AstraZeneca Pharmaceuticals (Ireland) Ltd

Diprivan 1% w/v Emulsion for Injection or Infusion, Pre-filled Syringe.

Contains propofol 10 mg/ml.

Each 20 ml pre-filled syringe contains 200 mg propofol.

Each 50 ml pre-filled syringe contains 500 mg propofol.

Contains sodium 0.0018 mmol/ml.

Contains soya-bean oil, refined 100 mg/ml.

For a full list of excipients, see section 6.1.

White emulsion for injection or infusion, supplied in pre-filled syringes.

Diprivan is a short-acting intravenous general anaesthetic for:

• Induction and maintenance of general anaesthesia in adults and children over one month of age.

• Sedation for diagnostic and surgical procedures, alone or in combination with local or regional anaesthesia in adults and children over one month of age.

• Sedation of ventilated patients over 16 years of age in the intensive care unit.

Diprivan may be administered by a Diprifusor TCI system for induction and maintenance of general anaesthesia and conscious sedation for surgical and diagnostic procedures in adults only. Administration of Diprivan by a Diprifusor TCI system is not recommended for any indication in children or adolescents under 16 years old. Administration of Diprivan by a Diprifusor TCI system is not recommended for intensive care sedation.

Supplementary analgesic agents are generally required in addition to Diprivan.

For specific guidelines relating to the administration of Diprivan using the Diprifusor target controlled infusion (TCI) system, which incorporates Diprifusor TCI software, see section E. Such use is restricted to induction and maintenance of anaesthesia and conscious sedation for surgical and diagnostic procedures in adults. The Diprifusor TCI system is not recommended for use in ICU sedation, or in children or adolescents under 16 years old.

The glass pre-filled syringe (PFS) has a lower frictional resistance than plastic disposable syringes and operates more easily. Therefore, if Diprivan is administered using a hand held pre-filled syringe, the line between the syringe and the patient must not be left open if unattended.

A) Adults

Induction of General Anaesthesia

Diprivan 1% may be used to induce anaesthesia by slow bolus injection or infusion.

In unpremedicated and premedicated patients, it is recommended that Diprivan should be titrated (approximately 40 mg every 10 seconds in an average healthy adult by bolus injection or infusion) against the response of the patient until the clinical signs show the onset of anaesthesia. Most adult patients aged less than about 55 years are likely to require 1.5 to 2.5 mg/kg of Diprivan. The total dose required can be reduced by lower rates of administration (20–50 mg/min). Over this age, the requirement will generally be less. In patients of ASA grades 3 and 4, lower rates of administration should be used (approximately 20 mg every 10 seconds).

Maintenance of General Anaesthesia

Anaesthesia can be maintained by administering Diprivan either by continuous infusion or by repeat bolus injections to maintain the depth of anaesthesia required.

Continuous Infusion: Diprivan 1% may be used. The required rate of administration varies considerably between patients but rates in the region of 4 to 12 mg/kg/h usually maintain satisfactory anaesthesia.

Repeat Bolus Injection: If a technique involving repeat bolus injection is used, increments of 25 mg to 50 mg may be used according to clinical need.

Sedation of Ventilated Patient in the Intensive Care Unit

For sedation during intensive care it is advised that Diprivan should be administered by continuous infusion. The infusion rate should be determined by the desired depth of sedation. In most patients sufficient sedation can be obtained with a dosage of 0.3–4 mg/kg/h of Diprivan (see section 4.4). Diprivan is not indicated for sedation in intensive care of patients of 16 years of age or younger (see section 4.3). Administration of Diprivan by Diprifusor TCI system is not advised for sedation in the intensive care unit.

Conscious Sedation for Surgical and Diagnostic Procedures

To provide sedation for surgical and diagnostic procedures rates of administration should be individualised and titrated to clinical response.

Most patients will require 0.5 to 1 mg/kg over 1 to 5 minutes to initiate sedation.

Maintenance of sedation may be accomplished by titrating Diprivan infusion to the desired level of sedation – most patients will require 1.5 to 4.5 mg/kg/h. In addition to the infusion, bolus administration of 10 to 20 mg may be used if a rapid increase in the depth of sedation is required. In patients of ASA grades 3 and 4 the rate of administration and dosage may need to be reduced.

