What it is and what it is used for

for Morphine is one of a group of medicines called opioid analgesics, which are used to relieve moderate to severe pain. Morphine is used for the relief of severe pain and it is also used to treat breathlessness caused by fluid in the lungs and as a pre-medication before operations in adults.

What you need to know before you take it

Morphine sulfate Do not use Morphine sulfate if you:

• are allergic to active substance or any of the other ingredients of this medicine (listed in section 6);
• have conditions that make breathing difficult, such as obstructive airways disease or your breathing is weak;
• are taking, or have recently taken (in the past two weeks) any drugs for depression known as monoamine oxidase inhibitors (MAOIs);
• have head injuries, headaches or have increased pressure in the skull (raised intracranial pressure);
• have problems related to fluid on the brain (cerebral oedema);
• suffer from convulsions (fits);
• have severe stomach cramps caused by a condition known as biliary colic;
• are suffering from acute alcoholism;
• suffer from antibiotic induced pseudomembranous colitis;
• have ulcerative colitis;
• have been told you have a tumour of the adrenal gland near your kidney called phaeochromocytoma;
• are at risk from a blocked intestine (paralytic ileus);
• are suffering from severe diarrhoea caused by food poisoning or an infection.

these side effects can increase with a higher dose and longer duration of use. Dependence or addiction can make you feel that you are no longer in control of how much medicine you need to take or how often you need to take it. The risk of becoming dependent or addicted varies from person to person. You may have a greater risk of becoming dependent on or addicted to Morphine sulfate if:

• you or anyone in your family have ever abused or been dependent on alcohol, prescription medicines or illegal drugs ("addiction").
• you are a smoker.
• you have ever had problems with your mood (depression, anxiety, or a personality disorder) or have been treated by a psychiatrist for other mental illnesses. If you notice any of the following signs whilst using Morphine sulfate, it could be a sign that you have become dependent or addicted:
• you need to take the medicine for longer than advised by your doctor.
• you need to take more than the recommended dose.
• you are using the medicine for reasons other than prescribed, for instance, 'to stay calm' or 'help you sleep'.
• you have made repeated, unsuccessful attempts to quit or control the use of the medicine.
• when you stop taking the medicine you feel unwell, and you feel better once taking the medicine again ('withdrawal effects').

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

If you notice any of these signs, speak to your doctor to discuss the best treatment pathway for you, including when it is appropriate to stop and how to stop safely (see section 3, If you stop using Morphine sulfate). Acute generalized exanthematous pustulosis (AGEP) Acute generalized exanthematous pustulosis (AGEP) has been reported in association with Morphine sulfate treatment. Symptoms usually occur within the first 10 days of treatment. Tell your doctor if you have ever developed a severe skin rash or skin peeling, blistering and/or mouth sores after taking Morphine sulfate or other opioids. Stop using Morphine sulfate and seek medical attention immediately, if you notice any of the following symptoms: blistering, widespread scaly skin or pus-filled spots together with fever. Sleep-related breathing disorders Morphine sulfate can cause sleep-related breathing disorders such as sleep apnoea (breathing pauses during sleep) and sleep related hypoxemia (low oxygen level in the blood). The symptoms can include breathing pauses during sleep, night awakening due to shortness of breath, difficulties to maintain sleep or excessive drowsiness during the day. If you or another person observe these symptoms, contact your doctor. A dose reduction may be considered by your doctor.

Children Morphine sulfate is never given to patients in This medicine is not recommended for use in a coma. If any of the above applies to you, do not use this children. medicine and talk to your doctor or nurse. Other medicines and Morphine sulfate Tell your doctor if you are taking have recently Warnings and precautions taken or might take any other medicines. In Talk to your doctor or nurse before you are particular, tell your doctor if you are taking any given Morphine sulfate if you: of the following:

