Depodur 10 mg/ml Suspension for Injection

Each vial contains 1ml, 1.5ml or 2ml of 10 mg/ml morphine sulfate pentahydrate.

For full list of excipients, see Section 6.1

Suspension for Injection

White to off-white homogeneous suspension

For the relief of post-operative pain following major orthopaedic, abdominal or pelvic surgery.

Posology

Adults and the elderly

For major orthopaedic surgery of the lower extremity, lower abdominal or pelvic surgery the recommended dose of Depodur is 10 - 15 mg.

Some patients may benefit from a 20 mg dose of Depodur. However, the incidence of serious adverse events, including delayed respiratory depression, was dose-related in clinical trials.

For caesarean section, the recommended dose of Depodur is 10 mg (Note: contraindicated in patients who have received epidural local anaesthetics for analgesia during labour − see Sections 4.3 and 4.5.)

For operations associated with less severe pain and/or where freedom from the usual side effects of morphine is a priority, and in elderly, frail or debilitated patients, lower doses may suffice. The maximum recommended dose in elderly patients ( 65 years) is 15 mg.

Paediatric population

The safety and effectiveness of Depodur in patients below the age of 18 years has not been established (see Section 4.3 below).

Method of administration

Depodur is only for epidural administration.

Depodur should only be administered by or under the direction of a physician experienced in epidural administration of opioids, and only where there are full resuscitation facilities immediately available, including staff trained in airway management and artificial ventilation.

Depodur is administered peri-operatively via needle or catheter at the lumbar or lower thoracic levels. Administration of Depodur at the mid-thoracic level or higher has not been studied. Depodur may be administered undiluted or diluted up to 5-ml total volume with preservative-free 0.9% normal saline.

Before administration of Depodur, the physician must ensure that the needle or catheter is properly placed in the epidural space. Techniques to exclude misplacement of the needle or catheter include aspiration to check that blood or cerebrospinal fluid cannot be aspirated and administration of a test dose of local anaesthetic with epinephrine. If a test dose is administered, in order to minimise a pharmacokinetic interaction of Depodur, the epidural catheter should be flushed with 1 ml of preservative-free 0.9% normal saline, and Depodur should not be administered for at least a further 15 minutes (see Section 4.5 Interactions with other medicinal products and other forms of interaction).

Depodur should not be mixed with any other medications. Once Depodur has been administered, no other medication, including a repeat dose of the product, should be administered into the epidural space for at least 48 hours.

Protect Depodur from freezing. Do not administer Depodur if it is suspected that the vial has been frozen, as this may cause the modified release mechanism to fail, resulting in overdose and an increased risk of serious adverse events (see Section 6).

Monitoring for signs of respiratory depression

Following administration of Depodur, patients should be monitored for a minimum of 48 hours because of the risk of respiratory depression, which may be delayed, profound and of sudden onset (see Section 4.4). Patients should be carefully assessed and closely monitored for adequacy of ventilation (e.g. respiratory rate, depth of respiration), oxygenation (e.g. pulse oximetry when appropriate) and level of consciousness. The recommended frequency of monitoring for respiratory depression is:

At least hourly for the first 12 hours; at least 2 hourly from 12 to 24 hours; at least 4 hourly after 24 hours for a minimum of 48 hours.

Increased monitoring may be warranted in patients at increased risk of respiratory depression (e.g. unstable medical conditions, extremes of age, obesity or sleep apnoea – see Section 4.4.). Ultimately the environment, level and nature of monitoring must be dictated by patient status, nature of surgery and local policies/ guidelines.

Rescue analgesia may be required. The use of concomitant systemic opioids may increase the risk of serious adverse events (see Section 4.4).

A single dose of Depodur should be considered to be equivalent to a continuous epidural infusion of morphine, and attendant monitoring requirements must reflect this, in line with relevant guidelines.

In line with best practice, monitoring should include heart rate and blood pressure (see Section 4.4).

Depodur is contraindicated in patients with known hypersensitivity to morphine, morphine salts, or any components of the product.

Depodur is contraindicated for intravenous, intramuscular and intrathecal administration.

Depodur is contraindicated in patients receiving concurrent epidural anaesthesia, as local anaesthetics may cause the modified release mechanism to fail, resulting in overdose (see Section 4.5 Interactions with other medicinal products and other forms of interaction).