B) Elderly Patients

In elderly patients the dose requirement for induction of anaesthesia with Diprivan is reduced. The reduction should take account of the physical status and age of the patient. The reduced dose should be given at a slower rate and titrated against the response. Where Diprivan is used for maintenance of anaesthesia or sedation the rate of infusion or 'target concentration' should also be reduced. Patients of ASA grades 3 and 4 will require further reductions in dose and dose rate. Rapid bolus administration (single or repeated) should not be used in the elderly as this may lead to cardiorespiratory depression.

C) Children

Diprivan is not recommended for use in children less than one month of age.

Administration of Diprivan by a Diprifusor TCI system is not recommended for any indication in children.

Induction of General Anaesthesia: For induction of anaesthesia in children over 1 month of age, Diprivan 1% should be titrated slowly until clinical signs show the onset of anaesthesia. The dose should be adjusted according to age and/or body weight. Most patients over 8 years of age require approximately 2.5 mg/kg body weight of Diprivan 1% for induction of anaesthesia. In younger children, especially between the age of 1 month and 3 years, dose requirements may be higher (2.5–4 mg/kg body weight).

Maintenance of General Anaesthesia: Anaesthesia can be maintained by administering Diprivan by infusion or repeated bolus injection to maintain the depth of anaesthesia required. The required rate of administration varies considerably between patients but rates in the region of 9–15 mg/kg/h usually achieve satisfactory anaesthesia. In younger children, especially between the age of 1 month and 3 years, dose requirements may be higher.

For ASA 3 and 4 patients lower doses are recommended (see also Section 4.4).

Conscious Sedation for Surgical and Diagnostic Procedures: Diprivan 1% is not recommended for surgical and diagnostic procedures in children aged less than 1 month.

In children over 1 month of age, doses and adminisation rates should be adjusted according to the required depth of sedation and the clinical response. Most paediatric patients require 1–2 mg/kg body weight of Diprivan 1% for onset of sedation. Maintenance of sedation may be accomplished by titrating Diprivan 1% infusion to the desired level of sedation. Most patients require 1.5–9 mg/kg/h Diprivan 1%. The infusion may be supplemented by bolus administration of up to 1 mg/kg body weight if a rapid increase of depth of sedation is required.

In ASA 3 and 4 patients lower doses may be required.

D) Administration

Diprivan can be used for infusion undiluted from plastic syringes or glass infusion bottles or Diprivan pre-filled syringes. When Diprivan is used undiluted to maintain anaesthesia, it is recommended that equipment such as syringe pumps or volumetric infusion pumps should always be used to control infusion rates.

Diprivan 1% may also be used diluted with 5% Dextrose Intravenous Infusion only, in PVC infusion bags or glass infusion bottles. Dilutions, which must not exceed 1 in 5, should be prepared aseptically immediately before administration. The mixture is stable for up to 6 hours.

The dilution may be used with a variety of infusion control techniques but a giving set used alone will not avoid the risk of accidental, uncontrolled infusion of large volumes of diluted Diprivan. A burette, drop counter or volumetric pump must be included in the infusion line. The risk of uncontrolled infusion must be taken into account when deciding the maximum amount of dilution in the burette.

Diprivan may be administered by a Y-piece close to the injection site, into infusions of Dextrose 5% Intravenous Infusion, Sodium Chloride 0.9% Intravenous Infusion or Dextrose 4% with Sodium Chloride 0.18% Intravenous Infusion.

In order to reduce pain on initial injection, Diprivan 1% used for induction may be mixed with Lidocaine Injection in a plastic syringe in the ratio of 20 parts Diprivan 1% with up to one part of 0.5 or 1% Lidocaine Injection immediately prior to administration.

Diprivan 1% may be premixed with alfentanil injection containing 500 micrograms/ml alfentanil ('Rapifen'; Janssen Pharmaceuticals Ltd) in the ratio of 20:1 to 50:1 v/v. Mixtures should be prepared using sterile technique and used within 6 hours of preparation at room temperature and under normal lighting conditions.

The neuromuscular blocking agents atracurium and mivacurium should not be given through the same IV line as Diprivan without prior flushing.

