficiency

Diazepam should not be used in phobic or obsessional states, nor be used alone in the treatment of depression or anxiety associated with depression due to the risk of suicide being precipitated in this patient group. Diazepam should not be used for the primary treatment of psychotic illness. In common with other benzodiazepines the use of diazepam may be associated with amnesia and diazepam should not be used in cases of loss or bereavement as psychological adjustments may be inhibited.

4.4 Special Warnings And Precautions For Use

Diazepam should be used with caution in patients with renal or hepatic dysfunction (see 4.2 Posology and Method of Administration), chronic pulmonary insufficiency, porphyria, myasthenia gravis, coma, organic brain changes, particularly arteriosclerosis.

Diazepam may enhance the effects of other CNS depressants; their concurrent use should be avoided.

Elderly and debilitated patients are more prone to the CNS effects of benzodiazepines and, therefore, lower doses are required (see section 4.2 Posology and Method of Administration).

Dependence and withdrawal symptoms

Use of benzodiazepines may lead to the development of physical and psychological dependence upon these products. This should be considered when treating patients for more than a few days. The dependence potential of diazepam is low when limited to short-term use but increases with the dose and duration of treatment; it is also greater in patients with a history of alcohol or drug abuse.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms (See Section 4.8 Withdrawal symptoms).

Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dose is decreased gradually.

When benzodiazepines with a long duration of action, such as diazepam, are being used, it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.

Treatment of anxiety (see 4.2 Posology and Method of Administration)

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. In certain cases, extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient's status with special expertise.

Rebound anxiety, a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes or sleep disturbances and restlessness. It is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued.

Benzodiazepines should not be given to children for anxiety without careful assessment of the need to do so.

Amnesia

Benzodiazepines may induce anterograde amnesia (see 4.8 Undesirable Effects). The condition occurs most often several hours after administration. To reduce the risk, where appropriate and possible, patients should be able to have an uninterrupted sleep of 7-8 hours after administration.

Psychiatric and paradoxical reactions

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 (See 4.8 Undesirable Effects). Should they occur, use of diazepam should be discontinued.

Use in patients with concomitant mental illness or addiction

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse. As with other benzodiazepines, extreme caution should be used if prescribing diazepam for patients with personality disorders.

The disinhibiting effects of benzodiazepines may be manifested as the precipitation of suicide in patients who show aggressive behaviour towards self and others.

The excipient benzoic acid may be mildly irritant to mucous membranes

This medicinal product contains 0.85mmol sodium per dose. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Alcohol : Concomitant intake of alcohol is not recommended. The sedative effect of diazepam may be enhanced. This affects the ability to drive or use machines (see 4.7 Effects on ability to drive and use machines).

Anaesthetics and narcotic analgesics : Enhanced sedation or respiratory and cardiovascular depression. . In the case of narcotic analgesics, enhancement of euphoria may also occur leading to an increase in psychological dependence.

Antibacterials: Agents that interfere with metabolism by hepatic enzymes (e.g. erythromycin and isoniazid) may reduce the clearance of benzodiazepines and potentiate their actions. Known inducers of hepatic enzymes, for example, rifampicin, may increase the clearance of benzodiazepines.

Antidepressants: Enhanced sedation or respiratory and cardiovascular depression. Diazepam plasma levels increased by concomitant fluvoxamine.

Antiepileptics: Enhanced sedation or respiratory and cardiovascular depression. Known inducers of hepatic enzymes, for example, carbamazepine and phenytoin, may increase the clearance of benzodiazepines. Serum phenytoin levels may rise, fall or remain unaltered. In addition, phenytoin may cause diazepam serum levels to fall. Concomitant sodium valproate may increase serum levels of diazepam, with associated drowsiness.

Antihistamines: Enhanced sedation or respiratory and cardiovascular depression with sedative antihistamines.

Antihypertensives : Enhanced hypotensive effect, enhanced sedative effect with alpha-blockers and possibly moxonidine.

Antipsychotics Enhanced sedation or respiratory and cardiovascular depression. Increased plasma concentrations of zotepine. Severe hypotension, collapse, respiratory depression, potentially fatal respiratory arrest and unconsciousness have been reported in a few patients on benzodiazepines and clozapine. Caution is advised when initiating clozapine therapy in patients taking benzodiazepines.

Antivirals: Amprenavir and ritonavir have been shown to reduce the clearance of benzodiazepines and may potentiate their actions, with risk of extreme sedation and respiratory depression – avoid concomitant use.

Anxiolytics: Enhanced sedation or respiratory and cardiovascular depression with other anxiolytics..

Digoxin: Reduced clearance of digoxin.

Disulfiram: has been shown to reduce clearance and may potentiate actions of benzodiazepines.

Dopaminergic agents: diazepam may cause inhibition of levodopa.

Hypnotics, Enhanced sedation or respiratory and cardiovascular depression.

Lofexidine: Enhanced sedation or respiratory and cardiovascular depression.