• have low blood pressure (hypotension);
• monoamine oxidase inhibitors (MAOIs) such
• have a disease that causes difficulty in as moclobemide or phenelzine used in the breathing as asthma, emphysema, cor treatment of depression. pulmonale (high blood pressure causing failure of the right side of the heart), abnormal – tricyclic antidepressants, which are used in the treatment of depression. spinal shape and excessive obesity;
• gabapentin or pregabalin to treat epilepsy and
• have an under-active thyroid pain due to nerve problems (neuropathic pain). (hypothyroidism) or adrenal gland
• tranquillising drugs or sleeping tablets such as (adrenocortical insufficiency); diazepam, nitrazepam and temazepam.
• have a liver or kidney disease;
• medicines used to treat mental illnesses,
• have an inflammatory or obstructive bowel including schizophrenia (e.g. chlorpromazine, disease such as Crohn`s disease or ulcerative haloperidol). colitis;
• medicines used for diarrhoea (e.g. loperamide,
• are in circulatory collapse (shock); kaolin).
• are male and have an enlarged prostate or
• medicines which are used as premedication have difficulty passing water (prostatic before operations and after heart attacks such hypertrophy); as atropine.
• have muscle weakness (myasthenia gravis); medicines used to treat nausea and vomiting,
• have biliary disorders; such as metoclopramide or domperidone.
• have a tendency to abuse drugs or have ever
• mexiletine, used to control heart rhythm. suffered from drug abuse;
• some antihistamines, used to treat allergies,
• are elderly. hay fever and asthma.
• certain antibiotics, used to treat infections Talk to your doctor or nurse if you experience (e.g. ciprofloxacin and linezolid). any of the following symptoms while using
• selegiline, used in the treatment of Morphine sulfate: Parkinson's disease.
• increased sensitivity to pain despite the fact
• pethidine, used to treat pain. that you are taking increasing doses
• cimetidine, used as anti-ulcer drug. (hyperalgesia). Your doctor will decide
• rifampicin to treat e.g. tuberculosis. whether you will need a change in dose or
• ritonavir, used in the treatment of HIV. a change in strong analgesic ("painkiller"),
• some medicines used to treat blood clots (e.g. (see section 2). clopidogrel, prasugrel, ticagrelor) may have
• weakness, fatigue, lack of appetite, nausea, delayed and decreased effect when taken vomiting or low blood pressure. This may be together with morphine. a symptom of the adrenals producing too little of the hormone cortisol, and you may need to – concomitant use of Morphine sulfate and sedative medicines such as benzodiazepines take hormone supplement. or related drugs increases the risk of
• loss of libido, impotence, cessation of drowsiness, difficulties in breathing menstruation. This may be because of (respiratory depression), coma and may be decreased sex hormone production. life-threatening. Because of this, concomitant
• severe upper abdominal pain possibly use should only be considered when other radiating to the back, nausea, vomiting or treatment options are not possible. However if fever as this could be symptoms associated your doctor does prescribe Morphine sulfate with inflammation of the pancreas together with sedative medicines the dose and (pancreatitis) and the biliary tract system. duration of concomitant treatment should be
• if you have once been dependent on drugs or limited by your doctor. Please tell your doctor alcohol. Also tell if you feel that you are about all sedative medicines you are taking, becoming dependent on Morphine sulfate and follow your doctor's dose recommendation while you are using it. You may have started closely. It could be helpful to inform friends or to think a lot about when you can take the relatives to be aware of the signs and next dose, even if you do not need it for the symptoms stated above. Contact your doctor pain. when experiencing such symptoms.
• abstinence symptoms or dependence. The most common abstinence symptoms are Morphine sulfate with alcohol mentioned in section 3. If this occurs, your doctor may change the type of medicine or the You should not drink alcohol whilst being given Morphine sulfate, as it will increase its effects. times between doses. Tolerance, dependence, and addiction This medicine contains morphine which is an opioid medicine. Repeated use of opioids can result in the drug being less effective (you become accustomed to it, known as tolerance). Repeated use of Morphine sulfate can also lead to dependence, abuse, and addiction, which may result in life-threatening overdose. The risk of

Pregnancy and breast-feeding If you are pregnant, in labour or breastfeeding, Morphine sulfate will only be given to you if your doctor considers the benefit of treatment outweighs the risk to the infant foetus or new-born baby. Morphine may reduce contractions during labour, cause breathing problems to the infant

The following information is intended for healthcare professionals only:

about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician. Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

1. NAME OF THE MEDICINAL PRODUCT Morphine sulfate 10 mg/ml solution for injection Morphine sulfate 15 mg/ml solution for injection Morphine sulfate 30 mg/ml solution for injection 4.

CLINICAL PARTICULARS

4.1 Therapeutic indications Morphine is used for the symptomatic relief of severe pain; relief of dyspnoea of left ventricular failure and pulmonary oedema of cardiogenic origin; pre-operative use in adults. 4.2 Posology and method of administration Posology Adults The dosage should be based on the severity of the pain and the response and tolerance of the patient. The usual adult subcutaneous or intramuscular dose is 10 mg every 4 hours, if necessary, but may range from 5 mg to 20 mg. The usual adult intravenous dose is 2.5 mg to 15 mg not more than 4-hourly, where necessary, but dosage and dosing interval must be titrated against the patient's response and adjustments made until analgesia is achieved. Elderly Because of the depressant effect on respiration, caution is necessary when giving morphine to the elderly and reduced doses may be required.

