MORPHINE 2 MG / ML SOLUTION FOR INFUSION IN PRE-FILLED SYRINGE - summary of medicine characteristics

Morphine 2 mg/ml solution for infusion in pre-filled syringe

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of the solution for infusion contains 2 mg of morphine sulfate equivalent to 1.5 mg of morphine.

Each pre-filled syringe of 50 ml contains 100 mg of morphine sulfate equivalent to 75 mg of morphine.

Excipient with known effect:

A 50 ml pre-filled syringe contains 179 mg (7.81 mmol) of sodium. Each ml contains 3.59 mg (0.156 mmol) of sodium.

For the full list of excipients, see section 6.1.

Solution for infusion

Clear, colourless solution, pH between 2.5 and 6.5, osmolality between 265 and 325 mOsm/kg.

4.1 Therapeutic indications

Morphine is indicated for symptomatic relief of severe pain in adults which can be adequately managed only with opioid analgesics.

4.2 Posology and method of administration

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with morphine in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

The dose of morphine must be adjusted according to the severity of the pain and the individual response and tolerance of the patient.

Adults

The initial dose is 1–2 mg morphine sulfate per hour. Dose and dosing interval must be titrated against the patient’s response and adjustments made until analgesia is achieved.

In general, the maximum daily dose of 100 mg of morphine sulfate should not be exceeded. In the case of palliative care, however, higher doses may be necessary for most severe pain.

Special instructions for dose adjustment

In general, the highest necessary dose administered should be the lowest dose with which the pain can be kept under control. In patients undergoing another pain therapy (e.g. surgery, plexus blockade), the dose should be readjusted after the procedure.

Morphine must not be used for longer than necessary. If longer-lasting pain treatment is required, it should be checked regularly and at short intervals (if necessary due to application breaks), if and in which dose morphine can be given. If necessary, a switch to a more suitable pharmaceutical form should be made.

Discontinuation of therapy

An abstinence syndrome may be precipitated if opioid administration is suddenly discontinued. Therefore the dose should be gradually reduced prior to discontinuation.

Special populations

Hepatic impairment

In patients with severe hepatic impairment, a doubling of the dose interval should be considered. Caution is advised when giving morphine to patients with hepatic impairment.

Renal impairment

Morphine is one of the opioids whose dosing is greatly affected by renal failure. As a result of decreased renal clearance, accumulation of the metabolites can lead to serious adverse effects. Morphine doses must be carefully titrated in patients with decreased renal function or renal failure. For concomitant illnesses/con­ditions where dose reduction may be appropriate see section 4.4

Elderly

Elderly (> 75 years old) and patients in poor physical condition can be more sensitive to morphine. For this reason, the dose adjustment is more careful and/or longer dose intervals need to be selected.

If necessary, switch to lower strengths is required.

Paediatric Population

Use in children and adolescents is not recommended.

Method of administration

Morphine is for intravenous use.

Morphine must not be diluted prior to use.

The solution should be examined visually before administration. Only solutions without visible particles should be used.

One pre-filled syringe must be used for one patient only.

When Morphine is used, it is recommended that equipment such as syringe pumps or volumetric infusion pumps should always be used to control infusion rates.

Users must be familiar with the infusion pump users’ manual and with the correct use of the syringe identification system.

When the pre-filled syringe presentation is used in a syringe pump appropriate compatibility should be ensured. In particular, the pump should be designed to prevent syphoning and should have an occlusion alarm. When programming the pump for the infusion, select “BD Plastipak” as the syringe setting.

