Remifentanil 1 mg powder for concentrate for solution for injection / infusion

1. Name Of The Medicinal Product

Remifentanil 1 mg powder for concentrate for solution for injection/infusion

2. Qualitative And Quantitative Composition

Remifentanil 1 mg powder for concentrate for solution for injection/infusion:

1 vial contains 1 mg remifentanil (as remifentanil hydrochloride).

After reconstitution the solution contains 1 mg/ml remifentanil (as hydrochloride), if prepared as recommended (see section 6.6)

Excipients: sodium 1.15 mg

3. Pharmaceutical Form

Powder for concentrate for solution for injection/infusion

Lyophilized white to slightly yellow cake or powdery mass.

4. Clinical Particulars

4.1 Therapeutic Indications

Remifentanil is indicated as an analgesic agent for use during induction and/or maintenance of general anaesthesia.

Remifentanil is indicated for provision of analgesia in mechanically ventilated intensive care patients of 18 years of age and older.

4.2 Posology And Method Of Administration

Remifentanil should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by persons specifically trained in the use of anaesthetic drugs and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation. Such training must include the establishment and maintenance of a patent airway and assisted ventilation.

Continuous infusions of remifentanil must be administered by a calibrated infusion device into a fast flowing IV line or via a dedicated IV line. This infusion line should be connected at, or close to, the venous cannula to minimise the potential dead space (see section 6.6 for additional information, including tables with examples of infusion rates by body weight to help titrate remifentanil to the patient's anaesthetic needs). Care should be taken to avoid obstruction or disconnection of infusion lines and to adequately clear the lines to remove residual remifentanil after use (see section 4.4). IV lines/infusion system should be removed after cessation of use to avoid inadvertent administration.

Remifentanil may be given by target-controlled infusion (TCI) with an approved infusion device incorporating the Minto pharmacokinetic model with covariates for age and lean body mass (LBM).

Congestion of the infusion drips or tearing off should be avoided, and the infusion drips should be sufficiently rinsed in order to remove residual Remifentanil after discontinuation of medication (see also section 4.4).

Remifentanil is for intravenous use only and must not be administered by epidural or intrathecal injection (see section 4.3).

Dilution

Remifentanil should not be administered without further dilution after reconstitution of the lyophilized powder. See section 6.3 for storage conditions and section 6.6 for recommended diluents and instructions on reconstitution / dilution of the product before administration.

For manually-controlled infusion [Invented name] can be diluted to concentrations of 20 to 250 micrograms /ml (50 micrograms /ml is the recommended dilution for adults and 20 to 25 micrograms /ml for paediatric patients aged 1 year and over).

For TCI the recommended dilution of Remifentanil is 20 to 50 micrograms /ml.

General Anaesthesia

The administration of Remifentanil must be individualised based on the patient's response.

Adults

Administration by manually-controlled infusion (MCI)

DOSING GUIDELINES FOR ADULTS

	REMIFENTANIL BOLUS INJECTION (micrograms /kg)	REMIFENTANIL CONTINUOUS INFUSION (micrograms/kg/min)
Starting Rate	Range
	1 (within at least 30 seconds)	0.5 to 1	_
	Maintenance of anaesthesia in ventilated patients
• Nitrous oxide (66 %)	0.5 to 1	0.4	0.1 to 2
• Isoflurane (starting dose 0.5 MAC)	0.5 to 1	0.25	0.05 to 2
• Propofol (Starting dose 100 microtrams /kg/min)	0.5 to 1	0.25	0.05 to 2

When given by bolus injection at induction Remifentanil should be administered over not less than 30 seconds.

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil.

No data are available for dosage recommendations for simultaneous use of other hypnotics other than those listed in the table with remifentanil.

Induction of anaesthesia

Remifentanil should be co-administered with a hypnotic agent, such as propofol, thiopentone, or isoflurane, for the induction of anaesthesia. Administering Remifentanil after a hypnotic agent will reduce the incidence of muscle rigidity. Remifentanil can be administered at an infusion rate of 0.5 to 1 micrograms /kg/min, with or without an initial bolus injection of 1 micrograms /kg given over not less than 30 seconds. If endotracheal intubation is to occur more than 8 to 10 minutes after the start of the infusion of [Invented name], then a bolus injection is not necessary.

Maintenance of anaesthesia in ventilated patients

After endotracheal intubation, the infusion rate of Remifentanil should be decreased, according to anaesthetic technique, as indicated in the above table. Due to the fast onset and short duration of action of remifentanil, the rate of administration during anaesthesia can be titrated upward in 25% to 100% increments or downward in 25% to 50% decrements, every 2 to 5 minutes to attain the desired level of μ-opioid response. In response to light anaesthesia, supplemental bolus injections may be administered every 2 to 5 minutes.

Anaesthesia in spontaneously breathing patients

In spontaneously breathing anaesthetised patients with a secured airway respiratory depression is likely to occur. Therefore attention must be given to respiratory effects eventually combined with muscular rigidity. Special care is needed to adjust the dose to the patient requirements and ventilatory support may be required. Adequate facilities should be available for monitoring of patients administered remifentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression (intubation equipment must be available) and/or muscle rigidity (for more information see section 4.4).

The recommended starting infusion rate for supplemental analgesia in spontaneously breathing anaesthetised patients is 0.04 μg/kg/min with titration to effect. A range of infusion rates from 0.025 to 0.1 μg/kg/min has been studied.

Bolus injections are not recommended in spontaneously breathing anaesthetised patients.

Remifentanil should not be used as an analgesic in procedures where patients remain conscious or do not receive any airway support during the procedure.

Concomitant medication

Remifentanil decreases the amounts or doses of inhalational anaesthetics, hypnotics and benzodiazepines required for anaesthesia (see section 4.5).

Doses of the following agents used in anaesthesia: isoflurane, thiopentone, propofol and temazepam have been reduced by up to 75 % when used concurrently with remifentanil.

Guidelines for discontinuation/continuation during immediate postoperative period

Due to the very rapid offset of action of remifentanil no residual opioid activity will be present within 5 to 10 minutes after discontinuation. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of remifentanil. Sufficient time must be allowed to reach the maximum effect of the longer acting analgesic. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of post-operative care.

In case the longer acting analgesic has not reached the appropriate effect before the end of surgery, the administration of remifentanil can be continued to maintain analgesia during immediate postoperative period until the longer acting analgesic has reached the maximum effect.

If remifentanil is continued post-procedural, it should only be used in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function, under the close supervision of persons specifically trained in the recognition and management of the respiratory effects of potent opioids.

Furthermore it is recommended that patients should be closely monitored post-operatively for pain, hypotension and bradycardia.

Further information about the administration in mechanically ventilated intensive care patients is given in section 4.2.

In spontaneously breathing patients the initial infusion rate of remifentanil may be decreased to 0.1 µg/kg/min and thereafter can be increased or decreased every 5 min in steps of 0.025 µg/kg/min to balance the extent of analgesia against the degree of respiratory depression.

In spontaneously breathing patients bolus doses for analgesia are not recommended during postoperative period.

Administration by Target-Controlled Infusion (TCI)

Induction and maintenance of anaesthesia in ventilated patients

Remifentanil TCI should be used in association with an intravenous or inhalational hypnotic agent during the induction and maintenance of anaesthesia in ventilated adult patients (see table 1 above for manually controlled infusion). In association with these agents, adequate analgesia for induction of anaesthesia and surgery can generally be achieved with target blood remifentanil concentrations ranging from 3 to 8 ng/ml. Remifentanil should be titrated to individual patient response. For particularly stimulating surgical procedures target blood concentrations up to 15 ng/ml may be required.