Dilution and Co-administration of Diprivan with other Drugs or Infusion Fluids

E) Target Controlled Infusion – Administration of Diprivan by Diprifusor TCI System in Adults

Administration of Diprivan by a Diprifusor TCI system is restricted to induction and maintenance of general anaesthesia and conscious sedation for surgical and diagnostic procedures in adults. It is not recommended for use in ICU sedation or in children or adolescents under 16 years old.

To achieve induction and maintenance of anaesthesia and conscious sedation for surgical and diagnostic procedures in adults, Diprivan may be administered with the assistance of a Target Controlled Infusion (TCI) system. Such systems allow the anaesthetist or intensivist to achieve and control a desired speed of induction and depth of anaesthesia or conscious sedation by setting and adjusting target (predicted) blood concentrations of propofol. Diprivan may be administered by TCI only with a Diprifusor TCI system incorporating Diprifusor TCI software. Such systems will operate only on recognition of electronically tagged pre-filled syringes containing Diprivan 1% Injection. The Diprifusor TCI system will automatically adjust the infusion rate for the concentration of Diprivan recognised. Users must be familiar with the infusion pump users manual, and with the administration of Diprivan by TCI and with the correct use of the syringe identification system, all of which are set out in the Diprifusor training manual, available from AstraZeneca at the address below.

The pharmacokinetic model in Diprifusor TCI system assumes that the initial blood propofol concentration in the patient is zero. Therefore, in patients who have received prior propofol, there may be a need to select a lower initial target concentration when commencing Diprifusor TCI. Similarly, the immediate recommencement of Diprifusor TCI is not recommended if the pump has been switched off; if this has occurred, the Diprifusor TCI system indicates that it has been switched off by requiring re-entry/confirmation of patient data.

Guidance on propofol target concentrations is given below. In view of interpatient variability in propofol pharmacokinetics and pharmacodynamics, in both premedicated and unpremedicated patients the target propofol concentration should be titrated against the response of the patient in order to achieve the depth of anaesthesia or conscious sedation required.

In adult patients under 55 years of age, anaesthesia can usually be induced with target propofol concentrations in the region of 4 to 8 micrograms/ml. An initial target of 4 micrograms/ml is recommended in premedicated patients and in unpremedicated patients an initial target of 6 micrograms/ml is advised. Induction time with these is generally within the range of 60–120 seconds. Higher targets will allow more rapid induction of anaesthesia but may be associated with more pronounced haemodynamic and respiratory depression.

A lower initial target concentration should be used in patients over the age of about 55 years and in patients of ASA grades 3 and 4. The target concentration can then be increased in steps of 0.5 to 1.0 microgram/ml at intervals of 1 minute to achieve a gradual induction of anaesthesia.

Supplementary analgesia will generally be required and the extent to which target concentrations for maintenance of anaesthesia can be reduced will be influenced by the amount of concomitant analgesia administered. Target propofol concentrations in the region of 3 to 6 micrograms/ml usually maintain satisfactory anaesthesia.

The predicted propofol concentration on waking is generally in the region of 1.0 to 2.0 micrograms/ml and will be influenced by the amount of analgesia given during maintenance.

Conscious Sedation for Surgical and Diagnostic Procedures

Target blood propofol concentration settings in the range of 0.5 to 2.5 micrograms/ml will generally be required. The target concentration setting should be titrated against the response of the patient to achieve the depth of conscious sedation required.

An initial target concentration towards the upper end of this range will allow more rapid induction of conscious sedation.

An initial target concentration towards the lower end of this range should be used in elderly patients and in patients of ASA grades 3 and 4.

Routine oxygen supplementation should be provided.

Known hypersensitivity for any of the components of Diprivan.

Diprivan 1% must not be used in patients of 16 years of age or younger for sedation in intensive care (see section 4.4).

Diprivan contains soya oil and should not be used in patients who are hypersensitive to peanut or soya.

Diprivan is intended for use in hospitals only.

Diprivan should be given by those trained in anaesthesia, or where appropriate, doctors trained in the care of patients in Intensive Care. Patients should be constantly monitored and facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment and other resuscitative facilities should be readily available at all times. Diprivan should not be administered by the person conducting the surgical or diagnostic procedure.

When Diprivan is administered for conscious sedation for surgical and diagnostic procedures, patients should be continually monitored for early signs of hypotension, airway obstruction and oxygen desaturation.