Depodur, like all opioids, is contraindicated in patients with respiratory depression, acute or severe bronchial asthma, or upper airway obstruction, unless elective postoperative mechanical ventilation is planned.

Depodur, like all opioids, is contraindicated in any patient who has or is suspected of having paralytic ileus.

Any contraindications for an epidural injection preclude the administration of Depodur.

Paediatric population

Depodur is contraindicated in children 6 years of age and under because of the dilution factor required for appropriate dosage administration in this age group.

Delayed respiratory depression is a potentially life threatening complication following epidural administration of opioids, especially hydrophilic agents such as morphine. It has been reported in patients who have received Depodur (see Section 4.8).

Hospitals using Depodur must have protocols/policies in place stipulating the identification of patients receiving Depodur and the monitoring requirements for those patients (see Section 4.2) for a minimum of 48 hours.

Close monitoring and immediate availability of full resuscitation facilities is mandatory for a period of 48 hours following administration of Depodur (see Section 4.2).

The action of Depodur persists for up to 48 hours. Respiratory depression can be severe if surgical pain is limited or absent. Extreme care must be taken if Depodur is given and surgery is subsequently cancelled or changed to a more minor procedure, or if alternative or additional analgesic techniques are used.

Systemic opioids may increase the risk of serious adverse events including respiratory depression. Particular caution is necessary with opioid agents of an intermediate or prolonged duration of action. Short acting agents may be more suitable if analgesic supplements are needed.

No clinical studies have evaluated the safety of administration of Depodur into the intrathecal space. Studies in dogs administered Depodur intrathecally demonstrated no toxicity attributable to the lipid component of Depodur. Cases of intrathecal administration of Depodur have been reported during post-marketing experience. In all cases, signs of prolonged respiratory depression were observed requiring narcotic antagonist (naloxone) administration or ventilatory support.

Experience of Depodur in clinical trials has been limited to patients assessed as ASA grade I to III. Depodur is not recommended in patients graded ASA IV or V.

Prior to drug administration, the physician should be familiar with patient conditions (such as infection at the injection site, bacteraemia, bleeding diathesis, current and anticipated anticoagulant therapy) that call for special evaluation of the benefit versus risk potential.

Use with caution in opiate-dependent patients and in patients with decreased pulmonary function, raised intracranial pressure, hypotension with hypovolaemia, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy, sleep apnoea, and adrenocortical insufficiency.

In addition, Depodur may cause hypotension, paralytic ileus, urinary retention, biliary colic, somnolence, pruritis, nausea, and vomiting.

When hypotension occurs after surgery, other common causes should be considered and excluded e.g. bleeding, myocardial insufficiency, sepsis, pulmonary embolus, dehydration.

Depodur contains less than 1 mmol sodium (23 mg) per 10 ml.

Paediatric population

Depodur has not been studied in patients less than 18 years of age and is not recommended in this patient population (see Sections 4.2 and 4.3 with regard to use in children).

Local Anaesthetics: Clinical studies have demonstrated that administration of Depodur shortly after a test dose of local anaesthetic increases peak serum concentrations of morphine. An interval between administration of the test dose and administration of Depodur of at least 15 minutes should be observed, to minimise this pharmacokinetic interaction. Where it is intended to administer Depodur after an analgesic dose of local anaesthetic, an interval of at least 30 minutes following administration of the local anaesthetic should be observed. Following Depodur administration, the catheter should be flushed through with 1 mL of preservative-free 0.9% normal saline.

Please see the dosage recommendations in Section 4.2 in respect of this interaction and note the contraindication in patients receiving concurrent epidural anaesthesia (Section 4.3).

Other than the interaction with local anaesthetics described above, no other pharmacokinetic drug-drug interactions have been examined in vivo. In vitro studies suggest a similar interaction could be expected with other amide local anaesthetics. No in vitro or in vivo studies have been performed with ester-type local anaesthetics.

Concurrent systemic or spinal administration of α₂ agonists (e.g. clonidine) may potentiate opioid analgesia. Pharmacodynamic and pharmacokinetic interactions between Depodur and neuraxially or systemically administered α2 agonists were not evaluated. Therefore, concomitant use of these drugs should not be attempted.