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil (see table 1 above for manually controlled infusion).

The following table provides the equivalent blood remifentanil concentration using a TCI approach for various manually controlled infusion rates at steady state:

Remifentanil blood concentrations (nanograms/ml) estimated using the Minto (1997) pharmacokinetic model in a 70 kg, 170 cm, 40 year old male patient for various manually controlled infusion rates (micrograms/kg/min) at steady state

Remifentanil Infusion Rate (micrograms /kg/min)	Remifentanil Blood Concentration (nanograms/ml)
0.05	1.3
0.10	2.6
0.25	6.3
0.40	10.4
0.50	12.6
1.0	25.2
2.0	50.5

As there are insufficient data, the administration of remifentanil by TCI for spontaneous ventilation anaesthesia is not recommended.

Guidelines for discontinuation/continuation into the immediate post-operative period

At the end of surgery when the TCI infusion is stopped or the target concentration reduced, spontaneous respiration is likely to return at calculated remifentanil concentrations in the region of 1 to 2 ng/ml. As with manually controlled infusion, post-operative analgesia should be established before the end of surgery with longer acting analgesics (see also Guidelines for discontinuation / continuation during immediate postoperative period in section above for Manually Controlled Infusion).

As there are insufficient data, the administration of [Invented name] by TCI for the management of post-operative analgesia is not recommended.

Paediatric patients (1 to12 years of age)

Co-administration of remifentanil with induction agents has not been studied. The use of remifentanil for induction of anaesthesia by TCI in patients aged 1 to12 years is not recommended as there are no data available in this patient population.

Maintenance of anaesthesia

The following doses of remifentanil (see table) are recommended for maintenance of anaesthesia:

DOSING GUIDELINES FOR PAEDIATRIC PATIENTS (1 to12 years of age)

*CONCOMITANT ANAESTHETIC AGENT	REMIFENTANIL BOLUS INJECTION (micrograms /kg)	REMIFENTANIL CONTINUOUS INFUSION
Starting Rate (micrograms /kg/min)	Range for maintenance of anaesthesia (micrograms /kg/min)
Halothane (starting dose 0.3 MAC)	1	0.25	0.05 to 1.3
Sevoflurane (starting dose 0.3 MAC)	1	0.25	0.05 to 0.9
Isoflurane (starting dose 0.5 MAC)	1	0.25	0.06 to 0.9

*co-administered with nitrous oxide/oxygen in a ratio of 2:1

When given by bolus injection, Remifentanil should be administered over not less than 30 seconds. Surgery should not commence until at least 5 minutes after the start of the Remifentanil infusion, if a simultaneous bolus dose has not been given.

For exclusive administration of nitrous oxide (70 %) and Remifentanil infusion rates for maintenance of anaesthesia should be between 0.4 und 3 micrograms/kg/min. Data gained from adults suggest that 0.4 micrograms/kg/min may be a convenient initial dose although specific studies are lacking.

Paediatric patients should be monitored and the dose titrated to the depth of analgesia appropriate for the surgical procedure.

Concomitant medication

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane, halothane and sevoflurane should be administered as recommended above to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil. No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil (see in section above: Administration by Manually Controlled Infusion (MCI), Concomitant medication).

Guidelines for patient management in the immediate post-operative period

Establishment of alternative analgesia prior to discontinuation of Remifentanil:

Due to the very rapid offset of action of remifentanil, no residual activity will be present within 5 to 10 minutes after discontinuation. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of remifentanil. Sufficient time must be allowed to reach the therapeutic effect of the longer acting analgesic. The choice of agent(s), the dose and the time of administration should be planned in advance and individually tailored to be appropriate for the patient's surgical procedure and the level of post-operative care anticipated (see section 4.4).

Neonates/infants (aged less than 1 year):

The pharmacokinetic profile of remifentanil in neonates and infants (aged less than 1 year) is comparable to that seen in adults after correction for body weight differences. However, because there are insufficient clinical data, the administration of remifentanil is not recommended for this age group.

Special Patient groups

For dosage recommendations for special patient groups (elderly and obese patients, renally and hepatically impaired patients, patients undergoing neurosurgery and ASA III/IV patients; see section 4.2).

Cardiac Surgery

Administration by Manually-Controlled Infusion

For dosage recommendations in patients undergoing cardiac surgery see table below:

DOSING GUIDELINES FOR CARDIAC ANAESTHESIA

INDICATION	REMIFENTANIL BOLUS INJECTION (micrograms /kg)	REMIFENTANIL CONTINUOUS INFUSION (micrograms /kg/min)
Starting Rate	Typical infusion rates
Intubation	Not recommended	1	_
Maintenance of anaesthesia
• Isoflurane (starting dose 0.4 MAC)	0.5 to 1	1	0.003 to 4
• Propofol (Starting dose 50 micrograms /kg/min)	0.5 to 1	1	0.01 to 4.3
Continuation of post-operative analgesia, prior to extubation	Not recommended	1	0 to 1

Induction of anaesthesia

After administration of hypnotic to achieve loss of consciousness, Remifentanil should be administered at an initial infusion rate of 1 micrograms /kg/min. The use of bolus injections of Remifentanil during induction in cardiac surgical patients is not recommended. Endotracheal intubation should not occur until at least 5 minutes after the start of the infusion.

Maintenance period of anaesthesia

After endotracheal intubation the infusion rate of Remifentanil should be titrated according to the patient need. Supplemental bolus doses may also be administered as required.

High risk cardiac patients, such as those undergoing valve surgery or with poor left ventricular function, should be administered a maximum bolus dose of 0.5 micrograms/kg.

These dosing recommendations also apply during hypothermic cardiopulmonary bypass (see section 5.2).

Concomitant medication

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil. No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil (see in section above: Administration by Manually Controlled Infusion (MCI), Concomitant medication).

Guidelines for postoperative supply of patient

Continuation of Remifentanil post-operatively to provide analgesia prior to extubation

It is recommended that the infusion of Remifentanil is maintained at the final intra-operative rate during transfer of patients to the post-operative care area. The patient's level of analgesia and sedation should be closely monitored and the Remifentanil infusion rate adjusted to meet the individual patient's requirements (see Intensive care, below, for further information on management of intensive care patients.

Establishment of alternative analgesia prior to discontinuation of Remifentanil

Due to the very rapid offset of action of remifentanil, no residual opioid activity will be present within 5 to 10 minutes after discontinuation. Prior to discontinuation of Remifentanil, patients must be given alternative analgesic and sedative agents at a sufficient time in advance to allow the therapeutic effects of these agents to become established. It is therefore recommended that the choice of agent(s), the dose and the time of administration are planned, before weaning the patient from the ventilator.

Guidelines for discontinuation of Remifentanil

Due to the very rapid offset of action of Remifentanil, hypertension, shivering and aches have been reported in cardiac patients immediately following discontinuation of Remifentanil (see section 4.8 Undesirable effects). To minimise the risk of these events, adequate alternative analgesia must be established (as described above), before the Remifentanil infusion is discontinued. The infusion rate should be reduced by 25% decrements in at least 10-minute intervals until the infusion is discontinued.

During weaning from the ventilator the Remifentanil infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics. Haemodynamic changes such as hypertension and tachycardia should be treated with alternative agents as appropriate.

When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the patient must be carefully monitored. The benefit of providing adequate post-operative analgesia must always be balanced against the potential risk of respiratory depression with these agents.