As with other sedative agents, when Diprivan is used for sedation during operative procedures, involuntary patient movements may occur. During procedures requiring immobility these movements may be hazardous to the operative site.

An adequate period is needed prior to discharge of the patient, to ensure full recovery after general anaesthesia. Very rarely the use of Diprivan may be associated with the development of a period of postoperative unconsciousness, which may be accompanied by an increase in muscle tone. This may or may not be preceded by a period of wakefulness. Although recovery is spontaneous, appropriate care of an unconscious patient should be administered.

As with other intravenous anaesthetic agents, caution should be applied in patients with cardiac, respiratory, renal or hepatic impairment or in hypovolaemic or debilitated patients. Propofol clearance is blood flow dependent, therefore, concomitant medication that reduces cardiac output will also reduce propofol clearance.

Diprivan lacks vagolytic activity and has been associated with reports of bradycardia (occasionally profound) and also asystole. The intravenous administration of an anticholinergic agent before induction, or during maintenance of anaesthesia should be considered, especially in situations where vagal tone is likely to predominate or when Diprivan is used in conjunction with other agents likely to cause bradycardia.

When Diprivan is administered to an epileptic patient, there may be a risk of convulsion.

Propofol is not advised for general anaesthesia in children younger than 1 month of age. The safety and efficacy of Diprivan for (background) sedation in children younger than 16 years of age have not been demonstrated. Although no causal relationship has been established, serious undesirable effects with (background) sedation in patients younger than 16 years of age (including cases with fatal outcome) have been reported during unlicensed use. In particular these effects concerned occurrence of metabolic acidosis, hyperlipidemia, rhabdomyolysis and/or cardiac failure. These effects were most frequently seen in children with respiratory tract infections who received dosages in excess of those advised in adults for sedation in the intensive care unit.

Similarly very rare reports have been received of occurrence of metabolic acidosis, rhabdomyolysis, hyperkalaemia and/or rapidly progressive cardiac failure (in some cases with fatal outcome) in adults who were treated for more than 58 hours with dosages in excess of 5 mg/kg/h. This exceeds the maximum dosage of 4 mg/kg/h currently advised for sedation in the intensive care unit. The patients affected were mainly (but not only) seriously head-injured patients with raised ICP. The cardiac failure in such cases was usually unresponsive to inotropic supportive treatment. Treating physicians are reminded if possible not to exceed the dosage of 4 mg/kg/h. Prescribers should be alert to these possible undesirable effects and consider decreasing the Diprivan dosage or switching to an alternative sedative at the first sign of occurrence of symptoms. Patients with raised ICP should be given appropriate treatment to support the cerebral perfusion pressure during these treatment modifications.

Appropriate care should be applied in patients with disorders of fat metabolism and in other conditions where lipid emulsions must be used cautiously.

It is recommended that blood lipid levels be monitored should Diprivan be administered to patients thought to be at particular risk of fat overload. Administration of Diprivan should be adjusted appropriately if the monitoring indicates that fat is being inadequately cleared from the body. If the patient is receiving other intravenous lipid concurrently, a reduction in quantity should be made in order to take account of the amount of lipid infused as part of the Diprivan formulation: 1.0 ml of Diprivan contains approximately 0.1 g of fat.

The use of Diprivan 1% is not recommended for newborn infants for induction and maintenance of anaesthesia as this patient population has not been fully investigated. Pharmacokinetic data (see Section 5.2) indicate that clearance is considerably reduced in neonates with a very high inter-individual variability. Relative overdose could occur administering doses recommended for older children resulting in severe cardiovascular depression (see sections 4.2 and 4.8).

EDTA is a chelator of metal ions, including zinc. The need for supplemental zinc should be considered during prolonged administration of Diprivan, particularly in patients who are predisposed to zinc deficiency, such as those with burns, diarrhoea and/or major sepsis.

Diprivan contains 0.0018 mmol sodium per ml and 100 mg refined soya-bean oil per ml.

Additional precautions

Diprivan contains no antimicrobial preservatives and supports growth of micro-organisms.When Diprivan is to be aspirated, it must be drawn aseptically into a sterile syringe or giving set immediately after opening the ampoule or breaking the vial seal. Administration must commence without delay. Asepsis must be maintained for both Diprivan and infusion equipment throughout the infusion period. Any infusion fluids added to the Diprivan line must be administered close to the cannula site. Diprivan must not be administered via a microbiological filter.