4.3 Contraindications

– hypersensitivity to the active substance or to any of the excipients listed in section 6.1

– ileus

– respiratory depression

– severe chronic obstructive pulmonary disease

– acute abdomen

– severe acute hepatic disease

– acute cranial trauma and intracranial hypertension in absence of controlled ventilation

– uncontrolled epilepsy

– concomitant use of morphonic agonists-antagonists (eg buprenorphine,

nalbuphine, pentazocine), morphonic partial antagonists (e.g naltrexone, nalmefene) or sodium oxybate

4.4 Special warnings and precautions for use

The following cases require very careful monitoring and possibly dose reduction:

– addiction to opioids

– reduced consciousness

– disorders that involve an impairment of the respiratory center and respiratory function or disorders for which such an impairment must be avoided

– pulmonary heart disease

– disorders in which cerebral pressure is elevated, if the patient is not receiving artificial ventilation

– hypotension in patients with hypovolemia

– prostate hyperplasia involving post void residual urine (risk of bladder rupture as a result of urine retention)

– narrowing of urinary tracts or ureteric colic

– disorders of the bile ducts

– obstructive and inflammatory disorders of the large intestine

– pheochromocytoma

– pancreatitis

– hypothyroidism

– epileptic seizure or increased susceptibility to seizures

– constipation.

Respiratory depression is the most significant risk of an opioid overdose.

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained online, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced.

Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with morphine.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

Adrenal insufficiency

Opioid analgesics can cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency can include e.g. nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.

Decreased Sex Hormones and increased prolactin

Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or amenorrhea.

Acute chest syndrome (ACS) in patients with sickle cell disease (SCD)

Due to a possible association between ACS and morphine use in SCD patients treated with morphine during a vaso-occlusive crisis, close monitoring for ACS symptoms is warranted.

Sodium content

Morphine 2 mg/ml solution for infusion in pre-filled syringe

This medicinal product contains 7.81 mmol (or 179 mg) sodium per pre-filled syringe, equivalent to 9% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Anti-doping warning

The use of Morphine may produce positive results in doping controls.

4.5 Interaction with other medicinal products and other forms of interaction

The following interaction of this medicinal product should be taken into account:

The concomitant use of morphine and other central nervous system depressants like      tranquilizers, anesthetics, hypnotics and sedatives, neuroleptics,

barbiturates, antidepressants, antihistamines, anti-emetics and other opioids or alcohol can increase the adverse effects of a normal dose of morphine. This applies

in particular to the    possible occurrence of respiratory depression, sedation,

hypotension and even coma.

Sedative medicinal products such as benzodiazepines or related medicinal products

The concomitant use of opioids with sedative medicinal products such as benzodiazepines or related medicinal products increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

Medicinal products with anticholinergic effects (e.g. psychotropic medicinal products, antihistamines, anti-emetics, medicinal products for Parkinson's di­sease) can increase adverse anticholinergic effects of opioids (e.g. constipation, dry mouth or micturition disorders).

Cimetidine and other medicinal products that can negatively affect liver metabolism can increase the plasma levels of morphine by inhibiting morphine’s de­gradation.

Life-threatening interactions with pethidine have been observed with effects on the central nervous system and respiratory/cir­culatory functioning in patients who were treated with certain antidepressants (MAO inhibitors) 14 days or fewer prior to the administration of opioids.

Morphine can increase the effect of muscle relaxants.

Combined morphine agonists/anta­gonists (buprenorphine, nalbuphine, pentazocine) decrease the analgesic effect through competitive inhibition of receptors, which

increase the risk of withdrawal symptoms.

Combined use with morphic partial antagonists (e.g. naltrexone, nalmefene) may cause reduction of the analgesic effect.

Combined use with sodium oxybate increases the risk of respiratory depression, which can be fatal in case of overdose.

The concomitant use of rifampicin and morphine can lead to the loss of morphine’s anal­gesic effect.

Plasma concentrations of morphine may be reduced by rifampicin. The analgesic effect of morphine should be monitored and doses of morphine adjusted during and after treatment with rifampicin.

Gabapentin

Attention should be paid to the risk of CNS symptoms in the choice of treatment. If the two medicinal products are given concomitantly, reducing the gabapentin dose should be considered. Patients should therefore be monitored carefully regarding signs of CNS depression such as somnolence, and the gabapentin or morphine dose should be reduced accordingly.

4.6 Fertility, pregnancy and lactation

Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Breast feeding

Administration to nursing women is not recommended as morphine may be secreted in breast milk and may cause respiratory depression in the infant.