Administration by Target-Controlled Infusion

Induction and maintenance of anaesthesia in ventilated patients

Remifentanil TCI should be used in association with an intravenous or inhalational hypnotic agent during the induction and maintenance of anaesthesia in ventilated adult patients (see the table in section 4.2 under Cardiac surgery/Administration by Manually-Controlled Infusion/Dosing guidelines for cardiac anaesthesia). In association with these agents, adequate analgesia for cardiac surgery is generally achieved at the higher end of the range of target blood remifentanil concentrations used for general surgical procedures. Following titration of remifentanil to individual patient response, blood concentrations as high as 20 nanograms /ml have been achieved in clinical studies.

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil (see table in section 4.2 under Cardiac surgery/Administration by Manually-Controlled Infusion/Dosing guidelines for cardiac anaesthesia).

For information on blood remifentanil concentrations achieved with manually controlled infusion see Table 6

Guidelines for discontinuation/continuation into the immediate post-operative period

At the end of surgery when the TCI infusion is stopped or the target concentration reduced, spontaneous respiration is likely to return at calculated remifentanil concentrations in the range of 1 to 2 nanograms /ml. As with manually-controlled infusion, post-operative analgesia should be established before the end of surgery with longer acting analgesics (see section 4.2 under Cardiac surgery/Administration by Manually-Controlled Infusion/Guidelines for discontinuation of Remifentanil.

As there are insufficient data, the administration of Remifentanil by TCI for the management of post-operative analgesia is not recommended.

Intensive Care – Adults

Remifentanil can be used in mechanically ventilated intensive care patients. If required, additionally sedating drugs should be applied.

Remifentanil has been studied in intensive care patients in well controlled clinical trials for up to three days. As patients were not studied beyond three days, no evidence of safety and efficacy for longer treatment has been established. Therefore, a usage longer than three days is not recommended.

Due to the lack of data the administration of remifentanil by TCI is not recommended for ICU patients.

In adults, it is recommended that Remifentanil is initiated at an infusion rate of 0.1 micrograms /kg/min (6 micrograms /kg/h) to 0.15 micrograms /kg/min (9 micrograms /kg/h). The infusion rate should be titrated in increments of 0.025 micrograms /kg/min (1.5 micrograms /kg/h) to achieve the desired level of analgesia. A period of at least 5 minutes should be allowed between dose adjustments. The patient should be carefully monitored, regularly reassessed and the Remifentanil infusion rate adjusted accordingly. If an infusion rate of 0.2 micrograms /kg/min (12 micrograms /kg/h) is reached and the desired level of sedation is not achieved, it is recommended that dosing with an appropriate sedative agent is initiated (see below). The dose of the sedative agent should be titrated to obtain the desired level of sedation. Further increases to the [Invented name] infusion rate in increments of 0.025 micrograms /kg/min (1.5 micrograms /kg/h) may be made if additional analgesia is required.

The following table summarises the starting infusion rates and typical dose range for provision of analgesia in individual patients:

DOSING GUIDELINES FOR USE OF REMIFENTANIL WITHIN THE INTENSIVE CARE SETTING

CONTINUOUS INFUSION micrograms /kg/min (micrograms /kg/h)
Starting Rate	Range
0.1 (6) to 0.15 (9)	0.006 (0.36) to 0.74 (44.4)

Bolus doses of Remifentanil are not recommended in the intensive care setting.

The use of Remifentanil will reduce the dosage requirement of any concomitant sedative agents. Typical starting doses for sedative agents, if required, are given below.

RECOMMENDED STARTING DOSE OF SEDATIVE AGENTS, IF REQUIRED

Sedative Agent	Bolus (mg/kg)	Infusion rate (mg/kg/h)
Propofol	Up to 0.5	0.5
Midazolam	Up to 0.03	0.03

To allow separate titration of the respective agents, sedative agents should not be administered as an admixture.

Additional analgesia for ventilated patients undergoing painful procedures

An increase in the existing Remifentanil infusion rate may be required to provide additional analgesic cover for ventilated patients undergoing stimulating and/or painful procedures such as endotracheal suctioning, wound dressing and physiotherapy. It is recommended that a Remifentanil infusion rate of at least 0.1 micrograms /kg/min (6 micrograms /kg/h) is maintained for at least 5 minutes prior to the start of the stimulating procedure. Further dose adjustments may be made every 2 to 5 minutes in increments of 25%-50% in anticipation of, or in response to, additional requirement for analgesia. A mean infusion rate of 0.25 micrograms /kg/min (15 micrograms /kg/h), maximum 0.75 micrograms kg/min (44,4 micrograms /kg/h), has been administered for provision of additional analgesia during stimulating procedures.

Establishment of alternative analgesia prior to discontinuation of Remifentanil

Due to the very rapid offset of action of remifentanil, no residual opioid activity will be present within 5 to 10 minutes after discontinuation regardless of the duration of infusion. After administration of remifentanil the potential for the development of tolerance and hyperalgesia should be attended. Therefore, prior to discontinuation of remifentanil, patients must be given alternative analgesic and sedative agents at a sufficient time in advance to allow the therapeutic effects of these agents to become established and to prevent hyperalgesia and concomitant haemodynamic changes. It is therefore recommended that the choice of agent(s), the dose and the time of administration are planned prior to discontinuation of remifentanil. Long acting analgetics or intravenous or local analgetics, which can be controlled by the health care staff or the patient are alternative options for analgesia and should be chosen carefully according to the patients needs.

Prolonged administration of µ-opioid agonists may induce development of tolerance.

Guidelines for extubation and discontinuation of Remifentanil

In order to ensure a smooth emergence from a remifentanil-based regimen it is recommended that the infusion rate of Remifentanil is titrated gradually to 0.1 micrograms /kg/min (6 micrograms /kg/h) over a period up to 1 hour prior to extubation.

Following extubation, the infusion rate should be reduced by 25% decrements in at least 10-minute intervals until the infusion is discontinued. During weaning from the ventilator the Remifentanil infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics.

Upon discontinuation of Remifentanil, the IV cannula should be cleared or removed to prevent subsequent inadvertent administration.

When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the patient must be carefully monitored. The benefit of providing adequate analgesia must always be balanced against the potential risk of respiratory depression.

The following tables 1-5 give guidelines for infusion rates of Remifentanil for manually-controlled infusion:

Table 1: Remifentanil – Infusion rates (ml/kg/h)

Medicinal prodcuct delivery rate (µg/kg/min)	Infusion delivery rate (ml/kg/h) for solution concentrations of
20 micrograms /ml 1 mg/50 ml	25 micrograms /ml 1 mg/40 ml	50 micrograms /ml 1 mg/20 ml	250 micrograms /ml 10 mg/40 ml
0.0125 0.025 0.05 0.075 0.1 0.15 0.2 0.25 0.5 0.75 1.0 1.25 1.5 1.75 2.0	0.038 0.075 0.15 0.23 0.3 0.45 0.6 0.75 1.5 2.25 3.0 3.75 4.5 5.25 6.0	0.03 0.06 0.12 0.18 0.24 0.36 0.48 0.6 1.2 1.8 2.4 3.0 3.6 4.2 4.8	0.015 0.03 0.06 0.09 0.12 0.18 0.24 0.3 0.6 0.9 1.2 1.5 1.8 2.1 2.4	Not recommended Not recommended 0.012 0.018 0.024 0.036 0.048 0.06 0.12 0.18 0.24 0.3 0.36 0.42 0.48

Table 2: Remifentanil – Infusion rates (ml/h) for a 20 micrograms /ml solution

Infusion rate (micrograms /kg/min)	Patient weight (kg)
5	10	20	30	40	50	60
0.0125	0.188	0.375	0.75	1.125	1.5	1.875	2.25
0.025	0.375	0.75	1.5	2.25	3.0	3.75	4.5
0.05	0.75	1.5	3.0	4.5	6.0	7.5	9.0
0.075	1.125	2.25	4.5	6.75	9.0	11.25	13.5
0.1	1.5	3.0	6.0	9.0	12.0	15.0	18.0
0.15	2.25	4.5	9.0	13.5	18.0	22.5	27.0
0.2	3.0	6.0	12.0	18.0	24.0

Rythmodan 100mg Capsules.

