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Dolsin Injection


COMPANY CORE SAFETY INFORMATION 

1. NAME OF MEDICINAL PRODUCT

                                                         DOLSIN

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

                                                        Pethidine hydrochloride 50 mg/ml or 100 mg/2 ml.
                                                        For a full list of excipients, see section 6.1.
 
3. PHARMACEUTICAL FORM 

Solution for injections 
Description of the preparation: clear, colourless solution. 

4. CLINICAL PARTICULARS

4.1 Therapeutic indications 
The preparation is indicated for treatment of strong acute pain after serious injuries, after operations and for treatment of pain accompanying tumorous disease. It suppresses dyspnoe in heart failure, pulmonary oedema, pulmonary cancer or in other serious pulmonary diseases connected with dyspnoe. It relieves spasms of smooth muscles in gastrointestinal tract and in renal colic. It is used as pre-medication before anaesthesia. To alleviate painful labor contraction.

4.2 Posology and method of administration 

Children: 
Pethidine is administered to children subcutaneously or intramuscularly in a dose of 0.5 mg - 1 mg/kg of body mass. The usual therapeutic dose for children up to 1 year is 5 mg, for children between 1 - 6 years the individual dose is 5 -10 mg, for children between 6 -15 years 10 - 30 mg subcutaneously or intramuscularly, 1 to 3 times daily. For pre - medication it is administered intramuscularly 1 hour before beginning of anaesthesia, exceptionally intravenously 10 minutes before general anaesthesia. It is not recommended for pre - medication of children up to 1 year of age. 

Adults: 
Intramuscularly or intravenously it is administered in a dose of 25 - 100 mg, 1 to 3 times daily. Intravenously 25 -50 mg should be administered very slowly to a recumbent patient. In obstetrics is administered 50 - 100 mg of pethidine intramuscularly or subcutaneously. The dose can be repeated in 1 - 3 hours. In reduced renal function (decrease of glomerular filtration under 10 ml/min.) there is necessary to reduce the dose to one half.
The daily therapeutic dose is in intramuscular or subcutaneous administration 50 - 200 mg, in intravenous administration 50 - 150 mg . 
The maximal single dose of pethidine is 150 mg in intramuscular administration, 100 mg in intravenous administration. 
The maximal daily dose of pethidine is 500 mg in intramuscular and subcutaneous administrations, 300 mg in intravenous administration. 

4.3 Contraindications 
Administration of pethidine is contraindicated in patients: 
 in hypersensitivity to pethidine hydrochloride or any other ingredients
 in head injuries with possible increase of intracranial pressure (pethidine due to respiratory depression causes cerebral vasodilatation followed by increase of intracranial pressure), 
 in pheochromocytoma
 in convulsive status (status epilepticus, tetanus)
 in acute alcohol intoxication or with delirium tremens
 in threatening coma at diabetic acidosis
 in dysrythmia and acute myocardial infarction
Pethidine can temporarily increase the vascular resistance and blood pressure and therefore it should not be used in myocardial infarction. Increased caution is necessary in vestibular fluttery and supraventricular tachycardia, where pethidine can cause a rapid response of ventricles. 
in serious liver disease
in porphyria
in treatment with MAO inhibitors and two weeks after its discontinuation
in intoxication by poisons causing spasms or by local anaesthetics

4.4 Special warning and precautions for use
Among the life-threatening adverse reactions, depression of respiration, coma, cramps and hypotension are included. In respiratory depression the drug of choice is the opioidic antagonist naloxone and providing of managed respiration. Continuous drug administration causes drug dependence. In patients over 70 years of age, the increase of pethidine plasma concentration can occur due to changed binding to proteins, changed distribution volume and slowed down elimination, therefore at repeated administration it is recommended to reduce the total daily dose to one half of adult's dosage. In pacients with cirrhosis, after intravenous administration, an over a half reduced clearence of pethidine and 2 times prolonged drug half-life can occur, therefore, in repeated administration twofold prolonged period between doses, or reduced dose up to 50% - 70 % is necessary. In patients with impaired renal function rises the plasma concentration of metabolite norpethidine, which has excitatory effects on CNS and can cause higher excitation or cramps. Increased excretion of pethidine can be reached by acidification of the urine. 
Particular caution is needed in administration in patients with preexisting respiratory insufficiency (bronchial asthma, chronic obstructive pulmonary    disease, retention of bronchial secretion), in Addison disease and in hypothyroidism

4.5 Interaction with other medicinal products and other forms of interaction
The inhibitory effect of pethidine on CNS can be increased by other central inhibitory substances (alcohol, barbiturates, neuroleptic drugs, benzodiazepines, antidepressant drugs, antihistaminic drugs). Due to the interaction, depression of CNS and of respiration can appear. 