Muscle relaxants: Increased CNS depressant effects with baclofen and tizanidine.

Nabilone: Enhanced sedation or respiratory and cardiovascular depression.

Nicotine: Diazepam metabolism is accelerated by smoking.

Oral contraceptives: Reduce the clearance of benzodiazepines and may potentiate their actions.

Sedatives: Enhanced sedation or respiratory and cardiovascular depression.

Theophylline: Diazepam metabolism is accelerated by theophylline.

Ulcer-healing drugs: Cimetidine and omeprazole may reduce the clearance of benzodiazepines and potentiate their actions.

4.6 Pregnancy And Lactation

There is no evidence regarding the safety of diazepam in pregnancy. It should not be used, especially in the first and third trimesters, unless the benefit is considered to outweigh the risk.

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

There may be a small increase in the risk of congenital malformation, particularly oral cleft, with the use of benzodiazepines in the first trimester. In labour, high single doses or repeated low doses have been reported to produce effects on the neonate, such as hypothermia, hypotonia, moderate respiratory depression and poor suckling (floppy infant syndrome) and irregularities in the foetal heart .

Infants born to mothers who take benzodiazepines chronically during the latter stages of pregnancy may develop physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.

A small number of children exposed in utero to benzodiazepines have shown slow development in the early years but by four years of age have developed normally.

Diazepam is excreted in the breast milk and therefore its use during lactation should be avoided.

4.7 Effects On Ability To Drive And Use Machines

Patients treated with Diazepam Rectal Tubes should not drive or operate machines as sedation, amnesia, impaired concentration and impaired muscular function may adversely affect their ability. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased.

4.8 Undesirable Effects

Elderly or debilitated patients are particularly susceptible to the CNS effects of benzodiazepines. It is recommended that dosage be limited to the smallest effective dose and increased gradually, if necessary, to decrease the possibility of development of ataxia, dizziness, and oversedation, which may lead to falls and other accidents (see 4.2 Posology and method of administration).

Cardiovascular: Hypotension, particularly with high dosage, bradycardia, chest pain.

Disorders of the eye: Visual disturbances.

Gastrointestinal: Dry mouth, gastrointestinal disturbances.

General: Fatigue and a hangover effect.

Haematological: Blood dyscrasias.

Hepatic: Raised liver enzymes, jaundice

Immunological: Hypersensitivity reactions, including anaphylaxis, are rare.

Musculoskeletal: Muscle weakness.

Neurological: Headaches, confusion, slurred speech, tremor, reduced alertness. Anterograde amnesia may occur using therapeutic doses, the risk increasing at higher doses (see 4.4 Special Warnings and Special Precautions for Use). Amnestic effects may be associated with inappropriate behaviour.

Psychiatric: Numbed emotions. In susceptible patients, an unnoticed depression may become evident. Paradoxical reactions (including aggressive behaviour, hostility, disinhibition, euphoria, excitation, irritability, increased anxiety and insomnia are known to occur with benzodiazepines and may be quite severe with diazepam (see 4.4 Special Warnings and Special Precautions for Use). They are more likely to occur in children and the elderly.

Reproductive: Changes in libido, gynaecomastia.

Respiratory: Rarely, respiratory depression and apnoea, particularly with high dosage.

Skin: Skin reactions.

Urinary: Urinary retention, incontinence

Withdrawal symptoms: Development of dependence is common after regular use, even in therapeutic doses for short periods, particularly in patients with a history of drug or alcohol abuse or marked personality disorders. Discontinuation may result in withdrawal or rebound phenomena (see 4.4 Special Warnings and Special Precautions for Use). Symptoms of benzodiazepine withdrawal include anxiety, depression, impaired concentration, insomnia, headache, dizziness, tinnitus, loss of appetite, tremor, perspiration, irritability, perceptual disturbances such as hypersensitivity to physical, visual, and auditory stimuli and abnormal taste, nausea, vomiting, abdominal cramps, palpitations, mild systolic hypertension, tachycardia, and orthostatic hypotension.

Rare and more serious symptoms include muscle twitching, confusional or paranoid psychosis, convulsions, hallucinations, and a state resembling delirium tremens. Broken sleep with vivid dreams and increased REM sleep may persist for some weeks after withdrawal of benzodiazepines.

4.9 Overdose

a) Symptoms

The symptoms of mild overdose may include confusion, impairment of consciousness with somnolence or a sleep-like state, little or no respiratory depression, ataxia, dysarthria, hypotension, and muscular weakness. Cardiac rate and rhythm remain normal in the absence of anoxia or severe hypotension.