1. Name Of The Medicinal Product

Rythmodan 100mg Capsules.

2. Qualitative And Quantitative Composition

Capsule containing Disopyramide 100mg.

For excipients, see section 6.1.

3. Pharmaceutical Form

Capsule.

4. Clinical Particulars

4.1 Therapeutic Indications

Rythmodan is used in the treatment of cardiac arrhythmias as follows:-

1. The prevention and treatment of arrhythmias occurring after myocardial infarction.

2. Maintenance of normal rhythm following electroconversion eg atrial fibrillation, atrial flutter.

3. Persistent ventricular extrasystoles.

4. Control of arrhythmias following the use of digitalis or similar glycosides.

5. Suppression of arrhythmias during surgical procedures eg cardiac catheterisation.

6. The prevention of paraxysmal supraventricular tachycardia.

7. Other types of arrhythmias e.g. atrial extrasystoles, Wolff-Parkinson-White Syndrome.

4.2 Posology And Method Of Administration

Route of administration

Oral

300 mg to 800mg daily in divided doses.

Children :

Not recommended as insufficient data available.

Elderly

A dose reduction due to reduced renal and hepatic function in the elderly (especially elderly non-smokers) should be considered (see section 4.4)

4.3 Contraindications

Disopyramide is contra–indicated in un–paced second or third degree atrioventricular block; bundle–branch block associated with first–degree atrioventricular block ; unpaced bifasicular block; pre-existing long QT syndromes; severe sinus node dysfunction ; severe heart failure, unless of secondary to cardiac arrhythmia ; hypersensitivity to disopyramide. It is also contra–indicated in concomitant administration with other anti–arrhythmics or other drugs liable to provoke ventricular arrythmias, especially Torsade de Pointes (see section 4.5). The sustained release formulation is contra–indicated in patients with renal or hepatic impairment.

4.4 Special Warnings And Precautions For Use

Antiarrhythmic drugs belonging to the class 1c (Vaughan Williams Classification) were included in the Cardiac Arrhythmia Suppression Trial (CAST), a long term multicentre randomised, double blind study in patients with asymptomatic non life–threatening ventricular arrhythmia who have had a myocardial infarction more than six days but less than two years previously. A significant increase in mortality and non–fatal cardiac arrest rate was seen in patients treated with class 1c antiarrhythmic drugs when compared with a matched placebo group. The applicability of the CAST results to other antiarrhythmics and other populations (eg. those without recent infarction) is uncertain. At present, it is best to assume that the risk extends to other antiarrhythmic agents for patients with structural heart disease.

There is no evidence that prolonged suppression of ventricular premature contractions with antiarrhythmic drugs prevents sudden death. For this reason, antiarrhythmic drugs should not be prescribed for the treatment of patients with asymptomatic ventricular premature contractions.

All antiarrhythmic drugs can produce unwanted effects when they are used to treat symptomatic but not life threatening arrhythmia; the expected benefits should be balanced against their risks.

In patients with structural heart disease, proarrhythmia and cardiac decompensation are special risks associated with antiarrhythmic drugs. Special caution should be exercised when prescribing in this context.

Disopyramide should not be used in patients with uncompensated congestive heart failure, unless this heart failure is secondary to cardiac arrhythmia. If disopyramide is to be given under these circumstances, special care and monitoring are essential.

Life-threatening and haemodynamically significant arrhythmias are difficult to treat and affected patients have a high mortality risk. Treatment of these arrhythmias, by whatever modality, must be initiated in hospital.

Owing to its negative inotropic effect, disopyramide should be used with caution in patients suffering from significant cardiac failure.This group may be specially sensitive to the negative inotropic properties of disopyramide. Such patients should be fully digitalised or controlled with other therapy before treatment with disopyramide is commenced.

Aggravation of existing arrhythmia, or emergence of a new type of arrhythmia, demands urgent review of disopyramide treatment.

Similarly, if an atrioventricular block or a bifascicular block occurs during treatment, the use of disopyramide should be reviewed.

There have been reports of ventricular tachycardia, ventricular fibrillation and Torsade de Pointes in patients receiving disopyramide. These have usually, but not always, been associated with significant widening of the QRS complex or prolonged QT interval. The QT interval and QRS duration must be monitored and disopyramide should be stopped if these are increased by more than 25%. If these changes or arrhythmias develop the drug should be discontinued. Disopyramide should be used only with caution in patients with atrial flutter or atrial tachycardia with block as conversion of a partial AV block to a 1:1 response may occur, leading to a potentially more serious tachyarrhythmia.

The occurrence of hypotension following disopyramide administration requires prompt discontinuation of the drug. This has been observed especially in patients with cardiomyopathy or uncompensated congestive heart failure. Any resumption of therapy should be at a lower dose with close patient monitoring. Disopyramide should be used with caution in the treatment of digitalis intoxication.

Potassium imbalance: Antiarrhythmic drugs may be hazardous in patients with potassium imbalance, as potassium abnormalities can induce arrhythmias.

During treatment with disopyramide, potassium levels should be checked regularly. Patients treated with diuretics or stimulant laxatives are at particular risk of hypokalaemia.

Renal insufficiency: In renal insufficiency, the dosage of disopyramide should be reduced by adjusting the interval between administrations.

Hepatic insufficiency: Hepatic impairment causes an increase in the plasma half–life of Rythmodan and a reduced dosage may be required.

Hypoglycaemia: Hypoglycaemia has been reported in association with disopyramide administration. The risk of hypoglycaemia, sometimes severe, occurs particularly in elderly or malnourished subjects, treated diabetics and patients with renal insufficiency or cardiac failure. Blood sugar levels should be monitored in all patients. Strict adherence to the dosing recommendations is advised. If hypoglycaemia occurs then treatment with disopyramide should be stopped.

Hypoglycaemia may be associated with interactions with drugs metabolised by hepatic CYP3A (see Section 4.5 Interactions with other medicinal products and other forms of interaction).

Atropine–like effects : There is a risk of :

– ocular hypertension in patients with narrow–angle glaucoma

– acute urinary retention in patients with prostatic enlargement

– aggravation of myasthenia gravis

– cognitive disorders, especially in elderly patients (see also section 4.8).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Combination with other antiarrhythmic drugs: Combinations of antiarrhythmic drugs are not well researched and their effect may be unpredictable. Thus, antiarrhythmic combination should be avoided except under certain circumstances, eg. beta–blockers for angina pectoris ; digoxin with beta–blocker and verapamil for the control of atrial fibrillation, when defined as effective for an individual.

Interaction with drugs associated with risk of Torsade de Pointes, such as

– tricyclic and tetracyclic antidepressants

– All macrolide antibiotics (e.g. erythromycin, clarithromycin, azithromycin etc)

– astemizole ; cisapride ; pentamidine ; pimozide ; sparfloxacin ; terfenadine and thioridazone.

Phosphodiesterase Type 5 Inhibitors:

There is evidence that phosphodiesterase Type 5 inhibitors may be potentially associated with a risk of QT prolongation. Concomitant administration of disopyramide with such drugs may potentially enhance this QT prolongation effect and is not recommended.

The concomitant use of these medications whilst undergoing treatment with disopyramide increases the chance of cardiac arrhythmia.