Withdrawal (abstinence) syndrome The risk of withdrawal syndrome increases with the time the drug is used, and with higher doses. Symptoms can be minimised with adjustments of dose or dosage form, and gradual withdrawal of morphine. For individual symptoms, see section 4.8. Hyperalgesia Hyperalgesia that does not respond to a further dose increase of morphine may occur in particular in high doses. A morphine dose reduction or change in opioid may be required. Gastrointestinal disorders An unexplained increase in abdominal pain associated with disturbed intestinal motility, symptoms of constipation, bloating, abdominal distension and increased gastroesophageal reflux during treatment with morphine sulfate, may indicate the development of opioid-induced bowel dysfunction or narcotic bowel syndrome. In such situations consider the use of alternative analgesics and a morphine detoxification.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs Concomitant use of Morphine sulfate and sedative medicines such as benzodiazepines or Hepatic impairment related drugs may result in sedation, respiratory A reduction in dosage should be considered in depression, coma and death. Because of these hepatic impairment. risks, concomitant prescribing with these sedative medicines should be reserved for Renal impairment patients for whom alternative treatment options The dosage should be reduced in moderate to are not possible. If a decision is made to severe renal impairment. prescribe Morphine sulfate concomitantly with For concomitant illnesses/conditions where dose sedative medicines, the lowest effective dose reduction may be appropriate, see 4.4. should be used, and the duration of treatment should be as short as possible. Method of administration The patients should be followed closely for signs The injection may be given by the intravenous, and symptoms of respiratory depression and intramuscular or subcutaneous route. sedation. In this respect, it is strongly The subcutaneous route is not suitable for recommended to inform patients and their oedematous patients. caregivers to be aware of these symptoms (see section 4.5). Treatment goals and discontinuation Before initiating treatment with Morphine Oral P2Y12 inhibitor antiplatelet therapy sulfate, a treatment strategy including treatment Within the first day of concomitant P2Y12 duration and treatment goals, and a plan for end inhibitor and morphine treatment, reduced of the treatment, should be agreed together with efficacy of P2Y12 inhibitor treatment has been the patient, in accordance with pain management observed (see section 4.5). guidelines. During treatment, there should be frequent contact between the physician and the Palliative care patient to evaluate the need for continued In the control of pain in terminal illness, these treatment, consider discontinuation and to adjust conditions should not necessarily be a deterrent dosages if needed. When a patient no longer to use. requires therapy with Morphine sulfate, it may be advisable to taper the dose gradually to Acute chest syndrome (ACS) in patients with prevent symptoms of withdrawal. In absence of sickle cell disease (SCD) adequate pain control, the possibility of Due to a possible association between ACS and hyperalgesia, tolerance and progression of morphine use in SCD patients treated with underlying disease should be considered morphine during a vaso-occlusive crisis, close (see section 4.4). monitoring for ACS symptoms is warranted. Paediatric population Use in children is not recommended.

Hepatobiliary disorders Opioids such as morphine should either be avoided in patients with biliary disorders or they should be given with an antispasmodic. Morphine may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, in patients with biliary tract disorders morphine may exacerbate pain (use in biliary colic is a contraindication, see section 4.3). In patients given morphine after cholecystectomy, biliary pain has been induced.

Ritonavir: Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine, ritonavir induces the hepatic enzymes responsible for the glucuronidation of morphine, and may possibly decrease plasma concentrations of morphine.

Oral P2Y12 inhibitors: A delayed and decreased exposure to oral P2Y12 inhibitor antiplatelet therapy has been observed in patients with acute coronary syndrome treated with morphine. This interaction may be related to reduced gastrointestinal motility and apply to other opioids. The clinical relevance is Opioid Use Disorder (abuse and dependence) unknown, but data indicate the potential for Tolerance and physical and/or psychological reduced P2Y12 inhibitor efficacy in patients dependence may develop upon repeated co-administered morphine and a P2Y12 inhibitor administration of opioids such Morphine sulfate. (see section 4.4). In patients with acute coronary Repeated use of Morphine sulfate can lead to syndrome, in whom morphine cannot be Opioid Use Disorder (OUD). A higher dose and withheld and fast P2Y12 inhibition is deemed longer duration of opioid treatment, can increase crucial, the use of a parenteral P2Y12 inhibitor the risk of developing OUD. Abuse or may be considered. intentional misuse of Morphine sulfate may result in overdose and/or death. The risk of 4.6 Fertility, pregnancy and lactation developing OUD is increased in patients with a personal or a family history (parents or siblings) Pregnancy of substance use disorders (including alcohol use Since morphine rapidly crosses the placental disorder), in current tobacco users or in patients barrier, it is not advised to administer morphine with a personal history of other mental health during pregnancy and labour. It may reduce disorders (e.g. major depression, anxiety and uterine contractions, cause respiratory personality disorders). depression in the foetus and new-born infant, Before initiating treatment with Morphine and may have significant effects on foetal heart sulfate and during the treatment, treatment goals rate. New-borns whose mothers received opioid and a discontinuation plan should be agreed with analgesics during pregnancy should be the patient (see section 4.2). Before and during monitored for signs of neonatal withdrawal treatment the patient should also be informed (abstinence) syndrome. Treatment may include