Serious adverse reactions - excitedness, hyperthermia and cramps in simultaneous administration of monoaminooxidase inhibitors appear. The exact mechanism of adverse reactions appearance is not known, the assumed cause is the elevated production of nor pethidine due to inhibition of alternative metabolic pathway. 

Simultaneous administration of pethidine and phenothiazines can cause serious decrease of blood pressure and depression of breath. Simultaneous administration of pethidine and barbiturates leads, due to inductory affecting barbiturates, to an elevated amount of neurotoxically affecting norpethidine. The preparation increases the effect of oral anticoagulants. In simultaneous administration of pethidine and phenytoin, which induces liver biotransformation enzymes, the biological half-life at pethidine gets shorter and the production of norpethidine increasis. 

Cimetidine reduces clearance and the distribution volume of pethidine. Such adverse reaction does not occur at newer drugs from the group of H2 blockers. 

4.6 Pregnancy and lactation 
The unfavourable effect of pethidine on reproductional function and development of foetus is not reported in the literature. In newborn baby of drug dependent mother signs of abstinence after birth may appear. 
Pethidine can be widely used at relieving pain during delivery. Since it passes the placental barrier, it may cause danger to the newborn baby by depression of respiratory centre. Depression is more marked when pethidine was administered to mother more than 1 hour before delivery. Pethidine is bound in plasma to acid glycoprotein. 
Newborn babies have low concentration of this binding protein, therefore they have a large amount of free pethidine. With respect to immature biotransformation enzymes, the newborn has no ability to N-¬demetylate pethidine to norpethidine in such rate as adults do. Due to this, more pethidine than metabolites is found in the urine of newborn. The half-life of pethidine elimination, which has been administered during delivery, is in mother about 3 hours and in newborn baby 22 hours. 
Pethidine passes into breast milk, but the data on milk concentration are missing, 

4.7 Effects on ability to drive and use machines
With respect to pharmacodynamic effects, pethidine can unfavourably influence the concentration, coordination of movements and responsible decision making when driving cars and operating machines. 

4.8 Undesirable effects
 In usual dosage adverse reactions occur in about 4% of patients.  Most frequently occurs nausea and vomiting, with a frequency below 1% appears constipation, hypotension, mental changes associated with disorientation, drowsiness, confusion. Dry mouth, sweating, facial flushing, dizziness, bradycardia, palpitations, orthostatic hypotension, hypothermia, agitation, mood changes, hallucinations, miosis, urinary retention and spasm of bile ducts may also occur.
Metabolite of pethidine, norpethidine has excitatory effect on CNS, by which it can cause tremor, myoclonia or cramps. 
To adverse reactions are predisposed especially those patients with increased susceptibility to cramps in anamnesis, with renal insufficiency and at a dose higher than 100 mg, repeated in short periods. 
At higher dosage a marked respiratory depression can occur. Pethidine in analgesic doses inhibits the respiratory centre and lowers its sensitivity to pC02. It decreases mainly the respiratory volume, the respiratory frequency is not markedly influenced. 
Pethidine causes drug dependence of morphine type. 
Tolerance is developed slower than at morphine. Signs of abstinence appear sooner and last shorter than in morphine dependence. 
4.9. Overdose
The minimal lethal dose reported in human is 1 g of pethidine. Pethidine dependent patients tolerate doses of 3 - 4 g daily. The overdosage is manifested by depression of CNS, stupor up to coma, Cheyne-Stoke's breathing with cyanosis, cold skin, hypothermia and bradycardia. After fast intravenous injection apnoe with block of respiration and heart circulation and death may appear. Signs of excitedness appear especially in patients with tolerance to depressive effects of pethidine. They are manifested by increased muscular activity (twitches, tremor), tachycardia, dellirium with disorientation, hallucinations and seizures of grand mal type. 

In overdosage lavage of stomach with active charcoal is indicated. Pylorospasm provoked by the drug, limits the period of effectiveness of this procedure. For more intensive peristalsis salinic laxatives are applied. In overdosage supplementation of volume by plasma or electrolytes and managed respiration are necessary. In respiratory depression the drug of choice is the opioidic antagonist naloxone. It is administered intravenously in a dose of 0.4 mg, if necessary, repeated in 2 - 3 minute intervals. The recommended initial dose for children is 0,01 mg/kg of body mass. Acidification of the urine increases the excretion of pethidine from the circulation. 