Fertility

Animal studies have shown that morphine may reduce fertility (see section 5.3 Preclinical safety data).

4.7 Effects on ability to drive and use machines

Morphine can affect alertness and responsiveness to such an extent that the ability to actively participate in road traffic or operate machinery is impaired or no longer exists.

This should be anticipated particularly at the beginning of treatment, when dose is increased or the medicinal product is changed or when associated with concomitant use with alcohol or other sedative medicinal products. The assessment of the respective individual situation need to be carried out by the attending physician. With a stable therapy, a general driving ban is not mandatory required.

4.8 Undesirable effects

Adverse reactions listed below are classified according to frequency and MEdDRA System Organ Class (SOC). Frequency groupings are defined according to the following convention: Very common (>1/10), Common (>1/100 to <1/10),   Uncommon (>1/1,000 to <1/100), Rare (>1/10,000 to

<1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).

Endocrine disorders

Very rare: syndrome of inadequate ADH secretion (SIADH; leading symptom:                 ­hyponatremia)

Psychiatric disorders

Morphine has a large number of psychiatric adverse effects that can occur in various forms and degrees of severity and can differ from individual to individual (depending on personality and the duration of the treatment).

Very common:      mood changes, mostly euphoria but also dysphoria

Common:     changes in activity level (mostly suppressed, but also elevated,

or a                  s­tate of excitement), insomnia and changes in cognitive

and sensory                 ­performance (e.g. thought disorders, perception

disorders/                           ­hallucination­s, confusion)

Very rare: addiction (see also section 4.4), decreased libido or potency weakness

Unknown:    Drug dependence (see section 4.4)

Nervous system disorders

Morphine leads to a dose-dependent respiratory depression and sedation, varying from mild fatigue to drowsiness.

Common:    headaches, dizziness

Very rare: tremor, involuntary muscle twitching, epileptic seizures (particularly                  af­ter epidural or intrathecal administration)

Particularly in response to high doses hyperalgesia or allodynia can occur (see also section 4.4), which do not respond to a further dose increase of morphine (possibly dose reduction or opioid rotation required!).

The following adverse effects can also occur in response to epidural and intrathecal administration of morphine:

Uncommon: reactivation of herpes labialis infections

Very rare:     severe neurological symptoms such as paresis, which can

attributed                    to granuloma formation in the area of retract

catheter tip (see also                  s­ection 4.4)

delayed respiratory arrest (up to 24 hours).

Eye disorders

Very rare: blurred vision, diplopia and nystagmus. Miosis is a typical accompanying effect.

Cardiac disorders

Uncommon: clinically significant rise or fall in blood pressure and heart rate Erythema of the face, palpitations, general asthenia (that sometimes                  l­eads to syncope) and heart failure can occur

Respiratory ,thoracic and mediastinal disorders

Rare:        bronchos­pasms

Very rare:    dyspnea

Non-cardiogenic lung oedema has been reported from intensive care patients.

Gastrointestinal disorders

Nausea and dry mouth can occur, depending on the dose.

Constipation is a typical accompanying effect in the case of permanent treatment.

Hepatobiliary disorders

Skin and subcutaneous tissue disorders

It may lead to anaphylactic or anaphylactoid reactions.

Musculoskeletal and connective tissue disorders

Renal and urinary disorders

General disorders and administration site conditions

A tolerance development may occur.

Rare:        withdrawal symptoms*

Very rare:     asthenia, malaise, chills, amenorrhea. Changes in dentition;

however,                   a causal link with morphine treatment has not

been determined.

Unknown:    drug withdrawal syndrome

* Drug dependence and withdrawal (abstinence) syndrome

Use of opioid analgesics can be associated with the development of physical and/or psychological dependence or tolerance. An abstinence syndrome may be precipitated when opioid administration is suddenly discontinued or opioid antagonists administered, or can sometimes be experienced between doses. For management, see section 4.4.