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Duration of treatment Adrenal insufficiency Morphine sulfate should not be used longer than Opioid analgesics may cause reversible adrenal necessary. insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency may include e.g. nausea, 4.3 Contraindications vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure. Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Acute Decreased Sex Hormones and increased respiratory depression. Obstructive airways prolactin disease. Concurrent treatment with monoamine Long-term use of opioid analgesics may be oxidase inhibitors or within two weeks of their associated with decreased sex hormone levels discontinuation of treatment with them. Cerebral and increased prolactin. Symptoms include oedema. Head injuries. Coma. Convulsive decreased libido, impotence or amenorrhea. disorders. Raised intracranial pressure. Biliary colic. Acute alcoholism. Antibiotic induced Excipients pseudomembranous colitis. Ulcerative colitis This medicinal product contains less than because of the risk of toxic megacolon. 1 mmol sodium (23 mg) per ml of solution, that Phaeochromocytoma. Paralytic ileus. Acute is to say essentially 'sodium-free'. diarrhoea caused by poisoning or invasive pathogens. 4.5 Interaction with other medicinal products and other forms of interaction 4.4 Special warnings and precautions for use Alcohol: enhanced sedative and hypotensive Morphine is a potent medicine but with effects. considerable potential for harmful effect, including addiction. It should be used only if Anti-arrhythmics: There may be delayed other drugs with fewer hazards are inadequate, absorption of mexiletine. and with the recognition that it may possibly mask significant manifestations of disease which Antibacterials: The opioid analgesic should be identified for proper diagnosis and papaveretum has been shown to reduce plasma treatment. ciprofloxacin concentration. The manufacturer of ciprofloxacin advises that premedication with Use with caution or reduced doses opioid analgesics be avoided. Morphine should be given in reduced doses or with caution to patients with asthma or Antidepressants, anxiolytics, hypnotics: a reduced respiratory reserve (including Severe CNS excitation or depression emphysema, chronic cor pulmonale, (hypertension or hypotension) has been reported kyphoscoliosis, excessive obesity and sleep with the concurrent use of pethidine and apnoea). Avoid use during an acute asthma monoamine oxidase inhibitors (MAOIs) attack (see section 4.3). including selegiline, moclobemide and linezolid. Opioid analgesics in general should be As it is possible that a similar interaction may administered with caution or in reduced doses occur with other opioid analgesics, morphine to patients with hypotension, hypothyroidism, should be used with caution and consideration adrenocortical insufficiency, impaired kidney given to a reduction in dosage in patients or liver function, prostatic hypertrophy, receiving MAOIs. urethral stricture, shock, inflammatory or The sedative effects of morphine (opioid obstructive bowel disorders, or convulsive analgesics) are enhanced when used with disorders. depressants of the central nervous system such as gabapentin or pregabalin, hypnotics, Caution is advised when giving morphine to anxiolytics, tricyclic antidepressants and patients with impaired liver function due to its sedating antihistamines. hepatic metabolism (see section 4.2). Antipsychotics: possible enhanced sedative and Severe and prolonged respiratory depression has hypotensive effect. occurred in patients with renal impairment who have been given morphine (see section 4.2). Antidiarrhoeal and antiperistaltic agents (such as loperamide and kaolin): concurrent Dosage should be reduced in elderly and use may increase the risk of severe constipation. debilitated patients. Antimuscarinics: agents such as atropine Plasma concentrations of morphine may be antagonise morphine-induced respiratory reduced by rifampicin. The analgesic effect of depression and can partially reverse biliary morphine should be monitored and doses of spasm but are additive to the gastrointestinal and morphine adjusted during and after treatment urinary tract effects. Consequently, severe with rifampicin. constipation and urinary retention may occur during intensive antimuscarinic analgesic Sleep-related breathing disorders therapy. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) Metoclopramide and domperidone: There and sleep-related hypoxemia. Opioid use may be antagonism of the gastrointestinal effects increases the risk of CSA in a dose-dependent of metoclopramide and domperidone. fashion. In patients who present with CSA, consider decreasing the total opioid dosage. Sedative medicines such as benzodiazepines or related drugs: The concomitant use of Severe cutaneous adverse reactions (SCARs) opioids with sedative medicines such as Acute generalized exanthematous pustulosis benzodiazepines or related drugs increases the (AGEP), which can be life-threatening or fatal, risk of sedation, respiratory depression, coma has been reported in association with morphine and death because of additive CNS depressant treatment. Most of these reactions occurred effect. The dose and duration of concomitant use within the first 10 days of treatment. Patients should be limited (see section 4.4). should be informed about the signs and symptoms of AGEP and advised to seek medical Cimetidine: inhibits the metabolism of care if they experience such symptoms. morphine. If signs and symptoms suggestive of these skin reactions appear, morphine should be withdrawn Rifampicin: Plasma concentrations of morphine and an alternative treatment considered. may be reduced by rifampicin.