CNS Depressants: The concurrent use of other central nervous system (CNS) depressants including sedatives, hypnotics, general anaesthetics, droperidol, phenothiazines, or other tranquilizers or alcohol increases the risk of respiratory depression, hypotension, profound sedation, or coma. Use with caution and in reduced dosages in patients taking these agents.

Monoamine Oxidase Inhibitors (MAOIs): MAOIs markedly potentiate the action of morphine. Depodur should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

Paediatric population

Interaction studies have only been performed in adults (see also Section 4.3).

There are no or limited amount of data from the use of Depodur in pregnant women. Studies in animals have shown reproductive toxicity (see Section 5.3). Depodur is not recommended during pregnancy and in women of childbearing potential not using contraceptives. However, Depodur may be administered following clamping of the umbilical cord for caesarean section where facilities for post-operative monitoring are available (see Section 4.2).

In studies of epidural administration of morphine sulfate injection, small amounts of morphine have been detected in breast milk. Breast-feeding should be discontinued during the first 48 hours following Depodur administration.

Following repeated administration of morphine, effects have been seen in animals on both male and female offspring fertility (see Section 5.3). Such effects are unlikely after a single administration of Depodur.

Depodur, in common with other opioids, has CNS depressant effects. Effects on the ability to drive or operate machinery have not been studied, but it is expected to have a major influence on the ability to drive or operate machines within 48 hours of administration. Patients should not drive or use heavy machinery until all adverse CNS effects have fully worn off.

The tables below report adverse reactions by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on Depodur clinical trial data. The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

The frequencies are defined as: very common ( 1/10), common ( 1/100 to < 1/10).

Delayed respiratory depression, which may be of sudden onset and is potentially life threatening, occurred up to 48 hours post dosing in approximately 2% of patients who received Depodur in clinical trials. The majority of adverse events reported occurred in patients receiving doses of 20 mg Depodur or higher.

Paediatric population

No specific information is available at this time.

Overdosage of morphine is characterised by respiratory depression, with or without concomitant CNS depression. Since respiratory arrest may result either through direct depression of the respiratory centre or as the result of hypoxia, primary attention should be given to the establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. The opioid antagonist, naloxone, is a specific antidote. An initial dose of 0.4 to 2 mg of naloxone should be administered intravenously, simultaneously with respiratory resuscitation. Doses at the lower end of this range may reverse unwanted effects including (non-delayed) respiratory depression without reversing the analgesia produced by epidural morphine. Higher doses may also reverse analgesia. If the desired degree of counteraction and improvement in respiratory function is not obtained, naloxone may be repeated at 2- to 3-minute intervals. If no response is observed after 10 mg of naloxone has been administered, the diagnosis of opioid-induced or partial opioid-induced, toxicity should be questioned. Intramuscular or subcutaneous administration of naloxone may be used if the intravenous route is not available.

As the duration of effect of naloxone is considerably shorter than that of Depodur, repeated administration or continuous infusion of naloxone may be necessary.

Patients should be closely observed for evidence of recurrence of respiratory depression and for delayed respiratory depression.

Pharmacotherapeutic group: Natural opium alkaloid

ATC Code: N02A 01

Mechanism of action

Morphine acts as an agonist at opiate receptors in the CNS, particularly mu and, to a lesser extent, kappa receptors. Mu receptors are thought to mediate supraspinal analgesia, respiratory depression, and euphoria, and kappa receptors, spinal analgesia, miosis, and sedation. Morphine also has a direct action on the bowel wall nerve plexuses, causing constipation.

Pharmacodynamic effects

Epidural administration of morphine sulfate results in analgesia without attendant loss of motor, sensory, or sympathetic function. As compared to systemic administration of morphine at comparable doses, epidurally administered morphine results in improved analgesia with increased duration.

Depodur is a sustained-release formulation of the active ingredient morphine sulfate designed for epidural administration. Morphine released from Depodur is absorbed both neuraxially and systemically.

The analgesic action of Depodur persists for up to 48 hours.

Paediatric population

No information is available at this time.