In severe overdose, deep coma or other manifestations of severe depression of brainstem vital functions, particularly the respiratory centre, may occur. As drug levels fall severe agitation, insomnia and, possibly, major convulsions may develop.

b) Treatment

Treatment is symptomatic. Respiration, heart rate, blood pressure and body temperature should be monitored in intensive care and supportive measures taken to maintain cardiovascular and respiratory function. Activated charcoal may be administered to increase clearance as well as decrease absorption of diazepam. Flumazenil may be indicated to counteract the central depressive effect of benzodiazepines but expert advice is essential since adverse effects may occur (e.g. convulsions in patients dependent on benzodiazepines).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Diazepam is a psychotropic substance from the class of 1,4-benzodiazepines with marked properties of suppression of tension, agitation and anxiety as well as sedative and hypnotic effects. In addition, diazepam demonstrates muscle relaxant and anticonvulsive properties. It is used in the short-term treatment of anxiety and tension states, as a sedative and premedicant, in the control of muscle spasm and in the management of alcohol withdrawal symptoms.

Diazepam binds to specific receptors in the central nervous system and particular peripheral organs. The benzodiazepine receptors in the CNS have a close functional connection with receptors of the GABA-ergic transmitter system. After binding to the benzodiazepine receptor, diazepam augments the inhibitory effect of GABA-ergic transmission.

5.2 Pharmacokinetic Properties

After rectal administration of the solution, diazepam is absorbed rapidly and almost completely from the rectum.

The onset of the therapeutic effect occurs within a few minutes of rectal administration. The rapidity of the rise in the serum level following rectal administration corresponds approximately to that following an intravenous dose but peak plasma concentrations are lower after rectal tubes than after intravenous administration. In adults maximal plasma concentrations following the administration of 10 mg diazepam in rectal solution are reached after about 10 - 30 minutes (ca. 150 - 400 ng/ml).

Diazepam is extensively protein bound (95-99%). The volume of distribution is between 0.95 and 2 l/kg depending on age. Diazepam is lipophilic and rapidly enters the cerebrospinal fluid. Diazepam and its main metabolite, N-desmethyldiazepam, cross the placenta and are secreted in breast milk.

Diazepam is metabolised predominantly in the liver. Its metabolites, N-desmethyldiazepam (nordiazepam), temazepam and oxazepam, which appear in the urine as glucuronides, are also pharmacologically active substances. Only 20% of the metabolites are detected in the urine in the first 72 hours.

Diazepam has a biphasic half life with an initial rapid distribution phase followed by a prolonged terminal elimination phase of 1-2 days. The time to reach steady state plasma levels is therefore 4-10 days. For the active metabolites N-desmethyldiazepam, temazepam and oxazepam, the half lives are 30-100 hours, 10-20 hours and 5-15 hours, respectively.

Excretion is mainly renal and also partly biliary. It is dependent on age as well as hepatic and renal function.

Metabolism and elimination in the neonate are markedly slower than in children and adults. In the elderly, elimination is prolonged by a factor of 2 to 4. In patients with impaired renal function, elimination is also prolonged. In patients with hepatic disorders (liver cirrhosis, hepatitis), elimination is prolonged by a factor of 2.

5.3 Preclinical Safety Data

Chronic toxicity studies in animals have demonstrated no evidence of drug-induced changes. There are no long-term animal studies to investigate the carcinogenic potential of diazepam. Several investigations pointed to a weakly mutagenic potential at doses far above the human therapeutic dose.

Local tolerability has been studied following single and repeat dose applications into the conjunctival sac of rabbits and the rectum of dogs. Only minimal irritation was observed. There were no systemic changes.

In humans it would appear that the risk of congenital abnormalities from the ingestion of therapeutic doses of benzodiazepines is slight, although a few epidemiological studies have pointed to an increased risk of cleft palate. There are case reports of congenital abnormalities and mental retardation in prenatally exposed children following overdosage and intoxication with benzodiazepines.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Benzyl alcohol

Ethanol 96%

Propylene glycol

Benzoic acid

Sodium benzoate

Purified Water

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Do not store above 25^oC.

6.5 Nature And Contents Of Container

Packs of 2 or 5 rectal tubes each containing 2.5ml of solution

The tubes are made of low-density polyethylene.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

UK

8. Marketing Authorisation Number(S)

PL 29831/0066

9. Date Of First Authorisation/Renewal Of The Authorisation

UK: 06/05/2008

10. Date Of Revision Of The Text

UK: 27/04/2009

Dols

Dols may be available in the countries listed below.

Ingredient matches for Dols

Tramadol

Tramadol hydrochloride (a derivative of Tramadol) is reported as an ingredient of Dols in the following countries:

• India

International Drug Name Search

Dissociative Identity Disorder Medications

There are currently no drugs listed for "Dissociative Identity Disorder". See Psychiatric Disorders.

Definition of Dissociative Identity Disorder: Dissociative Identity Disorder (DID), previously referred to as multiple personality disorder (MPD), is a dissociative disorder involving a disturbance of identity in which two or more separate and distinct personality states (or identities) control the individual's behavior at different times. When under the control of one identity, the person is usually unable to remember some of the events that occurred while other personalities were in control. The different identities, referred to as alters, may exhibit differences in speech, mannerisms, attitudes, thoughts, and gender orientation. The alters may even differ in "physical" properties such as allergies, right-or-left handedness, or the need for eyeglass prescriptions.

Drug List: