Ultiva Injection

1. Name Of The Medicinal Product

Ultiva (remifentanil hydrochloride) for Injection 1 mg

Ultiva (remifentanil hydrochloride) for Injection 2 mg

Ultiva (remifentanil hydrochloride) for Injection 5 mg

2. Qualitative And Quantitative Composition

Ultiva is a sterile, endotoxin-free, preservative-free, white to off white, lyophilized powder, to be reconstituted before use.

When reconstituted as directed, solutions of Ultiva are clear and colourless and contain 1mg/ml of remifentanil base as remifentanil hydrochloride.

Ultiva for injection is available in glass vials containing 1 mg, 2 mg or 5 mg of remifentanil base.

3. Pharmaceutical Form

Lyophilized powder for reconstitution for intravenous administration.

4. Clinical Particulars

4.1 Therapeutic Indications

Ultiva is indicated as an analgesic agent for use during induction and/or maintenance of general anaesthesia under close supervision.

Ultiva is indicated for provision of analgesia and sedation in mechanically ventilated intensive care patients 18 years of age and over.

4.2 Posology And Method Of Administration

Ultiva 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 Ultiva 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 and primed, 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 Ultiva to the patient's anaesthetic needs).

Ultiva may also 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) (Anesthesiology 1997;86;10-23)

Care should be taken to avoid obstruction or disconnection of infusion lines and to adequately clear the lines to remove residual Ultiva after use (see section 4.4).

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

Dilution

Ultiva may be further diluted after reconstitution (see section 6.4 and 6.6 for storage conditions of the reconstituted/diluted product and the recommended diluents).

For manually-controlled infusion Ultiva 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 Ultiva is 20 to 50 micrograms/ml.

(See Section 6.6 Instructions for use/handling for additional information, including tables to help titrate Ultiva to the patient's anaesthetic needs).

4.2.1 General Anaesthesia

The administration of Ultiva must be individualised based on the patient's response. Specific dosing guidelines for patients undergoing cardiac surgery are provided in section 4.2.2 below.

4.2.1.1. Adults

Administration by Manually-Controlled Infusion

The following table summarises the starting infusion rates and dose range:

DOSING GUIDELINES FOR ADULTS

INDICATION	BOLUS INJECTION (micrograms/kg)	CONTINUOUS INFUSION (micrograms/kg/min)
Starting Rate	Range
Induction of anaesthesia	1(give over not less than 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 0.5MAC)	0.5 to 1	0.25	0.05 to 2
• Propofol (Starting dose 100 micrograms/kg/min)	0.5 to 1	0.25	0.05 to 2

When given by bolus injection at induction Ultiva 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 such as hypotension and bradycardia (see Concomitant medication below).

Induction of anaesthesia: Ultiva should be administered with a standard dose of an hypnotic agent, such as propofol, thiopentone, or isoflurane, for the induction of anaesthesia. Administering Ultiva after an hypnotic agent will reduce the incidence of muscle rigidity. Ultiva can be administered at an infusion rate of 0.5 to 1 micrograms/kg/min, with or without an initial slow bolus injection of 1 microgram/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 Ultiva, then a bolus injection is not necessary.

Maintenance of anaesthesia in ventilated patients: After endotracheal intubation, the infusion rate of Ultiva should be decreased, according to anaesthetic technique, as indicated in the above table. Due to the fast onset and short duration of action of Ultiva, 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 slow bolus injections may be administered every 2 to 5 minutes.

Anaesthesia in spontaneously breathing anaesthetised patients with a secured airway (e.g. laryngeal mask anaesthesia):In spontaneously breathing anaesthetised patients with a secured airway respiratory depression is likely to occur. Special care is needed to adjust the dose to the patient requirements and ventilatory support may be required. The recommended starting infusion rate for supplemental analgesia in spontaneously breathing anaesthetised patients is 0.04 micrograms/kg/min with titration to effect. A range of infusion rates from 0.025 to 0.1 micrograms/kg/min has been studied. Bolus injections are not recommended in spontaneously breathing anaesthetised patients.

Ultiva 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: Ultiva decreases the amounts or doses of inhaled anaesthetics, hypnotics and benzodiazepines required for anaesthesia (see Section 4.5 Interaction with other medicaments and other forms of interaction).

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 into the immediate post-operative period: Due to the very rapid offset of action of Ultiva 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 Ultiva. 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.

Care should be taken to avoid inadvertent administration of Ultiva remaining in IV lines and cannulae (see section 4.4 Special warnings and precautions for use).

In the event that longer acting analgesia has not been established prior to the end of surgery, Ultiva may need to be continued to maintain analgesia during the immediate post-operative period until longer acting analgesia has reached its maximum effect.

Guidance on provision of analgesia and sedation in mechanically ventilated intensive care patients is provided in section 4.2.3 below.

In patients who are breathing spontaneously, the infusion rate of Ultiva should initially be decreased to a rate of 0.1 micrograms/kg/min. The infusion rate may then be increased or decreased by not greater than 0.025 micrograms/kg/min every five minutes, to balance the patient's level of analgesia and respiratory rate. Ultiva 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.

The use of bolus injections of Ultiva to treat pain during the post-operative period is not recommended in patients who are breathing spontaneously.

Administration by Target-Controlled Infusion

Induction and maintenance of anaesthesia in ventilated patients: Ultiva 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 Dosing Guidelines For Adults under 4.2.1.1). 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 nanograms/ml. Ultiva should be titrated to individual patient response. For particularly stimulating surgical procedures target blood concentrations up to 15 nanograms/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 above to avoid an increase of haemodynamic effects such as hypotension and bradycardia (see Table and Concomitant medication subsection in 4.2.1.1).

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

There are insufficient data to make recommendations on the use of TCI for spontaneous ventilation anaesthesia.

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 nanograms/ml. As with manually-controlled infusion, post-operative analgesia should be established before the end of surgery with longer acting analgesics (see Guidelines for discontinuation under Administration by manually-controlled infusion in section 4.2.1.1)

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

4.2.1.2 Paediatric patients (1 to12 years of age)

Co-administration of Ultiva and an intravenous anaesthetic agent for induction of anaesthesia has not been studied in detail and is therefore not recommended.

Ultiva TCI has not been studied in paediatric patients and therefore administration of Ultiva by TCI is not recommended in these patients.

When given by bolus injection Ultiva should be administered over not less than 30 seconds. Surgery should not commence until at least 5 minutes after the start of the Ultiva infusion, if a simultaneous bolus dose has not been given. For sole administration of nitrous oxide (70%) with Ultiva, typical maintenance infusion rates should be between 0.4 and 3 micrograms/kg/min, and although not specifically studied, adult data suggest that 0.4 micrograms/kg/min is an appropriate starting rate. Paediatric patients should be monitored and the dose titrated to the depth of analgesia appropriate for the surgical procedure.

Induction of anaesthesia: The use of remifentanil for induction of anaesthesia 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 Ultiva are recommended for maintenance of anaesthesia:

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

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

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

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 such as hypotension and bradycardia. No data are available for dosage recommendations for simultaneous use of other hypnotics other than those listed in the table with remifentanil (see section 4.2.1.1 Adults- Concomitant medication).

Guidelines for patient management in the immediate post-operative period/ Establishment of alternative analgesia prior to discontinuation of Ultiva: Due to the very rapid offset of action of Ultiva, 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 Ultiva. 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. Special warnings and precautions for use).

4.2.1.3 Neonates/infants (aged less than 1 year):

There is limited clinical trial experience of remifentanil in neonates and infants (aged under 1 year old; see section 5.1). The pharmacokinetic profile of remifentanil in neonates/infants (aged less than 1 year) is comparable to that seen in adults after correction for body weight differences (see section 5.2). However, because there are insufficient clinical data, the administration of Ultiva is not recommended for this age group.

Use for Total Intravenous anaesthesia (TIVA): There is limited clinical trial experience of remifentanil of TIVA in infants (see section 5.1). However, there are insufficient clinical data to make dosage recommendations.

4.2.2 Cardiac anaesthesia

Administration by Manually-Controlled Infusion

DOSING GUIDELINES FOR CARDIAC ANAESTHESIA

INDICATION	BOLUS INJECTION (micrograms/kg)	CONTINUOUS INFUSION (micrograms/kg/min)
Starting Rate	Range
Induction of anaesthesia	Not recommended	1	_
Maintenance of anaesthesia in ventilated patients:
• Isoflurane (starting dose 0.4MAC)	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 period of anaesthesia: After administration of hypnotic to achieve loss of consciousness, Ultiva should be administered at an initial infusion rate of 1 microgram/kg/min. The use of bolus injections of Ultiva 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 Ultiva can be titrated upward in 25% to 100% increments, or downward in 25% to 50% decrements, every 2 to 5 minutes according to patient need. Supplemental slow bolus doses, administered over not less than 30 seconds, may also be given every 2 to 5 minutes as required. High risk cardiac patients, such as those with poor ventricular function or undergoing valve surgery, 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 Pharmacokinetic properties - Cardiac anaesthesia).

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 excessive depth of anaesthesia. No data are available for dosage recommendations for simultaneous use of other hypnotics other than those listed in the table with remifentanil (see section 4.2.1.1 Adults - Concomitant medication).

Guidelines for post-operative patient management

Continuation of Ultiva post-operatively to provide analgesia prior to weaning for extubation: It is recommended that the infusion of Ultiva should be maintained at the final intra-operative rate during transfer of patients to the post-operative care area. Upon arrival into this area, the patient's level of analgesia and sedation should be closely monitored and the Ultiva infusion rate adjusted to meet the individual patient's requirements (see section 4.2.3 for further information on management of intensive care patients).

Establishment of alternative analgesia prior to discontinuation of Ultiva: Due to the very rapid offset of action of Ultiva, no residual opioid activity will be present within 5 to 10 minutes after discontinuation. Prior to discontinuation of Ultiva, 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 Ultiva: Due to the very rapid offset of action of Ultiva, hypertension, shivering and aches have been reported in cardiac patients immediately following discontinuation of Ultiva (see section 4.8 Undesirable effects). To minimise the risk of these occurring, adequate alternative analgesia must be established (as described above), before the Ultiva 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 Ultiva 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: Ultiva 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 in Dosing Guidelines for Cardiac Anaesthesia under 4.2.2). 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 used 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 such as hypotension and bradycardia (see Table and Concomitant medication subsection in 4.2.2).

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 region 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 Guidelines for discontinuation under Administration by manually-controlled infusion in section 4.2.2.)

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

4.2.3 Use in Intensive Care

Ultiva can be used for the provision of analgesia in mechanically ventilated intensive care patients. Sedative agents should be added as appropriate.

Ultiva has been studied in mechanically ventilated 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, the use of Ultiva is not recommended for a duration of treatment greater than 3 days.

Ultiva TCI has not been studied in intensive care patients and therefore administration of Ultiva by TCI is not recommended in these patients.

In adults, it is recommended that Ultiva 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 sedation and analgesia. A period of at least 5 minutes should be allowed between dose adjustments. The level of sedation and analgesia should be carefully monitored, regularly reassessed and the Ultiva 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 sedative agent should be titrated to obtain the desired level of sedation. Further increases to the Ultiva 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 and sedation in individual patients:

DOSING GUIDELINES FOR USE OF ULTIVA 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 Ultiva are not recommended in the intensive care setting.

The use of Ultiva 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 (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 stimulating procedures: An increase in the existing Ultiva 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 an Ultiva infusion rate of at least 0.1 micrograms/kg/min (6 micrograms/kg/h) should be 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 (45 micrograms/kg/h), has been administered for provision of additional analgesia during stimulating procedures.

Establishment of alternative analgesia prior to discontinuation of Ultiva: Due to the very rapid offset of action of Ultiva, no residual opioid activity will be present within 5 to 10 minutes after discontinuation regardless of the duration of infusion. Following administration of Ultiva, the possibility of tolerance and hyperalgesia should be considered. Therefore, prior to discontinuation of Ultiva, patients must be given alternative analgesic and sedative agents to prevent hyperalgesia and associated haemodynamic changes. These agents must be given at a sufficient time in advance to allow the therapeutic effects of these agents to become established. The range of options for analgesia includes long acting oral, intravenous, or regional analgesics controlled by the nurse or the patient. These techniques should always be titrated to individual patient needs as the infusion of Ultiva is reduced. It is recommended that the choice of agent(s), the dose, and the time of administration are planned prior to discontinuation of Ultiva.

There is a potential for the development of tolerance with time during prolonged administration of µ-opioid agonists.

Guidelines for extubation and discontinuation of Ultiva: In order to ensure a smooth emergence from an Ultiva-based regimen it is recommended that the infusion rate of Ultiva is titrated in stages 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 Ultiva infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics.

Upon discontinuation of Ultiva, 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.

4.2.3.1 Paediatric intensive care patients

The use of remifentanil in intensive care patients under the age of 18 years is not recommended as there are no data available in this patient population.

4.2.3.2 Renally-impaired intensive care patients

No adjustments to the doses recommended above are necessary in renally-impaired patients, including those undergoing renal replacement therapy; however the clearance of the carboxylic acid metabolite is reduced in patients with renal impairment (see Section 5.2 Pharmacokinetic properties).

4.2.4 Special patient populations

4.2.4.1. Elderly (over 65 years of age)

General anaesthesia: The initial starting dose of remifentanil administered to patients over 65 should be half the recommended adult dose and then shall be titrated to individual patient need as an increased sensitivity to the pharmacological effects of remifentanil has been seen in this patient population. This dose adjustment applies to use in all phases of anaesthesia including induction, maintenance, and immediate post-operative analgesia.

Because of the increased sensitivity of elderly patients to Ultiva, when administering Ultiva by TCI in this population the initial target concentration should be 1.5 to 4 ng/ml with subsequent titration to response.

Cardiac anaesthesia: No initial dose reduction is required (see section 4.2.2.).

Intensive Care: No initial dose reduction is required (see section 4.2.3.).

4.2.4.2 Obese patients

For manually-controlled infusion it is recommended that for obese patients the dosage of Ultiva should be reduced and based upon ideal body weight as the clearance and volume of distribution of remifentanil are better correlated with ideal body weight than actual body weight.

With the calculation of lean body mass (LBM) used in the Minto model, LBM is likely to be underestimated in female patients with a body mass index (BMI) greater than 35 kg/m² and in male patients with BMI greater than 40 kg/m². To avoid underdosing in these patients, remifentanil TCI should be titrated carefully to individual response.

4.2.4.3 Renal impairment

On the basis of investigations carried out to date, a dose adjustment in patients with impaired renal function, including intensive care patients, is not necessary.

4.2.4.4. Hepatic impairment

Studies carried out with a limited number of patients with impaired liver function, do not justify any special dosage recommendations. However, patients with severe hepatic impairment may be slightly more sensitive to the respiratory depressant effects of remifentanil (see section 4.4). These patients shall be closely monitored and the dose of remifentanil shall be titrated to individual patient need.

4.2.4.5 Neurosurgery

Limited clinical experience in patients undergoing neurosurgery has shown that no special dosage recommendations are required.

4.2.4.6 ASA III/IV patients

General anaesthesia: As the haemodynamic effects of potent opioids can be expected to be more pronounced in ASA III/IV patients, caution should be exercised in the administration of Ultiva in this population. Initial dosage reduction and subsequent titration to effect is therefore recommended. In paediatric patients, there are insufficient data to make a dosage recommendation.

For TCI, a lower initial target of 1.5 to 4 nanograms/ml should be used in ASA III or IV patients and subsequently titrated to response.

Cardiac anaesthesia: No initial dose reduction is required (see section 4.2.2).

4.3 Contraindications

As glycine is present in the formulation, Ultiva is contra-indicated for epidural and intrathecal use.

Ultiva is contra-indicated in patients with known hypersensitivity to any component of the preparation and other fentanyl analogues.

Ultiva is contra-indicated for use as the sole agent for induction of anaesthesia.

4.4 Special Warnings And Precautions For Use

Ultiva 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. The use of Ultiva in mechanically ventilated intensive care patients is not recommended for a duration of treatment greater than 3 days.

Rapid offset of action /Transition to alternative analgesia

Due to the very rapid offset of action of Ultiva, no residual opioid activity will be present within 5 to 10 minutes after the discontinuation of Ultiva. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of Ultiva. The possibility of tolerance, hyperalgesia and associated haemodynamic changes should be considered when used in Intensive Care Unit. Prior to discontinuation of Ultiva, patients must be given alternative analgesic and sedative agents. 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. When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the benefit of providing adequate post-operative analgesia must always be balanced against the potential risk of respiratory depression with these agents.

Discontinuation of Treatment

Symptoms following withdrawal of Ultiva including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of more than 3 days. Where reported, re-introduction and tapering of the infusion has been beneficial. The use of Ultiva in mechanically ventilated intensive care patients is not recommended for duration of treatment greater than 3 days.

Inadvertent administration

A sufficient amount of Ultiva may be present in the dead space of the IV line and/or cannula to cause respiratory depression, apnoea and/or muscle rigidity if the line is flushed with IV fluids or other drugs. This may be avoided by administering Ultiva into a fast flowing IV line or via a dedicated IV line which is removed when Ultiva is discontinued.

Muscle rigidity - prevention and management

At the doses recommended muscle rigidity may occur. As with other opioids, the incidence of muscle rigidity is related to the dose and rate of administration. Therefore, bolus injections should be administered over not less than 30 seconds.

Muscle rigidity induced by remifentanil must be treated in the context of the patient's clinical condition with appropriate supporting measures including ventilatory support. Excessive muscle rigidity occurring during the induction of anaesthesia should be treated by the administration of a neuromuscular blocking agent and/or additional hypnotic agents. Muscle rigidity seen during the use of remifentanil as an analgesic may be treated by stopping or decreasing the rate of administration of remifentanil. Resolution of muscle rigidity after discontinuing the infusion of remifentanil occurs within minutes. Alternatively an opioid antagonist may be administered, however this may reverse or attenuate the analgesic effect of remifentanil.

Respiratory depression – prevention and management

As with all potent opioids, profound analgesia is accompanied by marked respiratory depression. Therefore, remifentanil should only be used in areas where facilities for monitoring and dealing with respiratory depression are available. The appearance of respiratory depression should be managed appropriately, including decreasing the rate of infusion by 50%, or by a temporary discontinuation of the infusion. Unlike other fentanyl analogues, remifentanil has not been shown to cause recurrent respiratory depression even after prolonged administration. However, as many factors may affect post-operative recovery it is important to ensure that full consciousness and adequate spontaneous ventilation are achieved before the patient is discharged from the recovery area.

Cardiovascular effects

The risk of cardiovascular effects such as hypotension and bradycardia (see section 4.8 Undesirable Effects), which may rarely lead to asystole/cardiac arrest may be reduced by lowering the rate of infusion of Ultiva or the dose of concurrent anaesthetics or by using IV fluids, vasopressor or anticholinergic agents as appropriate.

Debilitated, hypovolaemic, and elderly patients may be more sensitive to the cardiovascular effects of remifentanil.

Neonates/infants

There is limited data available on use in neonates/infants under 1 year of age (see sections 4.2.1.3 and 5.1).

Drug abuse

As with other opioids remifentanil may produce dependency.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Remifentanil is not metabolised by plasmacholinesterase, therefore, interactions with drugs metabolised by this enzyme are not anticipated.

As with other opioids, remifentanil, whether given by manually-controlled infusion or TCI, decreases the amounts or doses of inhaled and IV anaesthetics, and benzodiazepines required for anaesthesia (see section 4.2 Posology and method of administration, General Anaesthesia – Adults, Paediatric Patients, and Cardiac Surgery). If doses of concomitantly administered CNS depressant drugs are not reduced, patients may experience an increased incidence of adverse effects associated with these agents.

The cardiovascular effects of Ultiva (hypotension and bradycardia), may be exacerbated in patients receiving concomitant cardiac depressant drugs, such as beta-blockers and calcium channel blocking agents.

4.6 Pregnancy And Lactation

There are no adequate and well-controlled studies in pregnant women. Ultiva should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

It is not known whether remifentanil is excreted in human milk. However, because fentanyl analogues are excreted in human milk and remifentanil-related material was found in rat milk after dosing with remifentanil, nursing mothers should be advised to discontinue breast feeding for 24 hours following administration of remifentanil.

For a summary of the reproductive toxicity study findings please refer to Section 5.3 Preclinical safety data.

Labour and delivery

The safety profile of remifentanil during labour or delivery has not been demonstrated. There are insufficient data to recommend remifentanil for use during labour and Caesarean section. Remifentanil crosses the placental barrier and fentanyl analogues can cause respiratory depression in the child.

4.7 Effects On Ability To Drive And Use Machines

After anaesthesia with remifentanil the patient should not drive or operate machinery. The physician should decide when these activities may be resumed. It is advisable that the patient is accompanied when returning home and that alcoholic drink is avoided.

4.8 Undesirable Effects

The most common undesirable effects associated with remifentanil are direct extensions of μ-opioid agonist pharmacology. These adverse events resolve within minutes of discontinuing or decreasing the rate of remifentanil administration. The frequencies below are defined as very common (

Immune System Disorders

Rare:

Allergic reactions including anaphylaxis have been reported in patients receiving remifentanil in conjunction with one or more anaesthetic agents.

Psychiatric disorders

Not known:

Drug dependence

Nervous System Disorders

Rifamycin derivatives

A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes.

Rifamycin derivatives are antibiotics that work by binding to and inhibiting the mycobacterial DNA dependent RNA polymerase. These antibiotics are bacteriocidal and therefore extremely effective antituberculosis agents, but resistance can develop rapidly if used as a single agent. They easily penetrate into cells, body fluids and cerebrospinal fluid so can be used against organisms in the extracellular component and those that may be present in cells such as macrophages. Rifamycin antibiotics should be used throughout the course of tuberculosis treatment, which can be between nine months to a year.

See also

Medical conditions associated with rifamycin derivatives:

• Bartonellosis
• Endocarditis
• Haemophilus influenzae Prophylaxis
• Legionella Pneumonia
• Leprosy
• Leprosy, Borderline
• Leprosy, Tuberculoid
• Meningitis
• Meningococcal Meningitis Prophylaxis
• Mycobacterium avium-intracellulare, Prophylaxis
• Mycobacterium avium-intracellulare, Treatment
• Nasal Carriage of Staphylococcus aureus
• Tuberculosis, Active
• Tuberculosis, HIV Positive
• Tuberculosis, Latent
• Tuberculosis, Prophylaxis

Drug List:

Rifadin

Mycobutin

Priftin

Rifadin-Iv

Rimactane

Immukin

Immukin two times ten to the power of six International Units equivalent to 0.1mg solution for injection

Active substance: recombinant human interferon gamma-1b

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

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


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


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


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

In this leaflet:

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


• 2. Before you use IMMUKIN


• 3. How to use IMMUKIN


• 4. Possible side effects


• 5. How to store IMMUKIN


• 6. Further information

What Immukin Is And What It Is Used For

IMMUKIN contains a substance called recombinant human interferon gamma-1b. Interferons are so-called immunomodulators. These are small proteins that can stimulate the body’s immune system defences. They protect against micro-organisms (e.g. bacteria, viruses and fungi) that can cause disease.

IMMUKIN is for use by patients with chronic granulomatous disease (CGD). CGD is a defect in the metabolism of neutrophils, a type of white blood cell. These normally kill invading bacteria or fungi. The defect with CGD makes
neutrophils less able to prevent infections.

IMMUKIN is used to reduce the number of serious infections that may occur with this disease.

IMMUKIN is also used in patients with severe, progressive marble bone disease (osteopetrosis). This is an inherited defect in bone cells, which leads to excessive, abnormal bone growth. It also affects the bone marrow and the blood cells that are usually formed in it. As a result, patients with osteopetrosis are also at risk of serious infections.

Before You Use Immukin

Do NOT use IMMUKIN

• if you are allergic (hypersensitive) to interferon gamma or to other related interferons or any of the other ingredients of IMMUKIN (please refer to section 6 for further ingredients).

Ask your doctor or pharmacist if you are unsure about whether you are allergic to interferons.

Take special care with IMMUKIN

• if you have heart disease, because higher than usual doses can make your heart condition worse (see section 3 for
  dosage information)


• if you have seizure disorder and/or compromised central nervous system function


• if your liver does not function as well as normal (hepatic insufficiency)


• if your kidneys do not function as well as normal (renal insufficiency)


• if your bone marrow does not produce as many blood cells as normal (myelosuppression)

Consult your doctor if one of the warnings above applies to you now or if it did in the past.

You should avoid using IMMUKIN at the same time as other types of protein-based medicines. You should also avoid taking
IMMUKIN at the same time as you are given a vaccine. If you have any questions about this, ask your doctor.

You should continue to have the tests used in the management of CGD and severe, progressive osteopetrosis. Your blood count, urine, kidney and liver function should be carefully checked, both before and during the treatment.

High interferon gamma-1b levels in the body may possibly harm the fertility of men and women.

Using other medicines

You may also require antibiotics to treat infections that still occur while you are taking IMMUKIN for the treatment of CGD. There is no evidence that IMMUKIN affects how well antibiotics or corticosteroids work, commonly used medications in CGD and severe, malignant osteopetrosis patients.

Medicines that affect the liver or the kidneys may affect how quickly IMMUKIN is removed from the body.

It is possible that IMMUKIN might prolong the activity of other medicines that are broken down and removed from the body
by the liver.

If you use IMMUKIN at the same time as medicines that have effects upon the heart, blood, bone marrow or nervous system,
the risk of side effects may be increased.

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

Pregnancy and breast feeding

You should not use IMMUKIN during pregnancy, unless your doctor thinks it is essential. You are recommended not to
breast-feed while using IMMUKIN.

Ask your doctor or pharmacist for advice before using any medicine.

Driving and using machines

IMMUKIN can reduce your ability to respond and so can have a negative effect upon the ability to drive and use machines. This effect can be increased by alcohol use.

Important information about some of the ingredients of IMMUKIN

This medicinal product contains less than 1 mmol sodium (23 mg) per 0.5ml vial, i.e. it is ‘sodium-free’. This may be
important for people with high blood pressure and others wishing to maintain a low sodium diet.

How To Use Immukin

IMMUKIN is for injection under the skin (subcutaneous use) and can be administered by a doctor or nurse. You or a family
member could also administer IMMUKIN. You or your family member should be trained by a doctor or nurse in giving this type of injection.

The recommended dosage of Immukin for the treatment of patients with CGD or severe, malignant osteopetrosis is 50 micrograms per square metre for patients whose body surface area is greater than 0.5 square meters and 1.5 micrograms per kilogram for patients whose body surface area is equal to or less than 0.5 square metres.

Your doctor will decide how much IMMUKIN you need to take to treat CGD or severe, progressive osteopetrosis.

Always use IMMUKIN as your doctor has told you. Check with your doctor or pharmacist if you are not sure how to use IMMUKIN or if you need any other advice.

You should inject (or should have injected) under your skin the exact amount of IMMUKIN your doctor has told you that you
need. You should give the injections three times per week (for example, Monday, Wednesday and Friday), preferably in the
evening. The recommended injection sites are the upper arm or the top of the thigh.

• 
  Always check the amount of IMMUKIN solution before giving the injection.
  


• 
  Do not use IMMUKIN if you can see small particles or discolouration of the solution.
  


• 
  Do not mix IMMUKIN with other medicines.
  


• 
  Do not strongly shake IMMUKIN vials.
  

If you use more IMMUKIN than you should

Immediately consult your doctor if you have administered more IMMUKIN than your doctor has told you.

Symptoms after having administered too much IMMUKIN can include the following:

• central nervous system side effects such as difficulty in thinking, difficulty in walking, and dizziness


• if you have heart disease, this may get worse for a short time.


• blood disorders can occur during treatment with IMMUKIN.
  
  These include:
  
  
  • temporary changes in the number of some blood cells
  • increases in blood levels of certain substances (liver enzymes and triglycerides)
  These changes can be detected by your doctor with a blood test.

These symptoms resolve if you reduce the dose or stop using IMMUKIN.

If you forget to use IMMUKIN

Have your injections at the times your doctor has recommended. If you forget to take a dose, do not inject a double dose to make up for it. You can still administer it on the same or following day. Contact your doctor if you think you have gone too long without taking a dose.

If you stop using IMMUKIN

Please inform your doctor if you stop using IMMUKIN.

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

Immukin Side Effects

Like all medicines, IMMUKIN can cause side effects, although not everybody gets them. The risk of side effects occurring depends on the dose and the dosing schedule you have been given.

Very common side effects (more than 1 in 10 patients treated) are:

• Flu-like symptoms such as fever, headache and cold chills.
  
  These may become less severe over time as the treatment is continued. Some of these symptoms can be reduced by administering IMMUKIN just before going to sleep. A medicine such as paracetamol can be used to reduce some of these side effects.

Some people who take IMMUKIN may develop short-term skin problems. These include:

• a temporary skin rash


• spotty skin rash


• the sudden formation of blisters on the skin


• reddening of the skin at the injection site.

However, these are rarely severe enough to stop treatment with IMMUKIN.

Sensitivity to pressure at the injection site was also reported.

Common side effects (less than 1 in 10 patients treated) are:

• Flu-like symptoms, such as muscle pain or fatigue.


• vomiting


• nausea (feeling sick)


• joint aching or pain


• diarrhoea


• back pain


• stomach pain


• depression.

Rare side effects (less than 1 in 1000 patients treated) are:

• confusion


• autoimmune disease “lupus” or “SLE” (Systemic lupus erythematosus); Symptoms may include pain in joints, fatigue, fever, rashes, muscular weakness.


• autoimmune reaction (Autoantibody response); Symptoms may include flu-like symptoms, pain in joints, fatigue, fever, rashes, muscular weakness.

Side effects where the frequency is not known:

Proteins have been found in the urine in some cases. Raised levels of liver enzymes (AST and ALT) have been found in the blood.

A shortage of white blood cells (neutropenia) can occur. A shortage of blood platelets (thrombocytopenia) can also occur. This might be associated with bruises and a tendency to bleed.

Side effects have also been seen in patients with conditions other than CGD or malignant osteopetrosis. These events have not been seen in clinical trials involving CGD or osteopetrosis.

The following side effects have been reported in clinical trials with patients suffering from other diseases/conditions than CGD or osteopetrosis. Often the doses used in these studies were higher than the recommended dose for CGD and osteopetrosis. For this reason it is not possible to say accurately how often they occurred.

The side-effects include:

• low blood levels of sodium which can cause tiredness and confusion, muscle twitching, fits or coma (hyponatraemia)


• high levels of a sugar called glucose (hyperglycaemia) and fatty acids called triglycerides (hypertriglyceridaemia) in the blood


• nervous system disorders have been observed. These include:
  
  
  • confusion
  • disorientation
  • effects on ability to walk such as Parkinsonian gait
  • trembling
  • fits (seizures)
  • distorted or imaginary sensations (hallucinations)


• heart disorders have also been seen to occur. These include:
  
  
  • additional and irregular heart beats
  • disturbance in the heart rate, such as faster or slower heart
    rate
  • heart problems which can cause shortness of breath or ankle swelling (heart failure)
  • heart attack


• blood system disorders have also been reported. These include:
  
  
  • low blood pressure
  • fainting
  • mild, temporary stroke (transient ischemic attack)
  • blood clot or blockage of a lung artery (deep venous thrombosis and pulmonary embolism); Symptoms can include shortness of breath.


• respiratory disorders have occurred. These include:
  
  
  • rapid breathing
  • chest tightness (bronchospasm or interstitial lung disease).


• bleeding in the digestive system has occurred


• inflammation of the pancreas, which can lead to death, has occurred


• damage to the liver that affects its function (liver failure)


• damage to the kidneys that affect their function but can be
  treated effectively (reversible kidney failure)


• pains in the chest


• worsening of a skin condition called dermatomyositis (seen as a skin rash accompanying muscle weakness)


• development of the long-term disease called systemic lupus erythematosus (i.e. the patient’s own immune system attacks various parts of the body).

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

How To Store Immukin

Keep out of the reach and sight of children.

Do not use IMMUKIN after the expiry date which is stated on the carton and vial, after `Do not use after´ or `EXP´. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C – 8°C). Do not freeze.

IMMUKIN solution for injection vials are for single use only.

IMMUKIN contains no preservatives. Once opened, you should use the contents of a vial immediately. Dispose of any unused contents of the vial.

Do not use IMMUKIN if you notice particles or discolouration in it before use.

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

Further Information

What IMMUKIN contains

Each vial (0.5ml) contains two times ten to the power of six International Units equivalent to 0.1mg recombinant human interferon gamma 1-b. This is a substance produced using E. coli bacteria modified by gene technology.

The other ingredients are D-mannitol, disodium succinate hexahydrate, polysorbate 20, succinic acid and water for injections.

What IMMUKIN looks like and contents of the pack

IMMUKIN is a clear, colourless solution for injection. IMMUKIN is available in 3 ml vials containing 0.5 ml solution for injection.

Pack sizes: 1, 3, 5, 6 and 12 vial(s) in one folding box.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Boehringer Ingelheim Limited

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

United Kingdom

Manufacturer

Boehringer Ingelheim RCV GmbH & Co KG

Dr. Boehringer-Gasse 5-11

1121 Vienna

Austria

Tel:+43 1 80 105-0

Fax:+43 1 804 08 23

This leaflet was last approved in July 2009

© Boehringer Ingelheim Limited 2009

50777-08

Bonefos Capsules

Due to regulatory changes, the content of the following Patient Information Leaflet may vary from the one found in your medicine pack. Please compare the 'Leaflet prepared/revised date' towards the end of the leaflet to establish if there have been any changes.

If you have any doubts or queries about your medication, please contact your doctor or pharmacist.

Bonefos Capsules

sodium clodronate

Please read this leaflet carefully. It contains a summary of the information available on your medicine. The information in this leaflet applies to BONEFOS Capsules only. If after reading this you have any questions ask your doctor or pharmacist.

What You Should Know About Bonefos Capsules

The name of your medicine is BONEFOS Capsules. Each capsule contains 500 mg sodium clodronate tetrahydrate equivalent to 400 mg of sodium clodronate as the active ingredient.

The capsules also contain the following inactive ingredients: talc, calcium stearate, silica, lactose, gelatin, red iron oxide (E172), titanium dioxide (E171) and yellow iron oxide (E172).

BONEFOS Capsules are available in packs of 30 and 120 capsules.

BONEFOS Capsules belong to the group of medicines called bisphosphonates which help prevent the loss of calcium from bones.

The Product Licence for BONEFOS Capsules is held by:

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire

RG14 1JA

and the capsules are manufactured by:

Bayer Schering Pharma Oy

Pansiontie 47

20210 Turku

Finland

How BONEFOS Capsules Help You

BONEFOS Capsules help manage bone diseases, particularly those associated with cancer. BONEFOS also helps maintain normal levels of calcium in your blood.

Before Taking BONEFOS Capsules

Tell your doctor or pharmacist if:

• You are pregnant, likely to become pregnant, or if you are breast feeding



• You have had an allergic reaction (causing rash, itching, or more rarely shortness of breath) to BONEFOS Capsules or to similar medicines



• You have had an allergic reaction to any of the inactive ingredients, e.g. lactose, mentioned above



• You are already taking a similar kind of medicine



• You have any chronic kidney problems



• You are also taking non-steroidal anti-inflammatory drugs to relieve pain e.g. ibuprofen or diclofenac, or if you are taking antibiotics



• You are taking antacids or mineral supplements



• You have or have had pain, swelling or numbness of the jaw or a "heavy jaw feeling" or loosening of a tooth.

If you are having dental treatment or will undergo dental surgery, tell your dentist that you are being treated with a bisphosphonate, such as BONEFOS. Certain types of dental treatment are not recommended while taking bisphosphonates.

If in doubt ask your doctor or pharmacist.

Do not give BONEFOS Capsules to children

How to take BONEFOS Capsules

Follow your doctor's instructions about when and how to take your medicine and always read the label.

The usual recommended dose is 4 capsules a day taken as a single dose or in two divided doses (2 capsules per dose). However your doctor may prescribe up to 8 capsules a day.

Do not take more than the doctor has prescribed.

If you take an overdose tell your doctor immediately.

Swallow the tablets whole with a little liquid but NOT with milk. Take the capsules at least 1 hour before or 1 hour after food. If BONEFOS Capsules are taken with milk or with food, it is more difficult for them to enter your blood stream and so you will not get the full benefit of your medicine.

For the same reasons, DO NOT take BONEFOS Capsules with mineral supplements as these may also reduce the effectiveness of your medicine.

Make sure that you drink a lot of fluid e.g. water or diluted squash throughout your treatment with BONEFOS Capsules.

If your kidney function is abnormal your doctor will reduce your daily dose of BONEFOS Capsules.

DO NOT STOP TAKING THIS MEDICINE EXCEPT ON YOUR DOCTOR'S ADVICE.

If you forget to take your medicine, do not worry - just take the next dose at the usual time.

After Taking BONEFOS Capsules

All medicines sometimes cause side effects.

A few people experience upset stomachs, for example sickness and diarrhoea after taking BONEFOS Capsules. If you do experience any such symptoms they may improve if you follow the divided dose recommendations (i.e. take half the number of capsules in the morning and the remaining half in the evening). Skin reactions, such as rash, redness or itching have also been reported. These effects are usually mild.

Unwanted effects on the kidneys have been reported. This appears to be more common in patients receiving non-steroidal anti-inflammatory drugs such as ibuprofen or diclofenac, although no definite association has been established.

Occasionally increased levels of serum parathyroid hormone, certain enzymes and creatinine (a component of urine) have been reported. Rarely, blood calcium levels have fallen below normal. If any of these changes do occur, they are unlikely to cause any noticeable symptoms.

Your doctor will periodically carry out tests during treatment to ensure that your kidneys are working properly and to monitor the level of calcium in your blood.

Rarely, this type of drug has caused difficulty in breathing.

Isolated cases of osteonecrosis of the jaw (dead tissue in the jaw bone) have been reported, mainly in patients who have been treated in the past with bisphosphonates such as zoledronate and pamidronate. Symptoms include pain, swelling or numbness of the jaw, a "heavy jaw feeling" or loosening of a tooth.

If you experience any of these effects and they persist or become troublesome consult your doctor. You should also consult your doctor if you experience any other effects not mentioned above.

How To Store BONEFOS Capsules

Store BONEFOS Capsules below 25°C.

Keep this medicine out of the sight and reach of children.

Do not take this medicine after the expiry date which you will find printed on the packaging.

REMEMBER THIS MEDICINE IS FOR YOU (only a doctor can prescribe it for you). NEVER give it to others as it may harm them even if their symptoms are the same as yours.

This leaflet was revised in May 2008.

Up and Up Anti-Diarrheal Drug Facts

Generic Name: loperamide hydrochloride

Dosage Form: tablet
Target Corp. Anti-Diarrheal Drug Facts

Active ingredient (in each caplet)

Loperamide HCl 2 mg

Purpose

Anti-diarrheal

Uses

controls symptoms of diarrhea, including Travelers’ Diarrhea

Warnings

Allergy alert: Do not use if you have ever had a rash or other allergic reaction to loperamide HCl

Do not use

if you have bloody or black stool

Ask a doctor before use if you have

• fever


• mucus in the stool


• a history of liver disease

Ask a doctor or pharmacist before use if you are

taking antibiotics

When using this product

• tiredness, drowsiness or dizziness may occur. Be careful when driving or operating machinery.

Stop use and ask a doctor if

• symptoms get worse


• diarrhea lasts for more than 2 days


• you get abdominal swelling or bulging. These may be signs of a serious condition.

If pregnant or breast-feeding,

ask a health professional before use.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

Directions

• drink plenty of clear fluids to help prevent dehydration caused by diarrhea


• find right dose on chart. If possible, use weight to dose; otherwise, use age.

adults and children 12 years and over	2 caplets after the first loose stool; 1 caplet after each subsequent loose stool; but no more than 4 caplets in 24 hours
children 9-11 years (60-95 lbs)	1 caplet after the first loose stool; 1/2 caplet after each subsequent loose stool; but no more than 3 caplets in 24 hours
children 6-8 years (48-59 lbs)	1 caplet after the first loose stool; 1/2 caplet after each subsequent loose stool; but no more than 2 caplets in 24 hours
children under 6 years (up to 47 lbs)	ask a doctor

Other information

• store between 20-25°C (68-77°F)


• do not use if carton or bluster unit is broken or torn (BLISTER CONFIGURATION ONLY)


• do not use if printed foil under cap is broken or missing (BOTTLE CONFIGURATION ONLY)


• see end panel for lot number and expiration date

Inactive ingredients

anhydrous lactose, carnauba wax, D&C yellow no. 10, FD&C blue no. 1, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch

Questions?

Call 1-800-910-6874

Principal Display Panel

Loperamide Hydrochloride Tablets, 2 mg

Anti-Diarrheal

Compare to active ingredient in Imodium® A-D

Controls the Symptoms of Diarrhea

Easy to Swallow

Actual Size

# Caplets (Replace # with amount in package)

Each Caplet Contains 2 mg loperamide hydrochloride

(**Capsule-Shaped Tablets)

Anti-Diarrheal Carton

UP AND UP ANTI DIARRHEAL  loperamide hydrochloride  tablet

Product Information Product Type HUMAN OTC DRUG NDC Product Code (Source) 11673-224 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LOPERAMIDE HYDROCHLORIDE (LOPERAMIDE) LOPERAMIDE HYDROCHLORIDE 2 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color GREEN Score 2 pieces Shape CAPSULE Size 10mm Flavor Imprint Code L2 Contains

Packaging # NDC Package Description Multilevel Packaging 1 11673-224-62 4 BLISTER PACK In 1 CARTON contains a BLISTER PACK 1 6 TABLET In 1 BLISTER PACK This package is contained within the CARTON (11673-224-62) 2 11673-224-67 1 BOTTLE In 1 CARTON contains a BOTTLE 2 48 TABLET In 1 BOTTLE This package is contained within the CARTON (11673-224-67)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA075232	07/20/2009

Labeler - Target Corporation (006961700)

Revised: 08/2009Target Corporation

More Up and Up Anti-Diarrheal Drug Facts resources

• Up and Up Anti-Diarrheal Drug Facts Side Effects (in more detail)
• Up and Up Anti-Diarrheal Drug Facts Use in Pregnancy & Breastfeeding
• Drug Images
• Up and Up Anti-Diarrheal Drug Facts Drug Interactions
• Up and Up Anti-Diarrheal Drug Facts Support Group
• 8 Reviews for Up and Up Anti-Diarrheal Drug Facts - Add your own review/rating

Compare Up and Up Anti-Diarrheal Drug Facts with other medications

• Diarrhea
• Diarrhea, Acute
• Diarrhea, Chronic
• Lymphocytic Colitis
• Traveler's Diarrhea

Gammagard

Generic Name: immune globulin (Intramuscular route, Intravenous route, Subcutaneous route)

i-MUNE GLOB-ue-lin

Intravenous route(Powder for Solution;Solution)

Immune globulin intravenous (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Use caution in patients predisposed to acute renal failure and administer at the minimum concentration available and the minimum rate of infusion practicable in such patients. Higher rates of renal failure were associated with IGIV products containing sucrose . Flebogamma(R) 5%, Flebogamma(R) 5% DIF, Flebogamma(R) 10% DIF, Gammagard (R), Gamunex(R)-C, and Previgen(R) do not contain sucrose . Glycine is used as a stabilizer in Gamunex(R)-C .

Subcutaneous route(Solution)

Immune globulin intravenous (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Use caution in patients predisposed to acute renal failure and administer at the minimum concentration available and the minimum rate of infusion practicable in such patients. Higher rates of renal failure were associated with IGIV products containing sucrose. Gammagard(R) does not contain sucrose .

Commonly used brand name(s)

In the U.S.

• Baygam


• Carimune


• Gamimune N


• Gammagard


• Gammar-P


• Hizentra


• Iveegam EN


• Octagam


• Panglobulin NF


• Polygam S/D


• Sandoglobulin


• Vivaglobin

Available Dosage Forms:

• Solution


• Powder for Solution

Therapeutic Class: Immune Serum

Uses For Gammagard

Immune globulin injection belongs to a group of medicines known as immunizing agents. It is used to prevent or treat diseases that occur when your body has a weak immune system. Immune globulin contains antibodies that make your immune system stronger. It is used for patients who have primary humoral immunodeficiency (PI), idiopathic thrombocytopenic purpura (ITP), and chronic inflammatory demyelinating polyneuropathy (CIDP).

This medicine is to be administered only by or under the supervision of your doctor.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, immune globulin is used in certain patients with the following medical conditions:

• Chronic parvovirus B19 infection (treatment).


• Dermatomyositis (treatment).


• Guillain-Barré syndrome (treatment).


• Hyperimmunoglobulinemia E syndrome (treatment).


• Infections in low-birth-weight preterm high-risk neonates (prophylaxis and treatment adjunct).


• Lambert-Eaton myasthenic syndrome (treatment).


• Multifocal motor neuropathy (treatment).


• Relapsing-remitting multiple sclerosis (treatment).

Before Using Gammagard

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of immune globulin injection in children. However, safety and efficacy have not been established in children with CIDP, safety and efficacy have not been established for Flebogamma® and subcutaneous injection of Gamunex®-C in children with PI, and safety and efficacy have not been established for Gammagard Liquid and Vivaglobin® in children younger than 2 years of age.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of immune globulin injection in the elderly. However, elderly patients are more likely to have age-related blood clotting problems, kidney disease, or heart disease, which may require caution for patients receiving immune globulin injection.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Anemia, history of or


• Bleeding problems, history of or


• Hyponatremia (low sodium in the blood) or


• Kidney problems—Use with caution. May make these conditions worse.

• Atherosclerosis (hardening of the arteries), history of or


• Blood clotting problems, history of or


• Diabetes or


• Heart attack or stroke, recent or


• Heart or blood vessel disease or


• Hyperproteinemia (high protein in the blood) or


• Hyperviscosity (thick blood), known or suspected or


• Hypovolemia (low blood volume or major loss of body fluids) or


• IgA (immunoglobulin A) deficiency with antibodies against IgA or


• Paraproteinemia (paraproteins in the blood) or


• Sepsis (serious infection in the body)—Use with caution. May cause side effects to become worse.

Proper Use of immune globulin

This section provides information on the proper use of a number of products that contain immune globulin. It may not be specific to Gammagard. Please read with care.

A doctor or other trained health professional will give you or your child this medicine. This medicine is given through a needle placed in one of your veins, as a shot into one of your muscles, or as a shot under your skin.

This medicine comes with a patient information insert. Read and follow the instructions carefully. Ask your doctor if you have any questions.

While you or your child are being treated with immune globulin injection, do not have any immunizations (vaccines) without your doctor's approval. Live virus vaccines should not be given for 3 months after receiving immune globulin.

The Gammagard Liquid, Gamunex®-C, Hizentra®, and Vivaglobin® products may sometimes be given at home to patients who do not need to be in the hospital or clinic. They are given as an infusion under your skin once every week. If you or your child are using this medicine at home, your doctor will teach you how to prepare and infuse the medicine. Be sure you understand how to use the medicine.

Do not change the brand or type of your immune globulin unless your doctor tells you to. If you or your child must change the brand or type of medicine, talk to your doctor before giving yourself an injection.

If you or your child are using Gammagard Liquid, Gamunex®-C, Hizentra®, or Vivaglobin® at home, you will be shown the body areas where the medicine can be given. Use a different body area each time you give yourself an infusion. Keep track of where you give each infusion to make sure you rotate body areas. This will help prevent skin problems.

Allow the Gammagard Liquid, Gamunex®-C, or Vivaglobin® brand to reach room temperature before using it.

To use Gammagard Liquid, Gamunex®-C, Hizentra®, or Vivaglobin®:

• First, gather the items you will need on a clean, flat surface using a cloth or towel in a well-lighted area.


• Wash your hands with soap and water before and after using this medicine.


• If you have been told to wear gloves when preparing your infusion, put the gloves on.


• Check the liquid in the vial (glass container). It should be clear and slightly yellow to light brown in color. If it is cloudy, discolored, or contains large flecks (particles), do not use the vial. Select another vial.


• If the liquid is clear, place it on the clean, flat surface. Do not heat up or shake the medicine.


• Follow your doctor's instructions on how to prepare the correct amount of medicine.


• Choose an injection site on your body (e.g., abdomen or stomach area, thigh, upper arm, upper leg, or hip). Clean the injection site with a fresh alcohol wipe, and let it dry.