There is some evidence that disopyramide is metabolised by hepatic CYP3A. Concomitant administration of significant inhibitors of this isozyme (e.g. certain macrolide or azole antifungal antibiotics) may therefore increase the serum levels of disopyramide. On the other hand, inducers of CYP3A (e.g. rifampicin and certain anticonvulsants such as phenytoin, primidone and phenobarbital) may reduce disopyramide and increase MN–disopyramide serum levels. Since the magnitude of such potential effects is not foreseeable, such drug combinations are not recommended.

When prescribing a drug metabolised by CYP3A [such as theophylline, HIV protease inhibitors (e.g. ritonavir, indinavir, saquinavir), ciclosporin A, warfarin] it should be kept in mind that disopyramide is probably also a substrate of this isozyme and thus competitive inhibition of metabolism might occur, possibly increasing serum levels of these drugs.

Interactions with hypokalaemia inducing drugs : Concomitant use with drugs can induce hypokalaemia such as : diuretics, amphotericin B, tetracosactide (corticotropin analogue), gluco and mineralo–corticoids may reduce the action of the drug, or potentiate proarrhythmic effects. Stimulant laxatives are not recommended to be given concomitantly, due to their potassium lowering potential.

Other drug interactions :

Atropine and other anticholinergic drugs, including phenothiazines, may potentiate the atropine–like effects of disopyramide.

4.6 Pregnancy And Lactation

Pregnancy: Although Rythmodan has undergone animal tests for teratogenicity without evidence of any effect on the developing foetus, its safety in human pregnancy has not been established. Rythmodan has been reported to stimulate contractions of the pregnant uterus. The drug should only be used during pregnancy if benefits clearly outweigh the possible risks to the mother and foetus.

Lactation: Studies have shown that oral Rythmodan is secreted in breast milk, although no adverse effects to the infant have been noted. However, clinical experience is limited and Rythmodan should only be used in lactation if, in the clinician's judgement, it is essential for the welfare of the patient. The infant should be closely supervised, particularly for anticholinergic effects and drug levels determined if necessary. Ideally, if the drug is considered essential, an alternative method of feeding should be used.

4.7 Effects On Ability To Drive And Use Machines

Some adverse reactions may impair the patients ability to concentrate and react, and hence the ability to drive or operate machinery. (See section 4.8).

4.8 Undesirable Effects

Cardiac: It is accepted that the arrhythmogenic potential of disopyramide is weak. However, as with all antiarrhythmic drugs, disopyramide may worsen or provoke arrhythmias. This proarrhythmic effect is more likely to occur in the presence of hypokalemia with the associated use of antiarrhythmic drugs, in patients with severe structural heart disease with prolongation of the QT interval.

Intra–cardiac conduction abnormalities may occur: QT interval prolongation, widening of the QRS complex, atrioventricular block and bundle–branch block.

Other types of arrhythmia have been reported: Bradycardia, sinus block, ventricular fibrillation, ventricular tachycardia and torsades de pointes.

Episodes of severe heart failure or even cardiogenic shock have also been described particularly in patients with severe structural heart disease. The resulting low cardiac output can cause hypotension, renal insufficiency and/or acute hepatic ischemia.

Other adverse reactions include:

Atropine-like effects (see also section 4.4):

urinary: dysuria; acute urinary retention, especially in prostatism

ocular: disorders of accommodation; diplopia

gastrointestinal: dry mouth; abdominal pain; nausea, vomiting, anorexia, diarrhoea; constipation

impotence

cognitive disorders

Psychiatric disorders.

Skin reactions: very rarely, rashes.

Rarely: hypoglycaemia, sometimes severe (see Section 4.4 Special warnings and precautions for use). In some cases, severe hypoglycaemia resulted in coma.

Very rarely: cholestatic jaundice, headache, dizzy sensation, neutropenia.

Rapid infusion may cause profuse sweating.

4.9 Overdose

There is no specific antidote for disopyramide. Prostigmine derivatives can be used to treat anticholinergic effects. Symptomatic supportive measures may include : early gastric lavage ; administration of a cathartic followed by activated charcoal by mouth or stomach tube ; IV administration of isoprenaline, other vasopressors and/or positive inotropic agents ; if needed - infusion of lactate and/or magnesium, electro–systolic assistance, cardioversion, insertion of an intra–aortic balloon for counterpulsion and mechanically assisted ventilation. Haemodialysis, haemofiltration or haemoperfusion with activated charcoal has been employed to lower the serum concentrations of the drug.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Class 1 anti-arrhythmic agent.

It decreases membrane responsiveness, prolongs the effective refractory period (ERP) and slows automaticity in cells with augmented automaticity. Effective refractory period of the atrium is lengthened, ERP of the A-V node is shortened and conduction in accessory pathways is prolonged.

Disopyramide is a myocardial depressant and has anti-cholinergic effects.

5.2 Pharmacokinetic Properties

Elimination phase of plasma t1/2: 5-8 hours. Increased in hepatic impairment, cardiac and hepatic disease.

Protein binding: 50 - 60%. Saturable and concentration dependent.

Volume of distribution: Variable according to method of determination.

Metabolism: Approximately 25% of a dose metabolised to a mono-N-dealkylated derivative. Additional 10% as other metabolites.

Excretion: 75% unchanged drug via urine, remainder in faeces mono-N-dealkylated metabolite 25% in urine, 64% via faeces.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maize starch

Magnesium stearate

STA-RX 1500 (pregelatinised starch)

Talc.

Capsule shell:

Gelatin

Indigo carmine,

Iron oxide and

Titanium dioxide (E171)

6.2 Incompatibilities

Not known.

6.3 Shelf Life

PVC Blister :           36 months

6.4 Special Precautions For Storage

Do not store above 25°C

6.5 Nature And Contents Of Container

PVC Blister containing 84 capsules.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 04425/0607

9. Date Of First Authorisation/Renewal Of The Authorisation

12 February 2009

10. Date Of Revision Of The Text

24 February 2010

LEGAL STATUS

POM

Rocephin 250mg, 1g and 2g vials

1. Name Of The Medicinal Product

Rocephin 250mg vials.

Rocephin 1g vials.

Rocephin 2g vials.

2. Qualitative And Quantitative Composition

Each 250mg vial contains 250mg ceftriaxone as 298.3mg hydrated disodium ceftriaxone.

Each 1g vial contains 1g ceftriaxone as 1.19g hydrated disodium ceftriaxone.

Each 2g vial contains 2g ceftriaxone as 2.39g hydrated disodium ceftriaxone.

3. Pharmaceutical Form

Powder for solution for injection.

Powder for solution for injection.

Powder for solution for infusion.

4. Clinical Particulars

4.1 Therapeutic Indications

Ceftriaxone is indicated for the treatment of the following infections when known or likely to be due to one or more susceptible micro-organisms (see section 5.1) and when parenteral therapy is required:

Pneumonia.

septicaemia.

Meningitis.

Bone, skin and soft tissue infections.

Infections in neutropenic patients.

Gonorrhoea.

Peri-operative prophylaxis of infections associated with surgery.

Treatment may be started before the results of susceptibility tests are known.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology And Method Of Administration

Rocephin may be administered by deep intramuscular injection, slow intravenous injection, or as a slow intravenous infusion, after reconstitution of the solution according to the directions given below.

Diluents containing calcium, (e.g. Ringer's solution or Hartmann's solution), should not be used to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. Therefore, ceftriaxone and calcium-containing solutions must not be mixed or administered simultaneously (see sections 4.3, 4.4 and 6.2).