Diprivan and any syringe containing Diprivan are for single use in an individual patient. In accordance with established guidelines for other lipid emulsions, a single infusion of Diprivan must not exceed 12 hours. At the end of the procedure or at 12 hours, whichever is the sooner, both the reservoir of Diprivan and the infusion line must be discarded and replaced as appropriate.

Diprivan has been used in association with spinal and epidural anaesthesia and with commonly used premedicants, neuromuscular blocking drugs, inhalational agents and analgesic agents; no pharmacological incompatibility has been encountered. Lower doses of Diprivan may be required where general anaesthesia is used as an adjunct to regional anaesthetic techniques. The hypotensive effect of propofol may be potentiated by the concomitant administration of opiate analgesics. This effect may be more marked in elderly patients and when agents such as alfentanil are given by infusion.

Pregnancy: The safety of Diprivan during pregnancy has not been established. Therefore, Diprivan should not be used in pregnant women unless clearly necessary. Propofol crosses the placenta and may be associated with neonatal depression. High doses (more than 2.5 mg/kg for induction or 6 mg/kg/h for maintenance of anaesthesia) should be avoided.

Lactation: Safety to the neonate following the use of Diprivan in mothers who are breast-feeding has not been established. Studies in breast-feeding women showed that propofol is excreted in small amounts into the milk. Therefore, mothers should stop breast-feeding and discard breast milk for 24 hours after administration of propofol.

Patients should be advised that performance of skilled tasks, such as driving and operating machinery, may be impaired for some time after general anaesthesia.

General

Induction of anaesthesia is generally smooth with minimal evidence of excitation, although spontaneous movements may be seen in some patients. The most commonly reported ADRs are pharmacologically predictable side effects of an anaesthetic agent, such as hypotension. Given the nature of anaesthesia and those patients receiving intensive care, events reported in association with anaesthesia and intensive care may also be related to the procedures being undertaken or the recipient's condition.

(1) May be minimised by using the larger veins of the forearm and antecubital fossa. With Diprivan 1% local pain can also be minimised by the co-administration of lidocaine (see section 4.2, part D).

(2) Occasionally, hypotension may require use of intravenous fluids and reduction of the administration rate of Diprivan.

(3) Serious bradycardias are rare. There have been isolated reports of progression to asystole.

(4) Very rare reports of rhabdomyolysis have been received where Diprivan has been given at doses greater than 4 mg/kg/hr for ICU sedation.

In very rare cases rhabdomyolysis, metabolic acidosis, hyperkalaemia or cardiac failure, sometimes with fatal outcome, have been observed when Diprivan was administered at dosages in excess of 4 mg/kg/h for sedation in the intensive care unit (see section 4.4).

Reports from off-label use of Diprivan for induction of anaesthesia in neonates indicate that cardiorespiratory depression may occur if the paediatric dose regimen is applied (see sections 4.2 and 4.4).

Local

The local pain which may occur during the induction phase can be minimised by the use of the larger veins in the forearm and antecubital fossa. With Diprivan 1% local pain can also be minimised by the co-administration of lidocaine (see section 4.2). Thrombosis and phlebitis are rare. Accidental clinical extravasation and animal studies showed minimal tissue reaction. Intra-arterial injection in animals did not induce local tissue effects.

Accidental overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression would require lowering of the patient's head and, if severe, use of plasma expanders and pressor agents.

Propofol (2,6-diisopropylphenol) is a short-acting general anaesthetic agent with a rapid onset of action of approximately 30 seconds. Recovery from anaesthesia is usually rapid. The mechanism of action, like all general anaesthetics is poorly understood. However, propofol is thought to produce its sedative/anaesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABA_A receptors.

In general, falls in mean arterial blood pressure and slight changes in heart rate are observed when Diprivan is administered for induction and maintenance of anaesthesia. However, the haemodynamic parameters normally remain relatively stable during maintenance and the incidence of untoward haemodynamic changes is low.

Although ventilatory depression can occur following administration of Diprivan, any effects are quantitatively similar to those of the other intravenous anaesthetic agents and are readily manageable in clinical practice.