Epidural administration of Depodur results in both systemic absorption of morphine sulfate and absorption of morphine sulfate through the meninges into the intrathecal space. The relative absorption systemically versus intrathecally is unknown for both morphine sulfate injection and for Depodur.

Systemic Absorption of Morphine from Depodur

Relative systemic bioavailability of Depodur compared to epidurally administered morphine sulfate injection was determined in 21 patients (see Table below).

Pharmacokinetics of Depodur and Morphine Sulfate Injection (Mean +/- SD)

Depodur was 89% bioavailable compared to morphine sulfate injection and demonstrated dose proportionality over a dose range of 5 to 25 mg.

Distribution, Metabolism, and Excretion of Morphine Sulfate

After morphine sulfate has been released from Depodur and is absorbed systemically, its distribution, metabolism and excretion are the same as other morphine formulations. Depodur is intended for single dose administration; therefore accumulation of morphine or its metabolites is not expected even in patients with impaired hepatic or renal function.

Paediatric population

The pharmacokinetics of Depodur have not been studied in the paediatric population.

Preclinical data reveal no special hazard for humans based on conventional toxicology studies.

No formal studies to assess the teratogenic effects of Depodur in animals have been performed. Several literature reports indicate teratogenic effects following morphine administration subcutaneously during the early gestational period in mice and hamsters. Effects seen include exencephaly, hydronephrosis, intestinal haemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid in mice and exencephaly and cranioschisis in hamsters.

Exposure to morphine during pregnancy is associated with reduction in growth and behavioral abnormalities in the offspring of animals. Signs of embryofetal toxicity including decreased litter size, embryo-fetal viability, fetal and neonatal body weights, absolute brain and cerebellar weights, delayed motor and sexual maturation, and increased neonatal mortality were observed. Decreased fertility in female offspring, and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed.

Environmental Risk Assessment (ERA)

See section 6.6 below for disposal.

Dioleoylphosphatidylcholine

Dipalmitoylphosphatidylglycerol

Cholesterol

Triolein

Tricaprylin

Sodium chloride

Diluted (10%) hydrochloric acid

Water for injections

Do not mix Depodur with any other medications. Once Depodur has been administered, no other medication should be administered into the epidural space for at least 48 hours.

2 years

From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately.

Store in a refrigerator (2° to 8°C).

Do not freeze. Freezing may cause the modified release mechanism to fail. Where there is evidence or suspicion that Depodur has been frozen, it should be disposed of in the way specified for opioid drugs.

Keep the vials in the outer carton. The outer cartons contain 5 vials. A freeze indicator that is visible through the top of the carton indicates exposure to a temperature below 0ºC. It is important that the freeze indicator is inspected before removal of a vial from the carton. Vials from this carton should only be used if the solution in the bulb of the freeze indicator is clear. If the solution in the bulb is coloured, then the product should be destroyed.

Depodur may be held for up to 7 days at up to 25°C in sealed, intact (unopened) vials.

Depodur is available in 10 mg/ml single-use, Type I amber glass vials with ethylenetetrafluoroethylene (ETFE) stoppers and aluminium caps. Pack sizes are as follows:

10 mg/1 ml vials packaged in cartons of 5

15 mg/1.5ml vials packaged in cartons of 5

20mg/2ml vials packaged in cartons of 5

Not all pack sizes may be marketed.

Depodur consists of morphine encapsulated in multivesicular lipid-based particles that pose no known risk of handling to health care workers.

Because Depodur consists of lipid-based particles, an in-line filter must not be used during administration of Depodur.

Do not heat-sterilize or gas-sterilize.

Vials of Depodur should be gently inverted to re-suspend the particles immediately prior to withdrawal from the vial.

Avoid aggressive shaking.

Depodur is a sterile agent; it does not contain any preservatives. After preparation, the product should be used immediately.

Each vial of Depodur contains a potent opioid. Appropriate measures should be taken, including rigorous record keeping, control of wastage and restricted access, within the hospital.

Discard any unused portion in a manner appropriate for controlled drugs in accordance with local requirements.

Flynn Pharma Limited

Alton House

4 Herbert Street

Dublin 2

Ireland

Tel: 01438 727822

Fax: 01438 727805

e-mail: medinfo@flynnpharma.com

PL 13621/0040

20/04/2006

08/08/2011