Physiological withdrawal symptoms include: body aches, tremors, restless legs syndrome, diarrhoea, abdominal colic, nausea, flu-like symptoms, tachycardia and mydriasis.

Psychological symptoms include dysphoric mood, anxiety and irritability. In drug dependence, “drug craving” is often involved.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website:

www.mhra.gov.uk/y­ellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Symptoms of intoxication

Given that the sensitivity to morphine varies greatly from individual to individual, symptoms of intoxication in adults can occur after a single dose equivalent to approximately 30 mg administered subcutaneously or intravenously. In carcinoma patients, these values are often exceeded, without causing any serious adverse reactions.

The opiate poisoning manifests itself through the Triad: miosis, respiratory depression and coma:

The pupils are initially the size of a pinhead. In severe hypoxia, however, they dilate.

Breathing is greatly reduced (except for 2 – 4 breaths per minute). The patient becomes cyanotic.

Overdose with Morphine leads to drowsiness and stupor to coma.

The blood pressure initially remains normal, but falls rapidly off when intoxication progresses. Persistent drop in blood pressure can lead to into a state of shock. Tachycardia, bradycardia, rhabdomyolysis and aspiration pneumonia may occur. The body temperature drops. The skeletal musculature is relaxed, occasionally generalized cramps can occur, especially in children. Death usually occurs due to respiratory insufficiency or complications such as pulmonary edema.

Therapy of intoxications

In unconscious patients with respiratory arrest, ventilation, intubation and intravenous administration of an opiate antagonist (e.g. 0.4 mg naloxone IV.) are indicated. If respiratory failure persists, the single dose of the antagonist should be repeated 1 – 3 times at three-minute intervals until the respiratory rate is normalized and the patient reacts to pain stimuli.

Strict monitoring (for at least 24 hours) is required, as the effect of the opiate antagonist is shorter than that of the morphine, so that a recurrence of respiratory insufficiency must be expected.

Measures to protect against heat loss and volume therapy may also be required.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, opioids, natural opium alkaloids ATC code: N02AA01

Morphine is a phenantrene-alkaloid from the opium papaver (Papaver somniferum) with opiate-agonistic properties. It shows a clear affinity to li-receptors.

Central effects

Morphine has analgesic, antitussive, sedative, calming, respiration suppressant, miotic, antidiuretic, emetic and antiemetic late effect. It also has a mild hypotensive effect and contributes to a somewhat lower heart rate.

Peripheral effects

Constipation, contraction of the sphincters in the biliary tract, increased muscle tone  of the bladder muscle and bladder sphincter, delayed emptying of the

stomach      contents as a result of the contraction of the pylorus, skin erythema,

urticaria and pruritus as a result of the release of histamines, and bronchospasms in patients with asthma, an effect on the hypothalamic-pituitary axis that in turn has an effect on the hormonal effect of corticosteroids, sex hormones, prolactin and the antidiuretic hormone. Clinical symptoms can occur as a result of these hormonal changes.

For epidural or intrathecal administration, the analgesic effect is already achieved at plasma concentrations below 10 ng/ml.

In vitro- and in animal studies different effects of natural opioids, such as morphine are observed on components of the immune system. The clinical significance of these findings is not known.

5.2 Pharmacokinetic properties

After oral administration the effects occurs after 30 – 90 minutes. The duration of effect is approximately 4 to 6 hours and can be prolonged considerably in case of retarded release of active substance.

After intramuscular or subcutaneous administration, effects occur after 15–30 minutes and after intravenous administration within a few minutes. The duration of effects is approximately 4 to 6 hours, regardless of the route of administration. After epidural and intrathecal administration, localized analgesic effects are detectable within a few minutes. The duration of effect is after epidural administration about 12 hours and is even longer after intrathecal administration.

Absorption

Morphine is absorbed relatively quickly after oral administration, mainly from the upper small intestine and slightly from the stomach. The low absolute bioavailability (20% – 40%) is due to a pronounced first-pass effect.

It binds for approximately 20–35% to plasma proteins, preferably to the albumin fraction.