• With two fingers, pinch together the skin at the injection site. Insert the needle with the tube under the skin.


• Put sterile gauze and tape over the injection site to keep the needle from coming out.


• Before starting the infusion, make sure no blood is flowing into the infusion tube. If blood is present, remove and throw away the used needle and tube.


• Follow your doctor's instructions on how to use the infusion pump.


• Remove the peel-off portion of the label from the used vial. Place this label in your treatment diary or log book. Write down the amount of medicine you used, the date, and the time of your treatment.


• It usually takes about 60 minutes for each infusion.


• When all of the medicine has been infused, turn off the pump.


• Take the gauze off and remove the needle and tube from your skin.


• Clean and store the infusion pump.


• Throw away used needles and tubes in a hard, closed container that the needles cannot poke through. Keep this container away from children and pets.

Missed Dose

This medicine needs to be given on a fixed schedule. If you miss a dose or forget to use your medicine, call your doctor or pharmacist for instructions.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the Hizentra® product at room temperature, away from heat and moisture. Keep from freezing.

Protect the Hizentra® product from direct light. Keep the medicine in the original package until you are ready to use it.

Store the Gamunex®-C and Vivaglobin® products in the refrigerator, but do not freeze the medicine. Store it in the original container.

You may store the Gammagard Liquid product in the refrigerator for 36 months, or at room temperature for up to 12 months (if within the first 24 months of the date of manufacture). Check the box for the date of manufacture. Store it in the original container. Do not freeze. Talk with your pharmacist if you have questions about storage of this product.

Precautions While Using Gammagard

It is very important that your doctor check the progress of you or your child at regular visits for any problems that may be caused by this medicine. Blood and urine tests may be needed to check for unwanted effects.

Patients with idiopathic thrombocytopenic purpura (ITP) should not be treated with Gamunex®-C that is injected under the skin (subcutaneously). Doing so may increase the risk of having a hematoma (buildup of blood under the skin).

This medicine may cause fever, chills, flushing, headaches, nausea, and vomiting, especially if you are receiving it for the first time or if you have not received it for more than 8 weeks. Check with your doctor or nurse right away if you have any of these symptoms.

This medicine is made from donated human blood. Some human blood products have transmitted certain viruses to people who have received them. The risk of getting a virus from medicines made from human blood has been greatly reduced in recent years. This is the result of required testing of human donors for certain viruses, and required testing of the medicine when it is made. Although the risk is low, talk with your doctor if you have concerns.

This medicine may cause a serious type of allergic reaction, including anaphylaxis, which can be life-threatening and requires immediate medical attention. Tell your doctor right away if you or your child have a rash, itching, hives, chest pain, dizziness or lightheadedness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth after receiving this medicine. Certain people, including those with IgA (an immunoglobulin) deficiency and antibodies against IgA and a history of hypersensitivity to human immunoglobulin products should not use this medicine.

Check with your doctor right away if you or your child start to have a stiff neck, drowsiness, fever, severe headache, nausea or vomiting, painful eye movements, or eye sensitivity to light. These could be symptoms of a serious condition called aseptic meningitis syndrome (AMS).

This medicine may cause bleeding (hemolysis) or hemolytic anemia. Tell your doctor right away if you or your child have stomach or back pain, dark urine, decreased urination, difficulty with breathing, an increased heart rate, tiredness, or yellow eyes or skin after you receive the medicine.

Check with your doctor right away if you or your child start having chest pain; difficult, fast, or noisy breathing, sometimes with wheezing; blue lips and fingernails; fever; pale skin; increased sweating; coughing that sometimes produces a pink frothy sputum; shortness of breath; or swelling of the legs and ankles, after receiving this medicine. These may be symptoms of a serious lung problem.

This medicine may cause blood clots. This is more likely to occur if you have a history of blood clotting problems, heart disease, or atherosclerosis (hardening of the arteries), or if you are obese, take medicines containing estrogen, or must stay in bed for a long time because of surgery or illness. Check with your doctor right away if you or your child suddenly have chest pain, shortness of breath, a severe headache, leg pain, or problems with vision, speech, or walking. .

Check with your doctor right away if you or your child start having red or dark brown urine; lower back or side pain; a sudden weight gain; a swollen face, arms, or legs; decreased urine output; or any problems with urination after you receive this medicine. These may be symptoms of a serious kidney problem.

Make sure any doctor or dentist who treats you knows that you are using this medicine. This medicine may affect the results of certain medical tests.

Gammagard Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common

• Chills


• cough


• difficulty with breathing


• fast, pounding, or irregular heartbeat or pulse


• fever


• noisy breathing


• shortness of breath


• tightness in the chest


• troubled breathing


• unusual tiredness or weakness

Less common

• Bluish coloring of the lips or nailbeds


• burning sensation in the head


• faintness or lightheadedness

Rare

• Difficulty with swallowing


• hives or welts


• itching, especially of the feet or hands


• reddening of the skin, especially around the ears


• swelling of the eyes, face, or inside of the nose

Incidence not known

• Back, leg, or stomach pains


• bleeding gums


• blistering, peeling, or loosening of the skin


• bloody, black, or tarry stools


• blurred vision


• change in consciousness


• chest pain or discomfort


• cold, clammy, or pale skin


• confusion


• convulsions


• coughing that sometimes produces a pink frothy sputum


• dark urine


• decrease in urine amount


• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position


• fever with or without chills


• headache that is severe and occurs suddenly


• increased sweating


• light-colored stools


• loss of appetite


• loss of bladder control


• loss of consciousness


• low blood pressure or pulse


• muscle spasm or jerking of all extremities


• nausea or vomiting


• nosebleeds


• painful or difficult urination


• pains in the chest, groin, or legs, especially calves of the legs


• red skin lesions, often with a purple center


• red, irritated eyes


• shakiness in the legs, arms, hands, or feet


• shivering


• skin blisters


• slurred speech that occurs suddenly


• slow breathing


• sores, ulcers, or white spots in the mouth or on the lips


• sudden loss of consciousness


• sudden loss of coordination


• sudden vision changes


• sudden, severe weakness or numbness in the arm or leg


• sweating


• swelling in the legs and ankles


• tightness in the chest


• trembling or shaking of the hands or feet


• unusual bleeding or bruising


• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Diarrhea


• dizziness


• headache


• joint pain


• muscle pain


• redness, swelling, itching, or pain at the injection site


• skin rash

Less common

• Hip pain


• leg cramps

Incidence not known

• Feeling of warmth


• redness of the face, neck, arms, and occasionally, upper chest


• stomach pain


• swollen glands


• tiredness


• weakness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Gammagard side effects (in more detail)

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More Gammagard resources

• Gammagard Side Effects (in more detail)
• Gammagard Use in Pregnancy & Breastfeeding
• Gammagard Drug Interactions
• Gammagard Support Group
• 0 Reviews for Gammagard - Add your own review/rating

• Gammagard Consumer Overview


• Gammagard MedFacts Consumer Leaflet (Wolters Kluwer)


• Gamunex-C Prescribing Information (FDA)


• Gamunex-C MedFacts Consumer Leaflet (Wolters Kluwer)

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