Dosage and mode of administration should be determined by the severity of the infection, susceptibility of the causative organism and the patient's condition. Under most circumstances a once-daily dose - or, in the specified indications, a single dose - will give satisfactory therapeutic results.

Adults and children 12 years and over

Standard therapeutic dosage: 1g once daily.

Severe infections: 2 - 4g daily, normally as a single dose every 24 hours.

The duration of therapy varies according to the course of the disease. As with antibiotic therapy in general, administration of Rocephin should be continued for a minimum of 48 to 72 hours after the patient has become afebrile or evidence of bacterial eradication has been obtained.

Acute, uncomplicated gonorrhoea: A single dose of 250mg intramuscularly should be administered. Simultaneous administration of probenecid is not indicated.

Peri-operative prophylaxis: Usually 1g as a single intramuscular or slow intravenous dose. In colorectal surgery, 2g should be given intramuscularly (dosages greater than 1g should be divided and injected at more than one site), or by slow intravenous infusion, in conjunction with a suitable agent against anaerobic bacteria.

Elderly

These dosages do not require modification in elderly patients provided that renal and hepatic function are satisfactory (see below).

Neonates, infants and children up to 12 years

The following dosage schedules are recommended for once daily administration:

Neonates

A daily dose of 20 - 50mg/kg body weight, not to exceed 50mg/kg. In the neonate, the intravenous dose should be given over 60 minutes to reduce the displacement of bilirubin from albumin, thereby reducing the potential risk of bilirubin encephalopathy (see section 4.4).

Infants and children of up to 12 years

Standard therapeutic dosage: 20 - 50mg/kg body weight once daily.

In severe infections up to 80mg/kg body weight daily may be given. For children with body weights of 50kg or more, the usual adult dosage should be used. Doses of 50mg/kg or over should be given by slow intravenous infusion over at least 30 minutes. Doses greater than 80mg/kg body weight should be avoided because of the increased risk of biliary precipitates.

Renal and hepatic impairment

In patients with impaired renal function, there is no need to reduce the dosage of Rocephin provided liver function is intact. Only in cases of pre-terminal renal failure (creatinine clearance < 10ml per minute) should the daily dosage be limited to 2g or less.

In patients with liver damage there is no need for the dosage to be reduced provided renal function is intact.

In severe renal impairment accompanied by hepatic insufficiency, the plasma concentration of Rocephin should be determined at regular intervals and dosage adjusted.

In patients undergoing dialysis, no additional supplementary dosing is required following the dialysis. Serum concentrations should be monitored, however, to determine whether dosage adjustments are necessary, since the elimination rate in these patients may be reduced.

4.3 Contraindications

Rocephin is contraindicated in patients with known hypersensitivity to beta-lactam antibiotics.

. In patients hypersensitive to penicillin, the possibility of allergic cross-reactions should be borne in mind.

Hyperbilirubinaemic newborns and preterm newborns should not be treated with ceftriaxone. In vitro studies have shown that ceftriaxone can displace bilirubin from its binding to serum albumin and bilirubin encephalopathy can possibly develop in these patients.Premature newborns up to a corrected age of 41 weeks (weeks of gestation + weeks of life),

Full-term newborns (up to 28 days of age)

• with jaundice, or who are hypoalbuminaemic or acidotic because these are conditions in which bilirubin binding is likely to be impaired

• if they require (or are expected to require) IV calcium treatment, or calcium-containing infusions because of the risk of precipitation of ceftriaxone-calcium (see sections 4.4, 4.8 and 6.2).

Contraindications of lidocaine must be excluded before intramuscular injection of ceftriaxone when lidocaine is used as a solvent.

4.4 Special Warnings And Precautions For Use

As with other cephalosporins, anaphylactic shock cannot be ruled out even if a thorough patient history is taken.

Before therapy with ceftriaxone is instituted, careful inquiry should be made to determine whether the patient has had any previous hypersensitivity reactions to ceftriaxone, any other cephalosporin, or to any penicillin or other beta-lactam drug. Ceftriaxone is contraindicated in patients who have had a previous hypersensitivity reaction to any cephalosporin. It is also contraindicated in patients who have had a previous immediate and/or any severe hypersensitivity reaction to any penicillin or to any other beta-lactam drug (see Section 4.3). Ceftriaxone should be given with caution to patients who have had any other type of hypersensitivity reaction to a penicillin or any other beta-lactam drug.

Ceftriaxone should be given with caution to patients who have other allergic diatheses.

Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in premature and full-term newborns aged less than 1 month have been described. At least one of them had received ceftriaxone and calcium at different times and through different intravenous lines. In the available scientific data, there are no reports of confirmed intravascular precipitations in patients, other than newborns, treated with ceftriaxone and calcium-containing solutions or any other calcium-containing products. In vitro studies demonstrated that newborns have an increased risk of precipitation of ceftriaxone-calcium compared to other age groups.

In patients of any age ceftriaxone must not be mixed or administered simultaneously with any calcium-containing IV solutions, even via different infusion lines or at different infusion sites. However, in patients older than 28 days of age ceftriaxone and calcium-containing solutions may be administered sequentially one after another if infusion lines at different sites are used, or if the infusion lines are replaced or thoroughly flushed between infusions with physiological salt-solution to avoid precipitation. In patients requiring continuous infusion with calcium-containing TPN solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If use of ceftriaxone is considered necessary in patients requiring continuous nutrition,TPN solutions and ceftriaxone can be administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of TPN solution could be stopped for the period of ceftriaxone infusion, considering the advice to flush infusion lines between solutions. (see sections 4.3, 4.8, 5.2 and 6.2).

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Rocephin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Superinfections with non-susceptible micro-organisms may occur as with other antibacterial agents.

Antibiotic-associated diarrhoea, colitis and pseudomembranous colitis have all been reported with the use of ceftriaxone. These diagnoses should be considered in any patient who develops diarrhoea during or shortly after treatment. Ceftriaxone should be discontinued if severe and/or bloody diarrhoea occurs during treatment and appropriate therapy instituted.Ceftriaxone should be used with caution in individuals with a previous history of gastro-intestinal disease, particularly colitis.

As with other cephalosporins, prolonged use of ceftriaxone may result in the overgrowth of non-susceptible organisms, such as enterococci and Candida spp.

In severe renal and hepatic insufficiency, dosage should be reduced according to given recommendations (see section 4.2).

Rocephin may precipitate in the gallbladder and then be detectable as shadows on ultrasound (see section 4.8). This can happen in patients of any age, but is more likely in infants and small children who are usually given a larger dose of Rocephin on a body weight basis. In children, doses greater than 80mg/kg body weight should be avoided because of the increased risk of biliary precipitates. There is no clear evidence of gallstones or of acute cholecystitis developing in children or infants treated with Rocephin. As the condition appears to be transient and reversible upon discontinuation, therapeutic procedures are not normally indicated.

Shadows, which have been mistaken for gallstones are however, precipitates of calcium ceftriaxone which disappear on completion or discontinuation of Rocephin therapy. Rarely have these findings been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended.

Discontinuation of Rocephin treatment in symptomatic cases should be at the discretion of the physician.

Cephalosporins as a class tend to be absorbed onto the surface of the red cell membranes and react with antibodies directed against the drug to produce a positive Coombs' test and occasionally a rather mild haemolytic anaemia. In this respect, there may be some cross-reactivity with penicillins.

Cases of pancreatitis, possibly of biliary obstruction aetiology, have been rarely reported in patients treated with Rocephin. Most patients presented with risk factors for biliary stasis and biliary sludge, e.g. preceding major therapy, severe illness and total parenteral nutrition. A trigger or cofactor role of Rocephin-related biliary precipitation can not be ruled out.

Safety and effectiveness of Rocephin in neonates, infants and children have been established for the dosages described under Dosage and administration. Studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin.

During prolonged treatment a complete blood count should be performed at regular intervals.

In case lidocaine is used as a solvent Ceftriaxone solutions should only be used for intramuscular injection.

The stated dosage should not be exceeded.

Each gram of Rocephin contains approximately 3.6mmol sodium. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No impairment of renal function has so far been observed after concurrent administration of large doses of Rocephin and potent diuretics (e.g. furosemide).

No interference with the action or increase in nephrotoxicity of aminoglycosides has been observed during simultaneous administration with Rocephin.

No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of Rocephin. Ceftriaxone does not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems of certain other cephalosporins. The elimination of Rocephin is not altered by probenecid.

In an in-vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone. The clinical relevance of this finding is unknown, but caution is advised if concurrent administration of ceftriaxone with chloramphenicol is proposed.

Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute Rocephin vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when Rocephin is mixed with calcium-containing solutions in the same IV administration line. Rocephin must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, Rocephin and calcium-containing solutions may be administered sequentially, of one another, if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium.

Based on literature reports ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole and aminoglycosides.

In patients treated with Rocephin, the Coombs' test may rarely become false-positive. Rocephin, like other antibiotics, may result in false-positive tests for galactosaemia. Likewise, non-enzymatic methods for glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with Rocephin should be done enzymatically.

Ceftriaxone may adversely affect the efficacy of oral hormonal contraceptives. Consequently, it is advisable to use supplementary (non-hormonal) contraceptive measures during treatment and in the month following treatment.

4.6 Pregnancy And Lactation

Pregnancy

For ceftriaxone, limited clinical data on exposed pregnancies are available. Ceftriaxone crosses the placental barrier. Reproductive studies in animals have shown no evidence of embryotoxicity, foetotoxicity, teratogenicity or adverse effects on male or female fertility, birth or perinatal and postnatal development. In primates, no embryotoxicity or teratogenicity has been observed. Since safety in human pregnancy is not established ceftriaxone should not be used unless absolutely indicated.

Lactation

Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when ceftriaxone is administered to a nursing woman.

4.7 Effects On Ability To Drive And Use Machines

Since Rocephin sometimes induces dizziness the ability to drive and use machines can be impaired.

4.8 Undesirable Effects

The most frequently reported adverse events for ceftriaxone are diarrhoea, nausea and vomiting. Other reported adverse events include hypersensitivity reactions such as allergic skin reactions and anaphylactic reactions, secondary infections with yeast, fungi or resistant organisms as well as changes in blood cell counts.

Rarely, severe, and in some cases fatal, adverse reactions have been reported in preterm and full-term newborns (aged <28 days) who had been treated with intravenous ceftriaxone and calcium. Precipitations of ceftriaxone-calcium salt have been observed in lung and kidneys post-mortem. The high risk of precipitation in newborns is due to their low blood volume and the longer half life of ceftriaxone compared with adults (see sections 4.3, 4.4 and 5.2).

Infections and infestations

Rare (

Superinfections of various sites with yeasts, fungi or other resistant organisms are possible.

Blood and lymphatic system disorders

Rare (

Very rare (< 0.01 %) including isolated reports: Positive Coombs' test, coagulation disorders, agranulocytosis (< 500/m³), mostly after 10 days of treatment and following total doses of 20g ceftriaxone and more.

Immune system disorders

Rare (4.4)

Nervous system disorders

Rare (

Gastrointestinal disorders

Common (

Rare (

Very rare (< 0.01%) including isolated reports: Pseudomembranous colitis (mostly caused by Clostridium difficile), pancreatitis (possibly caused by obstruction of bile ducts). Therefore, the possibility of the disease should be considered in patients who present with diarrhoea following antibacterial agent use.

Hepato-biliary disorders

Rare (

Precipitation of ceftriaxone calcium salt in the gallbladder has been observed (see section 4.4), mostly in patients treated with doses higher than the recommended standard dose. In children, prospective studies have shown a variable incidence of precipitation with intravenous application, in some studies to above 30 %. The incidence seems to be lower with slow infusion (20-30 minutes). This effect is usually asymptomatic, but in rare cases, the precipitations have been accompanied by clinical symptoms such as pain, nausea and vomiting. Symptomatic treatment is recommended in these cases. Precipitation is usually reversible upon discontinuation of ceftriaxone.

Skin and subcutaneous tissue disorders

Uncommon (

Very rare (< 0.01%) including isolated reports: Erythema multiforme, Stevens Johnson Syndrome, Lyell's Syndrome/toxic epidermal necrolysis.

Renal and urinary disorders

Rare (

Very rare (< 0.01%) including isolated reports: Renal precipitation, mostly in children older than 3 years who have been treated with either high daily doses (80 mg/kg/day and more) or total doses exceeding 10g and with other risk factors such as dehydration or immobilisation. Renal precipitation is reversible upon discontinuation of ceftriaxone. Anuria and renal impairment have been reported in association.

General disorders and administration site conditions

Rare (

An intramuscular injection without lidocaine solution is painful.

4.9 Overdose

In the case of overdose nausea, vomiting, diarrhoea, can occur., Ceftriaxone concentration can not be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment is symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC classification

Pharmacotherapeutic group: cephalosporins and related substances, ATC code: J01DA13

Mode of action

Ceftriaxone has bactericidal activity resulting from the inhibition of bacterial cell wall synthesis ultimately leading to cell death. Ceftriaxone is stable to a broad range of bacterial β-lactamases and is active against a broad spectrum of bacterial pathogens including both Gram-positive and Gram-negative species.

Mechanism of resistance

Ceftriaxone is stable to a wide range of both Gram-positive and Gram-negative beta-lactamases, including those which are able to hydrolyse advanced generation penicillin derivatives and other cephalosporins. Resistance to ceftriaxone is encoded mainly by the production of some beta-lactam hydrolysing enzymes (including carbapenemases and some ESBLs) especially in Gram-negative organisms. For Gram-positive organisms such as S. aureus and S. pneumoniae, acquired resistance is mainly encoded by cell wall target site alterations. Outside of the advanced generation parenteral cephalosporins, cross-resistance to other drug classes is generally not encountered.

Breakpoints

Current MIC breakpoints used to interpret ceftriaxone susceptibility data are shown below. The use of NCCLS breakpoints predominate and are the breakpoints used in data presented in the Table. Values quoted comprise mg/L (MIC testing) or mm (disk diffusion testing) using a 30mg/L drug concentration.

