2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

Active substance:  Morphine hydrochloride trihydrate 10 mg in 1 ml or 20 mg in 2 ml. 

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM 

Solution for injection 

Clear, colourless or at most pale yellow solution. 

Morphine is indicated for treatment of strong acute pains after severe injuries, burns, operations, acute and chronic pain in myocardial infarction and for treatment of chronic tumours pain and as pre-medication before anaesthesia. 

a) Dosage for infants and children under 6 months of age: 

 iv bolus in non-ventilated patients: 25 μg/kg, respectively, 50 μg/kg in ventilated 

 iv continuous application in non-ventilated patients: 5 – 7 μg/kg/h, respectively 10 – 15 μg/kg/h in ventilated. 

 b) Dosage for Children: 

The dose for children between 6-12 months of age is 0,2 mg/1 kg of body mass applied subcutaneously or intramuscularly. The single dose for children between 1-6 years is 2-4 mg, 6-15 years 4-10 mg subcutaneously or intramuscularly. 

c) Dosage for adults: 

The usual single therapeutic dose of morphine is 10-20 mg subcutaneously or intramuscularly. The daily therapeutic dose is 10-40 mg. The maximal single dose is 20 mg, the maximal daily dose is 60 mg subcutaneously. When a rapid onset of the effect is required or in insufficient blood circulation (hypotension, shock), morphine can be administered very slowly intravenously (4-5 minutes) to a recumbent patient and the dose is cut by 1/3-1/2. In long lasting pain it is applied in 4 hour intervals. The dose is necessary to be reduced to 1/2 in decreased renal function (decrease of glomerular filtration under 10 minutes). The interval between doses gets 1.5 - 2 times longer in decreased liver function. In dialysis it is not necessary to adjust the dose. 

Administration of the medicinal product is contraindicated in hypersensitivity to the active ingredient morphine hydrochloride trihydrate or excipients, damage of lungs function with depression of respiratory centre, chronic obstructive pulmonary disease, paralytic ileus,  head injuries with elevated intracranial pressure. 

Care is necessary in asthma bronchiale, biliary colic, intoxication caused by spasmogenic poisons and in hypertrophy of prostate. Morphine should not be administered in the treatment with monoamineoxidase inhibitors and 2 weeks after its completion. In patients with severe hepatal disease and damaged renal function, it is necessary to reduce the doses. 

In endocrinological diseases (Addison's disease, myxedema) it is necessary to expect more expressive and prolonged effect. Morphine should not be administered to lactating mothers and to babies of less than 6 months. 

Risk of somatic and psychic dependence! 

The depressant effect of morphine may be potentiated by other central depressants (alcohol, barbiturates, neuroleptic agents, benzodiazepines, antidepressants,•antihistamines), monoamineoxidase inhibitors, physostigmine, neostigmine, amphetamine. Interaction causes CNS and respiratory depression. The effect of morphine is decreased by mixed opium-like agonists-antagonists and partial agonists (pentazocine, butorphanol, buprenor), These drugs can give rise to withdrawal symptoms in patients with long-term morphine administration 

Depressive effects on respiration are potentiated by simultaneous administration of morphine and thiopental. Tricyclic antidepressants, mainly desipramine, potentiate and prolongate the analgesic effect of morphine. Morphine decreases the effect of diuretics•by releasing antidiuretic hormone and also decreases the effect of laxatives. 

Morphine potentiates the toxicity of organophosphates 

Morphine passes placental barrier and therefore it may endanger the newborn by respiratory depression, when it was applied just before delivery. Newborns of morphine addicted mothers have lower birth weight and higher neonatal mortality. Withdrawal symptoms may occur after delivery: abnormal reflexes, increased muscle tonus, convulsions, diarrhoea, sweating. Less than 1 % of the administered dose passes into breast milk. 

With regard to pharmacodynamic effects morphine may unfavourably influence attention, motor coordination and responsible decisions when driving cars and operating machines. 

4.8 Undesirable effects 

 In normal doses adverse events occur in about 7% of patients, most frequently nausea, vomiting and constipation (3-4%). Respiratory depression, drowsiness and confusion occur in approximately 2% ,drop in blood pressure in about 0.5% of patients .  Morphine can cause biliary and urethral spasms, dry mouth, sweating, facial flushing, dizziness, bradycardia, tachycardia, palpitations, hypothermia, mood changes (euphoria, dysphoria), asthenia, headache, sleep disturbances, blurred vision, miosis, taste disturbance, decreased appetite, allergic reactions at the injection site (pruritus, urticaria) and total (bronchoconstriction).  Higher doses may result in significant respiratory depression. 

In patients with asthma bronchiale, morphine may induce bronchospasm.

 Among other serious adverse reactions belong the occurrence of psychic and somatic dependence. 

Sensitivity to morphine is individual and can be decreased in persons regularly using morphine preparations and narcotics On the contrary increased sensitivity is in children up to 2 years (mainly respiratory depression and paradoxical excitation) and in older people (respiratory depression). 

Average plasma therapeutic concentrations are 0.05-0.15 µg/ml. Symptoms of intoxication may occur at concentrations 0.1-0.5 µg/ml, lethal concentrations are above 1 µg /ml. 

Symptoms of a slight intoxication are euphoria, somnolence, miosis. and slowing down of intestinal function. Serious morphine intoxication is characterised by characteristic trinity of symptoms: coma, significant decrease of respiratory frequency and miosis with pin-like pupils. As a consequence of respiratory depression, cyanosis followed by hypoxia of tissues, capillary lesion and shock state development occur. To the other intoxication symptoms belong decrease of body temperature, relaxation of skeletal muscles, blockage of respiratory ways by fallen tongue (glossoptosis). 