foetus or new-born baby and affect the heart rate The other side effects which have been reported are: of the foetus. If Morphine sulfate is used for Very common (may affect more than 1 in a long time during pregnancy, there is 10 people): a risk of the new-born child having drug withdrawal (abstinence) symptoms which should – Seeing or hearing things that are not there (hallucinations) be treated by a doctor.

• Morphine is an addictive substance and its use If you are breast-feeding, ask your doctor for can result in dependence advice before using this medicine.
• Drowsiness and confusion
• Feeling (nausea) or being sick (vomiting) Driving and using machines Morphine sulfate may cause drowsiness. If this – Constipation happens to you, do not drive or use machinery. – Sweating This medicine can affect your ability to drive as – The drug no longer having the same effect as it used to (drug tolerance) it may make you sleepy or dizzy.
• do not drive while taking this medicine until Common (may affect up to 1 in 10 people): you know how it affects you
• it is an offence to drive if this medicine affects – Changes in your heart beat, such as slowing (bradycardia) or quickening (tachycardia) of your ability to drive the heart beat
• however, you would not be committing an
• Low body temperature (hypothermia) offence if:
• Raised pressure in the skull (increased
• the medicine has been prescribed to treat intracranial pressure) a medical or dental problem and
• Abdominal pain (biliary spasms)
• you have taken it according to the
• Constriction of the pupil (miosis) instructions given by the prescriber or in the information provided with the medicine – Blurred vision
• Involuntary eye movements (nystagmus) and
• A feeling of dizziness or "spinning" (vertigo)
• it was not affecting your ability to drive
• Dizziness/light headedness on standing safely. (orthostatic hypotension)
• Difficulty passing urine Talk to your doctor or nurse if you are not sure
• Headaches whether it is safe for you to drive while taking
• Changes of mood this medicine.
• Decreased libido (interest in sex) or inability to get an erection Morphine sulfate contains sodium This medicine contains less than 1 mmol sodium – Dry mouth
• Facial flushing (warmth and redness of the (23 mg) per ml of solution, that is to say skin) essentially 'sodium-free'.
• Restlessness
• Fits (convulsions)