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: N02AB02
Analgesic, anodyne 

Mechanism of action 
Pethidine acts by interaction with opiate receptors mainly of type µ (mi) in the cerebral cortex, thalamus, in formatio reticularis, in limbic-hypothalamic system, in periaqueductal grey and in substantia gelatinosa. 

Activation of receptors results in the hyperpolarisation of membrane of neural cells, or inhibition of excitatory neurons, The most marked agonistic effect of pethidine is manifested on µ (mi) receptors. Pethidine is bound on the anionic site in P-position one of three binding sites of the opiate receptor. The anionic site reacts with nitrogen from piperidine chain and P-binding site binds preferably hydroxylated aromatic nucleus of pethidine. The result is the activation of mi1 receptor with supraspinal analgesia, sedation, euphoria resp. dysphoria. By acting on mi2 receptors the drug causes miosis and respiratory depression. The affinity to kappa receptor is lower, but with marked response. 

Pethidine has an inhibitory effect on CNS. It relieves markedly the acute and chronic pain, causes total relaxation, euphoria. The activation of kappa receptors results in appearance of dysphoria, connected by unability to concentrate, with lethargy and hypersomnia. Analgesic effect of pethidine after subcutaneous or intramuscular administration appears In about 10 minutes with a maximum after about 1 hour and duration about 2 - 4 hours. 

Pethidine inhibits respiration less markedly than morphine. It lowers the sensitivity of respiratory centre to C02. The maximum of the respiratory depression appears at about 1 hour after parenteral administration, in about 2 hours after administration it returns to the initial values, although the minute respiratory volume remains still decreased also after 4 hours. The excitatory effect on CNS is manifested by tremor, myoclonia up to cramps. Pethidine activates receptors of smooth muscle of the stomach and intestines in the similar way than other opioides, but, in relation to analgesic effect, less intensively. In the case of an equianalgesic dose the increase of tonus of Oddi's sphincter and billary pressure is less marked than after morphine. 

Respiratory depression and retention of C02 cause cerebral vasodilatation and by this an increase of intracranial pressure. It irritates chemoreceptor vomiting zone and in this way causes nausea and vomiting. The liberation of histamine causes itching, urticaria in site of the administration, it is systemicly manifested by bronchospasm and hypotension, what can have serious consequences in asthmatic patient. 

5.2 Pharmacokinetic properties
Pethidine is administered mostly parenterally, most frequently intramuscularly and intravenously. After intramuscular administration there are considerable differences in resorption which, depending on the site of application, musculature, capillary return and dose, influence the maximum of reached plasma concentration. The systemic biological availability is 50 - 60%, in the case of intramuscular administration the biological availability is 80 - 85% and tmax 1 hour. About 40 % pethidine is bound to plasma proteins. Distribution volume is 4.2 L/kg. Pethidine is biotransformed in the liver. The active metabolite, norpethidine, has hallucinogenic and convulsive effects. Other metabolites are inactive. Pethidine is excreted by the urine. The elimination half-life is in average about 5 hours .It is getting longer in old age. 

Pharmacokinetios of pethidine is changed in kidneys and liver disorders or their reduced function due to the ageing process. The renal insufficiency can be a cause of metabolites cumulation. In case of renal insufficiency the elimination half-life, mainly of norpethidine, Is markedly getting longer; therefore the plasma concentration of norpethidine increases. Values of plasmatic clearance are getting lower and the elimination half-life is getting longer in cirrhosis and acute viral hepatitis. 

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients 
Water for injection 

6.2  Incompatibilities 
DOLSIN must not be mixed in one injection with phenytoin, barbiturates and aminophylline, due to formation of inactive complexes. 

6.3 Shelf life
5 years

6.4 Special precaution for storage
Store below 25°C. Do not refrigerate or freeze.

6.5. Nature and content of container 
Colourless glass ampoule with label, PVC mould with Al foil, paper folder, package insert. 
Size of the package: 10 ampoules of 1 ml 
10 ampoules of 2 ml 

6.6 Special precautions for disposal
No special requirements.

7. MARKETING AUTHORISATION HOLDER 
BB Pharma Pod Višňovkou 1662/21, 140 00 Prague 4, Czech Republic 
8. MARKETING AUTHORISATION NUMBER 
 65/764/92-S/C 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION 
 December 14, 1992

10. DATE OF REVISION OF THE TEXT