Distribution

Following a single intravenous dose of 4–10 mg, the volume of distribution ranges from 1.0–4.7 l/kg. High tissue concentrations are found in the liver, kidneys, gastrointestinal tract and muscles. Morphine passes the blood-brain barrier.

Biotransformation

Morphine is metabolized primarily in the liver but also in the intestinal epithelium. The essential step is the glucuronidation of the phenolic hydroxyl group by means of   hepatic UDP-glucuronyltran­sferase and N-demethylation.

Two main metabolites are morphine-3-glucuronide and, to a lesser extent, morphine- 6-glucuronide. In addition, sulfate conjugates and oxidative metabolites such as normorphin, morphine N-oxide and a 2-hydroxylated morphine can be formed. The   half-life of glucuronides is significantly longer than that of free

morphine. Morphine- 6-glucuronide is biologically active. The longer effect in patients with kidney insufficiency is attributed to this metabolite.

Elimination

After oral or parenteral administration, about 80% of the administered morphine is excreted in the urine (10% as free morphine, 4% as normorphine and 65% as glucuronides, with the ratio of morphine-3-glucuronide: morphine-6-glucuronide = 10:1). The elimination half-life of morphine is subject to large interindividual variations, ranging from 1.7 hours to 4.5 hours after parenteral administration. Values of roughly 9 hours have also been found.

Up to 10% of the morphine glucuronides may be excreted via the bile into the faeces.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity. Effects in non-clinical studies were observed for genotoxicity, and toxicity to reproduction and development.

Mutagenic and tumorigenic potential

There are clearly positive findings available with regards to mutagenicity, which indicate that morphine has a clastogenic effect and that, furthermore, this effect exerts an influence on gametes. Thus, morphine is to be regarded as a mutagenic substance and such an effect may also be assumed in humans.

There have been no long-term animal studies on the tumorigenic potential of morphine.

Reproductive toxicity

Animal studies showed a potential for damage in offspring throughout the entire duration of gestation (CNS malformations, growth retardation, testicular

atrophy, changes in neurotransmitter systems and behavioural patterns, dependence). In male rats, reduced fertility and chromosomal damage in gametes have been reported.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Di sodium edetate

Sodium chloride

Hydrochloric acid 0.1% (for pH adjustment)

Sodium hydroxide 0.1% (for pH adjustment) Water for injections

6.2 Incompatibilities

Morphine sulfate is physically incompatible with acyclovir sodium, aminophylline, amobarbital sodium, cefepime hydrochloride, chlorothiazide sodium, dolasetron mesilate, floxacillin sodium, furosemide, gallium nitrate, heparin sodium, meperidine hydrochloride, meperycline sodium, meticillin sodium -hydrochloride, pentobarbital sodium, phenytoin sodium, sargramostim, soda, thiopental sodium.

Physico-chemical incompatibilities (precipitation formation) between solutions with morphine sulfate and 5-fluorouracil have been demonstrated.

6.3 Shelf life

2 years.

Shelf life after first opening of the pouch: This medicinal product must be used immediately.

6.4 Special precautions for storage

Store in the original package in order to protect from light.

For storage conditions after first opening of the medicinal product, see section

6.5 Nature and contents of container

50 ml pre-filled syringe made of cyclic olefin copolymer (COP) fitted with a chlorobutyl elastomeric screw on tip cap with a bromobutyl plunger stopper, containing 50 ml of solution for infusion.

One PP plunger rod and one oxygen scavenger is included in an aluminium pouch along with a pre-filled syringe.

Morphine is packed in cartons each holding 1 or 5 sealed aluminium pouches each containing one pre-filled syringe, one plunger rod and one oxygen scavenger.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Morphine is compatible with both PVC and Non-PVC extension sets.

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

7 MARKETING AUTHORISATION HOLDER

Sun Pharmaceutical Industries Europe BV

Polarisavenue 87

2132 JH Hoofddorp

The Netherlands

8 MARKETING AUTHORISATION NUMBER(S)

PL 31750/0196

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

28/01/2022