How to take it

to you – Increased sensitivity to pain

• Tiredness (fatigue)
• Stopping the drug can lead to withdrawal Morphine sulfate will be given to you by symptoms such as agitation, anxiety, shaking a doctor or nurse in hospital. Your doctor will or sweating. This can also happen to babies choose the dose that is right for you. born to mothers addicted to morphine.
• Pain and irritation may occur at the site of the Before starting treatment and regularly during injection treatment, your doctor will discuss with you what you may expect from using Morphine Uncommon (may affect up to 1 in 100 people): sulfate, when and how long you need to use it, when to contact your doctor, and when you need – Being aware that your heart is beating or the rate has changed (palpitations) to stop it (see also, If you stop using Morphine
• Abdominal pain (urethral spasms) sulfate, in this section).
• An increase in liver enzymes may be noted during blood tests Adults
• The recommended adult dose for relief of pain Not known (cannot be estimated from the by subcutaneous injection (an injection available data): underneath the skin) or intramuscular
• Muscle stiffness with high doses injection (an injection into a muscle) is
• Pain, generally on the skin, caused by 10 mg every four hours, if necessary. something that would not normally cause pain
• However, the amount may range from 5 mg to such as light touch or pressure 20 mg depending on how severe your pain is
• Coma and how you respond to the drug.
• Kidney failure
• If the drug is injected into a vein, the
• Abstinence symptoms or dependence (for recommended dose for an adult is 2.5 mg to symptoms see section 3: If you stop using 15 mg with at least 4 hours between doses. Morphine sulfate)
• Your doctor or nurse may adjust the dose of
• Sleep apnoea (breathing pauses during sleep) your medicine and the number of injections
• Symptoms associated with inflammation of you are given each day until your pain is the pancreas (pancreatitis) and the biliary tract relieved. system, e.g. severe upper abdominal pain possibly radiating to the back, nausea, Elderly vomiting or fever As this medicine make breathing difficult, your doctor or nurse may reduce dose of your medicine. Reporting of side effects If you get any side effects, talk to your doctor or Use in children Morphine sulfate is not recommended for use in nurse. This includes any possible side effects not listed in this leaflet. You can also report side children. effects directly via: Yellow Card Scheme, Website: Hepatic impairment www.mhra.gov.uk/yellowcard or search for A reduction in dosage should be considered in MHRA Yellow Card in the Google Play or hepatic impairment. Apple App Store. Renal impairment By reporting side effects you can help provide The dosage should be reduced in moderate to more information on the safety of this medicine. severe renal impairment. If you think you have been given more Morphine sulfate than you should As this medicine will be given to you whilst you are in hospital, it is unlikely that you will be given too little or too much, however, tell your doctor or nurse if you have any concerns. Overdose may cause pneumonia from inhaling vomit or foreign matter, symptoms may include breathlessness, cough and fever. Symptoms of serious overdose include breathing difficulties leading to unconsciousness or even death, low blood pressure with your heart finding it difficult to pump blood around your body, a deepening coma, feeling cold, fits especially in infants and children and rapid break down of muscle tissue (characterized by dark coloured urine and muscle tenderness, stiffness or aching) progressing to kidney failure. If you have these symptoms, you will be given another medicine called Naloxone to reverse the effects of Morphine sulfate. If you have any further questions about the use of this medicine, ask your doctor or nurse. If you stop using Morphine sulfate Do not stop treatment with Morphine sulfate unless agreed with your doctor. If you want to stop the treatment with Morphine sulfate, ask your doctor how to slowly decrease the dose so you avoid abstinence symptoms. Abstinence symptoms may include body aches, tremors, diarrhoea, stomach pain, nausea, flu-like symptoms, fast heartbeat and large pupils. Psychological symptoms include an intense feeling of unsatisfaction, anxiety and irritability.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Seek immediate medical help if you have any of the following symptoms:

• Breathing difficulties (respiratory depression)
• Low blood pressure (hypotension) which may make you feel faint
• Your heart finding it difficult to pump blood around your body (circulatory failure) causing faintness, breathing difficulties, coughing up blood, excessive sweating and/or pale skin
• Serious allergic reaction which causes:
• Swelling of hands, feet, lips, mouth, tongue or throat
• Difficulty in breathing or dizziness
• Itchy skin rash (hives)
• Stomach pains, bloating, vomiting and constipation (obstructive bowel disorder)
• Severe skin reaction with blistering, widespread scaly skin, pus-filled spots together with fever. This could be a condition called Acute Generalized Exanthematous Pustulosis (AGEP)

How to store it

Morphine sulfate Keep this medicine out of the sight and reach of children. Keep the ampoules in the outer carton in order to protect from light. Product containing visible particles should not be used. Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Contents of the pack and other information

What Morphine sulfate contains

• The active substance is morphine sulfate 10 mg, 15 mg and 30 mg in each 1 ml of solution.
• The other ingredients are sodium chloride, hydrochloric acid (for pH adjustment), water for injections. What Morphine sulfate looks like and contents of the pack Clear colourless or almost colourless solution for injection. Morphine sulfate 10 mg/ml, 15 mg/ml and 30 mg/ml are presented in 1 ml amber glass ampoules with white open point cut. The ampoules are packed in transparent polyvinylchloride film liners. The liners together with leaflets are packed in cartons. Pack size: 5 or 10 ampoules. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer AS KALCEKS Krustpils iela 71E, Rīga, LV-1057, Latvia Tel.: +371 67083320 E-mail: [email protected] This leaflet was last revised in 05/2024