Diprivan reduces cerebral blood flow, intracranial pressure and cerebral metabolism. The reduction in intracranial pressure is greater in patients with an elevated baseline intracranial pressure.

Recovery from anaesthesia is usually rapid and clear headed with a low incidence of headache and postoperative nausea and vomiting.

In general, there is less postoperative nausea and vomiting following anaesthesia with Diprivan than following anaesthesia with inhalational agents.

Diprivan, at the concentrations likely to occur clinically, does not inhibit the synthesis of adrenocortical hormones.

Limited studies on the duration of propofol based anaesthesia in children indicate safety and efficacy is unchanged up to duration of 4 hours. Literature evidence of use in children documents use for prolonged procedures without changes in safety or efficacy.

The decline in propofol concentrations following a bolus dose or following the termination of an infusion can be described by a three compartment open model. The first phase is characterised by a very rapid distribution (half-life: 2–4 minutes), followed by rapid elimination (half-life: 30–60 minutes) and a slower final phase, representative of redistribution of propofol from poorly perfused tissue.

Propofol is extensively distributed and rapidly cleared from the body (total body clearance: 1.5–2 litres/minute). Clearance occurs by metabolic processes, mainly in the liver where it is blood flow dependent, to form inactive conjugates of propofol and its corresponding quinol, which are excreted in urine.

When Diprivan is used to maintain anaesthesia, blood concentrations of propofol asymptotically approach the steady-state value for the given administration rate. The pharmacokinetics are linear over the recommended range of infusion rates of Diprivan.

After a single dose of 3 mg/kg intravenously, propofol clearance/kg body weight increased with age as follows: Median clearance was considerably lower in neonates <1 month old (n=25) (20 ml/kg/min) compared to older children (n= 36, age range 4 months–7 years). Additionally inter-individual variability was considerable in neonates (range 3.7–78 ml/kg/min). Due to this limited trial data that indicates a large variability, no dose recommendations can be given for this age group.

Median propofol clearance in older aged children after a single 3 mg/kg bolus was 37.5 ml/min/kg (4-24 months) (n=8), 38.7 ml/min/kg (11–43 months) (n=6), 48 ml/min/kg (1–3 years) (n=12), 28.2 ml/min/kg (4–7 years) (n=10) as compared with 23.6 ml/min/kg in adults (n=6).

Propofol is a drug on which extensive clinical experience has been obtained. All relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

Soya-bean Oil, Refined Ph. Eur.

Purified Egg Phosphatide

Glycerol Ph. Eur. (E422)

Sodium Hydroxide Ph. Eur. (E524) (for the adjustment of pH)

Disodium Edetate Ph. Eur.

Water for Injections Ph. Eur.

Diprivan should not be mixed prior to administration with injections or infusion fluids with the exception of Diprivan 1% which can be mixed with 5% Dextrose, in PVC bags or glass infusion bottles or Lidocaine Injection in plastic syringes and alfentanil injection (see section 4.2).

The neuromuscular blocking agents, atracurium and mivacurium should not be given through the same IV line as Diprivan without prior flushing.

6.3.1 Shelf life of the product as packaged for sale:

2 years

6.3.2 Shelf life after dilution:

Use within 6 hours of dilution.

Do not store above 25°C. Do not freeze.

For storage precautions for diluted product see section 6.3.

Type I glass pre-filled syringes containing 20 ml or 50 ml.

Not all pack sizes may be marketed.

In-use precautions: Containers should be shaken before use. Any portion of the contents remaining after use should be discarded.

When the pre-filled syringe presentation is used in a syringe pump appropriate compatibility should be ensured. In particular, the pump should be designed to prevent siphoning and should have an occlusion alarm set no greater than 1000 mm Hg. If using a programmable or equivalent pump that offers options for use of different syringes then choose only the B-D 50/60 ml PLASTIPAK setting when using the Diprivan pre-filled syringe.

Asepsis for Diprivan and infusion equipment must be maintained (see Section 4.4 Warnings and precautions for use).

AstraZeneca UK Ltd.,

600 Capability Green,

Luton,

LU1 3LU,

United Kingdom

PA 970/5/4

19^th October 1995/6^th November 2007

27^th June 2011