In the case of intoxication symptoms, it is necessary to distinguish symptoms caused by histamine releasing, characterised by hypotension, tachycardia and erythema. 

Treatment: The treatment of hypotension, hypothermia and respiratory depression is symptomatic. The most important thing is to ensure free respiratory ways and sufficientventilation. In hypotension, isotonic sodium chloride solution or an other substitute solution is applied. At insufficient effect, when liquids have been complemented, it is possible to apply dopamine in a dose of 5-15 µg/kg/min. The specific antagonist of morphine is naloxone, which can quickly remove the intoxication symptoms. It is administered in a dose of 0.4 to 2 mg intravenously and the dose is repeated in 2-3 minute intervals until the patient awakes, the breathing and the cough reflex are settled. The effect of naloxone lasts 2-3 hours. If the effect of naloxone is unsatisfactory, it is necessary to look for other reason of this state (hypoglycaemia, intoxication with other substances ). In morphine intoxication, elimination methods are not used (peritoneal dialysis, haemodialysis, haemope rfusion). 

In intravenous application of morphine, it is recommended to have prepared naloxone injection and a device for control respiration. 

Pharmacotherapeutic group: analgesic, anodyne. 

ATC code: N02AA01

Mechanism of effect 

The strong analgesic effect of morphine is conditioned by agonistic effect on opioid receptors in cerebral cortex, thalamus, formatio reticularis, limbic-hypothalamus system, periaqueductal grey matter and in substantia gelatinosa. The agonistic effect of morphine is manifested most expressively on mí and kappa receptors. The influence on sigma and delta receptors is less expressive. Morphine, by activation of mí1 receptors, causes supraspinal analgesia, euphoria and induces drug dependence. The effect on mí2 receptors causes miosis, respiratory depression and slowing down of intestinal motility. Occupation of kappa receptors causes spinal analgesia, miosis and sedation. 

Morphine by influence on CNS expressively attenuates acute and chronic pains, causes psychomotor attenuation, total relaxation and euphoria. Morphine attenuates the respiratory volume and frequency, reduces the sensitivity of respiratory centre to CO2. 

Miosis is the excitatory effect of morphine, mediated by activation of mí and kappa receptors of oculomotor nerve nucleus. Pin-like pupils are typical morphine over-dosage symptom. 

Morphine activates smooth muscle receptors of stomach and intestine, increases their tonus and reduces the peristalsis. In this way it prolonges stomach evacuation. It decreases gastric, biliar and pancreatic secretion Prolonged intestinal passage causes water re-sorption and increase of stool viscosity. Consequence of these influences is an obstinate obstipation. Morphine by vasodilation effect decreases venous recurrence. Therefore it is suitable for treatment of cardiac failure and pulmonary oedema 

Biliary pressure is increased by increase of gallbladder contraction and by increase of Oddi's sphinCter tonus. Contraction of urethral sphincter may cause retention of urine. 

Chronic application causes tolerance, mainly to depressive components of morphine´s action (analgesia, respiratory depression), but not to miotic effect and to obstipation 

After subcutaneous or intramuscular injection morphine is quickly re-sorbed. The absorption is retarded in circulatory shock. 

After subcutaneous application the maximal effect is reached in 50-90 minutes, after intramuscular application in 30-60 minutes. Plasma biological half-life is 2 hours, duration of the effect is 4-5 hours. 

In PCA technique (analgesia controlled by the patient), the patient injects morphine, if frequent, by an implanted pump or into subcutaneously implanted entrance. This way is used mainly in the treatment of acute postoperative pain and chronic malignant pain. 

The binding to plasma proteins is 25-35%. Distribution volume in the equilibral state is 3.3 l/kg ± 0.9. Morphine is bio-transformed in the liver, the main metabolite is the inactive morphine-3 glucuronide. The active morphine-6-glucuronide forms the smaller part (about 5% of the applied dose). Less than 10% of morphine is excreted in unchanged form. 

The elimination half-life is about 1.9 hours. The high morphine clearance depends more upon its extraction than bio-transformation, therefore drugs with inductive effect on hepatic enzymes have not an expressive influence on morphine metabolism. Not even hepatic diseases expressively influence morphine pharmacokinetics. Decrease of creatinine clearance below 2 ml/min prolongs the plasma half-life more than 10 times. 

The blood-brain barrier controls the penetration of morphine into the brain. The onset of morphine effect is longer, than that one of other lipophilic opiates. 

Morphine passes through placental barrier, it is excreted into breast milk in small amount, less than 1 % of the applied dose. 

Embryotoxic, cytotoxic, teratogenic a kancerogenic effects of the preparation are not known. 

Sodium chloride

Glycine

Disodium edetate dihydrate

Water for injection 

Sodium content in the preparation: 2.964 mg/ml, what corresponds to 0.129 mMol/ml. 

6.2 Incompatibilities 

Morphine is incompatible with aminophylline, heparin, thiopental, pentobarbital, phenobarbital and metaraminol, therefore they must not be mixed in one syringe. 

5 years

Store at temperature 10- 25°C. Do not refrigerate or freeze. Store in the original folder in order to protect from light..

Colourless glass ampoule with label, PVC mould with Al-foil, paper folder. 

Size of the package: 10 ampoules of 1 ml 

10 ampoules of 2 ml 

Not all pack sizes may be marketed.

No special requirements.

BB Pharma Pod Višňovkou 1662/21, 140 00 Prague 4, Czech Republic 

8. MARKETING AUTHORISATION NUMBER(S) 

65/780/92-S/C

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

14.12.1992/2.2.2000 

May 17, 2006