Place for AS Kalceks internal code

05.06.2024 MUK/I/0/1

4.9 Overdose an opioid and supportive care. As with all drugs it is not advisable to administer Symptoms: respiratory depression, pin-point morphine during pregnancy. pupils, pneumonia aspiration and coma. In addition, shock, reduced body temperature and Breastfeeding The amount of morphine secreted in breast milk hypotension may occur. In mild overdose, symptoms include nausea and vomiting, tremor, after a single-dose administration seems to be compatible with breast feeding and insufficient miosis, dysphoria, hypothermia, hypotension, confusion and sedation. In cases of severe to cause major problems or dependence. However long-term treatment with morphine in poisoning, hypotension with circulatory failure, rhabdomyolysis progressing to renal failure, high doses may cause significant plasma concentration. That is why caution is advised on respiratory collapse may occur. Death may occur the use of morphine in breast-feeding patient and from respiratory failure. the benefit must outweigh the risk to the infant. If breast feeding is continued, the infant should Treatment: the patient must be given both respiratory and cardiovascular support and the be observed for possible adverse effects. specific antagonist, naloxone, should be administered using one of the recommended Fertility Animal studies have shown that morphine may dosage regimens. Fluid and electrolyte levels reduce fertility (see section 5.3). should be maintained. 4.7 Effects on ability to drive and use machines Morphine has major influence on the ability to drive and use machines. It may cause drowsiness so patients should avoid driving or operating machinery. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However, you would not be committing an offence (called 'statutory defence') if: o The medicine has been prescribed to treat a medical or dental problem and o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely 4.8 Undesirable effects Adverse effects can be listed in terms of their frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), not known (cannot be estimated from the available data). Morphine may cause the following adverse events: Nervous system disorders: Very common: Drowsiness, hyperhidrosis. Common: Convulsion, headache, increased intracranial pressure, myoclonus; opioid-induced hyperalgesia (or hyperaesthesia) (see section 4.4), vertigo. Allodynia (see section 4.4), Not known: coma.

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Natural opium alkaloids, ATC code: N02AA01. Morphine is a narcotic analgesic obtained from opium, which acts mainly on the central nervous system and smooth muscle. 5.2 Pharmacokinetic properties Absorption Variably absorbed after oral administration; rapidly absorbed after subcutaneous or intramuscular administration. Blood concentration After an oral dose of 10 mg as the sulfate, peak serum concentrations of free morphine of about 10 ng/ml are attained in 15 to 60 minutes. After an intramuscular dose of 10 mg, peak serum concentrations of 70 to 80 ng/ml are attained in 10 to 20 minutes. After an intravenous dose of 10 mg, serum concentrations of about 60 ng/ml are obtained in 15 minutes falling to 30 ng/ml after 30 minutes and to 10 ng/ml after three hours. Subcutaneous doses give similar concentrations to intramuscular doses at 15 minutes but remain slightly higher during the following 3 hours; serum concentrations measured soon after administration correlate closely with the ages of the subjects studied and are increased in the elderly. Half-life Serum half-life in the period 10 minutes to 6 hours following intravenous administration, 2 to 3 hours; serum half-life in the period 6 hours onwards, 10 to 44 hours. Distribution Widely distributed throughout the body, mainly in the kidneys, liver, lungs and spleen; lower concentrations appear in the brain and muscles. Morphine crosses the placenta and traces are secreted in sweat and milk. Protein binding, about 35% bound to albumin and to immunoglobulins at concentrations within the therapeutic range.