National Committee for Clinical Laboratory Standards (NCCLS) (M100-S12) – 2002

	Susceptible	Intermediate	Resistant
Enterobacteriaceae, P. aeruginosa and other non-Enterobacteriaceae, Staphylococcus spp.	Disk: < 13	16-32 Disk: 14 – 20	Disk:
Haemophilus spp.	Disk:	-	-
Neisseria spp.	Disk:	-	-
Streptococcus pneumoniae *		1
Other Streptococcus spp.**	Beta strep Viridans group:	-   Viridans group: 1 Disk: 25-26	-   Viridans group:

* Recent 2002 S. pneumoniae breakpoints (NCCLS M100-S12) defined as

** Recent 2002 Streptococcus viridans group breakpoints (NCCLS M100-S12) defined

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Ceftriaxone susceptibility among Gram-positive and Gram-negative bacterial species in Europe from January 1999-December 2001:

Commonly susceptible species (i.e. resistance < 10% in all EU Member States)

Gram-Positive aerobes: MSa coagulase negative Staphylococcus spp. (including S. epidermis)* MSbStaphylococcus aureus* Group B (Streptococcus agalactiae) Streptococcus bovis Streptococcus pneumoniae* Group A Streptococcus (Streptococcus pyogenes)* Streptococcus viridans*   Gram-Negative aerobes: Citrobacter spp. (including C.freundii) Escherichia coli* Haemophilus influenzae (including beta-lactamase positive isolates)c* Haemophilus para-influenzae* Klebsiella spp. (including K. pneumoniae and K. oxytoca)* Moraxella catarrhalis* Morganella morganii* Neisseria gonorrhoea (including penicillin-resistant isolates)* Neisseria meningitidis* Proteus spp. (including P. mirabilis and P. vulgaris)* Salmonella spp. (including S. typhimurium) Serratia spp. (including Serratia marsescens)* Shigella spp.   Anaerobes: Clostridium spp.*

Species for which acquired resistance may be a problem (i.e. resistance

Gram-Negative aerobes: Pseudomonas aeruginosa + Enterobacter spp. (including E. aerogenes and E. cloacae)*+ Acinetobacter spp. (including A. baumanii and A. calcoaceticus)*+   Anaerobes: Bacteroides spp.* Peptostreptococcus spp.*

Inherently resistant organisms

Gram-Positive aerobes: MRd coagulase negative Staphylococcus spp. (including S. epidermidis) MReStaphylococcus aureus Enterococcus spp.   Gram-Negative aerobes: Listeria monocytogenes Mycoplasma spp. Stenotrophomonas maltophilia Ureaplasma urealyticum   Others: Chlamydia spp.

^aMethicillin-susceptible Coagulase-Negative Staphylococcus

^bMethicillin-susceptible Staphylococcus aureus

^cNon-susceptible range (no resistant breakpoints defined)

^dMethicillin-resistant Coagulase-Negative Staphylococcus

^eMethicillin-resistant Staphylococcus aureus

* Species for which the efficacy of ceftriaxone has been demonstrated both in vitro and in vivo

+ Species for which high rates of resistance have been observed in one or more regions within the EU approximate guidance on probabilities whether micro-organisms will be susceptible. The table above comprises current levels of susceptibility according to routinely produced susceptibility test results in France, Germany, Greece, Italy, the Netherlands, Spain, and the United Kingdom. All data is presented using contemporary NCCLS derived susceptibility breakpoints except France (CA-SFM). Data is derived from The Surveillance Network™ (TSN) Databases in each respective region. The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information gives only to ceftriaxone or not.

5.2 Pharmacokinetic Properties

The pharmacokinetics of Rocephin are largely determined by its concentration-dependent binding to serum albumin. The plasma free (unbound) fraction of the drug in man is approximately 5% over most of the therapeutic concentration range, increasing to 15% at concentrations of 300mg/l. Owing to the lower albumin content, the proportion of free ceftriaxone in interstitial fluid is correspondingly higher than in plasma.

Plasma concentrations: Mean peak concentrations after bolus intravenous injection are about 120mg/l following a 500mg dose and about 200mg/l following a 1g dose; mean levels of 250mg/l are achieved after infusion of 2g over 30 minutes. Intramuscular injection of 500mg Rocephin in 1.06% Lidocaine produces mean peak plasma concentrations of 40 - 70mg/l within 1 hour. Bioavailability after intramuscular injection is 100%.

Excretion: Rocephin is eliminated mainly as unchanged ceftriaxone, approximately 60% of the dose being excreted in the urine (almost exclusively by glomerular filtration) and the remainder via the biliary and intestinal tracts. The total plasma clearance is 10 - 22ml/min. The renal clearance is 5

Pharmacokinetics in special clinical situations

In the first week of life, 80% of the dose is excreted in the urine; over the first month, this falls to levels similar to those in the adult. In infants aged less than 8 days the average elimination half-life is usually two to three times longer than that of young adults.

In elderly persons aged over 75 years, the average elimination half-life is usually 2 to 3 times longer than in the young adult group. As with all cephalosporins, a decrease in renal function in the elderly may lead to an increase in half-life. Evidence gathered to date with ceftriaxone however, suggests that no modification of the dosage regimen is needed.

In patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally altered and the elimination half-life is only slightly increased. If kidney function alone is impaired, biliary elimination of ceftriaxone is increased; if liver function alone is impaired, renal elimination is increased.

Cerebrospinal fluid: Rocephin crosses non-inflamed and inflamed meninges, attaining concentrations 4 - 17% of the simultaneous plasma concentration.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

None.

6.2 Incompatibilities

Solutions containing ceftriaxone should not be mixed with or added to solutions containing other agents. In particular, diluents containing calcium, (e.g. Ringer's solution, Hartmann's solution) should not be used to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions (see section 4.2, 4.3, 4.4 and 4.8). Based on literature reports, ceftriaxone is not compatible with amsacrine, vancomycin, fluconazole, aminoglycosides and labetalol.

6.3 Shelf Life

3 years.

For shelf life of diluted product see section 6.6.

6.4 Special Precautions For Storage

Do not store above 25°C. Keep vial in the outer carton.

For shelf life of diluted product see section 6.6.

6.5 Nature And Contents Of Container

Rocephin 250mg and 1g: Type 1 Ph. Eur 15ml glass vial with teflonised rubber stopper and aluminium cap, containing a sterile, white to yellowish-orange crystalline powder. Packs of 1 vial.

Rocephin 2g: Type II Ph. Eur 50ml glass vial with teflonised rubber stopper and aluminium cap, containing a sterile, white to yellowish-orange crystalline powder.

Packs of 1 vial.

Each gram of Rocephin contains approximately 3.6mmol sodium.

6.6 Special Precautions For Disposal And Other Handling

Instructions for use, handling and disposal

Preparation of solutions for injection and infusion

The use of freshly prepared solutions is recommended. These maintain potency for at least 6 hours at or below 25°C or 24 hours at 2-8°C. Protect from light.

Rocephin should not be mixed in the same syringe with any drug other than 1.06% Lidocaine Hydrochloride BP solution (for intramuscular injection only).

Intramuscular injection: 250mg Rocephin should be dissolved in 1ml of 1.06% Lidocaine Hydrochloride BP solution, or 1g in 3.5ml of 1.06% Lidocaine Hydrochloride BP solution. The solution should be administered by deep intramuscular injection. Dosages greater than 1g should be divided and injected at more than one site.

Solutions in Lidocaine should not be administered intravenously.

Intravenous injection: 250mg Rocephin should be dissolved in 5ml of Water for Injections BP or 1g in 10ml of Water for Injections BP. The injection should be administered over at least 2 - 4 minutes, directly into the vein or via the tubing of an intravenous infusion.

Intravenous infusion: 2g of Rocephin should be dissolved in 40ml of one of the following calcium-free solutions: Dextrose Injection BP 5% or 10%, Sodium Chloride Injection BP, Sodium Chloride and Dextrose Injection BP (0.45% Sodium Chloride and 2.5% Dextrose), Dextran 6% in Dextrose Injection BP 5%, Hydroxyethyl Starch 6 - 10% infusions. The infusion should be administered over at least 30 minutes.

The displacement value of 250mg of Rocephin is 0.194ml.

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

7. Marketing Authorisation Holder

Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom.

8. Marketing Authorisation Number(S)

Vials 250mg	PL 0031/0169
Vials 1g	PL 0031/0171
Vials 2g	PL 0031/0172

9. Date Of First Authorisation/Renewal Of The Authorisation

23 October 2003

10. Date Of Revision Of The Text

July 2010

LEGAL STATUS

POM