Psychiatric disorders: Very common: Confusional state, hallucinations, physical and psychological dependence. Decreased libido, mood swings, Common: Biotransformation restlessness. Mainly glucuronic acid conjugation to form morphine-3 and 6-glucuronides, with sulfate Eye disorders: conjugation. N-demethylation, O-methylation Blurred vision, miosis, Common: and N-oxide glucuronide formation occurs in the nystagmus. intestinal mucosa and liver; N-demethylation Respiratory, thoracic and mediastinal disorders: occurs to a greater extent after oral than parental administration; the O-methylation pathway to Very common: Respiratory depression. form codeine has been challenged and codeine Bronchospasm, pulmonary Common: and norcodeine metabolites in urine may be oedema, which can lead to formed from codeine impurities in the morphine death. Respiratory failure, which also sample studied. Not known: can lead to death, central sleep Elimination apnoea syndrome. After an oral dose, about 60% is excreted in the urine in 24 hours, with about 3% excreted as free Cardiac disorders: Bradycardia, circulatory failure, morphine in 48 hours. Common: After a parental dose, about 90% is excreted in tachycardia. 24 hours, with about 10% as free morphine, Palpitations. Uncommon: 65 to 70% as conjugated morphine, 1% as normorphine and 3% as normorphine Vascular disorders: glucuronide. Hypotension, orthostatic Common: After administration of large doses to addicts hypotension. about 0.1% of a dose is excreted as norcodeine. Urinary excretion of morphine appears to be pH Gastrointestinal disorders: Very common: Constipation, nausea, vomiting. dependent to some extent; as the urine becomes more acidic more free morphine is excreted and Dry mouth, paralytic ileus. Common: as the urine becomes more alkaline more of the Intestinal functional disorder, Not known: glucuronide conjugate is excreted; up to 10% of narcotic bowel syndrome, a dose may be excreted in the bile. pancreatitis. 5.3 Preclinical safety data Hepatobiliary disorders: Biliary spasm. Common: Non-clinical data based on conventional studies Hepatic enzyme increase. Uncommon: Spasm of the sphincter of Oddi. of safety pharmacology, repeated dose toxicity, Not known: genotoxicity, carcinogenic potential reveal no special hazard additional to the known safety Reproductive system and breast disorders: profile of morphine in humans. In male rats, Erectile dysfunction. Common: reduced fertility and chromosomal damage in gametes have been reported. Renal and urinary disorders: Urinary retention. Common: Urethral spasm. Uncommon: 6. PHARMACEUTICAL PARTICULARS Renal failure. Not known: Immune system disorders: Anaphylactic reaction, Uncommon: hypersensitivity. Anaphylactoid reactions Not known:

6.1 List of excipients Sodium chloride Hydrochloric acid (for pH adjustment) Water for injections

General disorders and administration site 2 years. conditions: Very common: Drug tolerance 6.4 Special precautions for storage Fatigue, facial flushing, Common: hypothermia, injection site pain, Keep the ampoules in the outer carton in order to injection site irritation, drug protect from light. withdrawal (abstinence) syndrome (babies born to 6.5 Nature and contents of container opioid-dependent mothers also at risk to present withdrawal Type I amber glass ampoules of 1 ml with white syndrome). open point cut. The ampoules are packed in transparent polyvinylchloride film liners. The Drug dependence and withdrawal (abstinence) liners together with leaflets are packed in syndrome cartons. Use of opioid analgesics may be associated with the development of physical and/or Pack size: 5 or 10 ampoules. psychological dependence or tolerance. Repeated use of Morphine sulfate can lead to Not all pack sizes may be marketed. drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on 6.6 Special precautions for disposal and a patient's individual risk factors, dosage, and other handling duration of opioid treatment (see section 4.4). An abstinence syndrome may be precipitated The medicinal product is for single use only; when opioid administration is suddenly discard any remaining contents after use. discontinued or opioid antagonists administered, or can sometimes be experienced between doses. The required volume should be calculated based For management, see section 4.4. on the prescribed dose. Physiological withdrawal symptoms include: Any unused medicinal product or waste material Body aches, tremors, restless legs syndrome, should be disposed of in accordance with local diarrhoea, abdominal colic, nausea, flu-like requirements. symptoms, tachycardia and mydriasis. Psychological symptoms include dysphoric MARKETING AUTHORISATION mood, anxiety and irritability. In drug HOLDER dependence, "drug craving" is often involved. AS KALCEKS, Krustpils iela 71E, Rīga, LV-1057, Latvia, Tel.: +371 67083320, E-mail: Reporting of suspected adverse reactions [email protected] Reporting suspected adverse reactions after authorisation of the medicinal product is MARKETING AUTHORISATION important. It allows continued monitoring of the NUMBER(S) benefit/risk balance of the medicinal product. Morphine Sulfate 10 mg/ml solution for injection Healthcare professionals are asked to report any PL 47015/0003 suspected adverse reactions via: Morphine Sulfate 15 mg/ml solution for injection Yellow Card Scheme, Website: PL 47015/0004 www.mhra.gov.uk/yellowcard or search for Morphine Sulfate 30 mg/ml solution for injection MHRA Yellow Card in the Google Play or PL 47015/0005 Apple App Store.

Place for bleedmarks

Musculoskeletal and connective tissue disorders: Muscle rigidity, Not known: 6.2 Incompatibilities rhabdomyolysis. Morphine salts may be precipitated in alkaline Skin and subcutaneous tissue disorders: solution. Morphine sulfate is incompatible with Very common: Pruritus. oxidizing agents. Angioedema, contact Common: Physicochemical incompatibility (formation of dermatitis, rash, urticaria. precipitates) has been demonstrated between Not known: Acute generalised solutions of morphine sulfate and 5-fluorouracil. exanthematous pustulosis (AGEP). 6.3 Shelf life