Alodan^®, 100 mg/2 ml solution for injection

 

1. NAME OF THE MEDICINAL PRODUCT
Alodan^® 100 mg/2 ml solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml solution for injection contains 50 mg pethidine hydrochloride.
One 2 ml ampoule contains 100 mg pethidine hydrochloride.

Excipient with known effect: less than 1 mmol sodium (for pH adjustment).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM
Solution for injection
Clear, colourless to slightly yellow solution
pH between 3.5 and 7.0

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
For short-term use in severe pain.
Alodan® is indicated in adults and adolescents aged 16 years and older.

4.2 Posology and method of administration
Posology
Adults and adolescents aged 16 years and older
Usual single doses are:
– between 25 and 100 mg pethidine hydrochloride when given intramuscularly (i.m.) or subcutaneously (s.c.),
– 50 mg pethidine hydrochloride (corresponding to 0.7 mg pethidine hydrochloride per kg body weight) when given intravenously (i.v.)
If required, the dose can be repeated at intervals of 3 to 6 hours.

A further increase in dosage does not lead to an increase in analgesic effect, but may aggravate undesirable effects.

A total daily dose of 500 mg should not be exceeded.
In obstetrics, a dose of 400 mg in 24 hours should not be exceeded.

Elderly patients (over 65 years)
In elderly patients reduced doses should be administered (see section 4.4).

In patients with hypo- or hyperthyroidism, adrenal insufficiency, and prostatic hypertrophy, cautious dosing is also required (see section 4.4).

Patients with impaired hepatic or renal function
Hepatic insufficiency may lead to higher pethidine serum concentrations, and dose adjustment may be indicated.
In patients with renal impairment longer intervals between doses will be appropriate to avoid accumulation of the active metabolites of pethidine.
Use is contraindicated in patients with severe hepatic impairment.

Paediatric population: children and adolescents under 16 years of age
Due to its high active substance content, pethidine should not be used in children and adolescents younger than 16 years.
Pethidine is contraindicated in children younger than 1 year (see section 4.3).

Method of administration
Intramuscular, intravenous or subcutaneous use.
In most cases, the injection for solution is administered i.m. into a large muscle. However, it may also be given subcutaneously or intravenously.
In case of i.v. administration, the injection should be given as slowly as possible to minimise the potential for side effects. If required, the Alodan® solution may be diluted with 10 ml of a 10% dextrose solution or physiological saline solution; it can also be applied as a short infusion (see section 6.6).

4.3 Contraindications

− Hypersensitivity to the active substance and related phenylpiperidine derivatives or to any of the excipients listed in section 6.1
− acute intoxication with alcohol, narcotics, analgesics or other psychoactive drugs
− during and up to 14 days after a therapy with MAO inhibitors (see section 4.5)
− disorders in which respiratory depression must be avoided (e.g. respiratory insufficiency, severe obstructive pulmonary diseases, asthma, emphysema)
− neuralgia, migraine (in these cases substances with a lower addictive potential are indicated)
− severe hepatic dysfunction, acute hepatic porphyria, biliary colics, post-cholecystectomy syndrome, pancreatitis
− cranial trauma, increased intracranial pressure, coma
− hypotension in hypovolaemic patients
− paralytic ileus
− supraventricular dysrhythmia
− children younger than 1 year (see section 4.2).

4.4 Special warnings and precautions for use

Special caution is required in case of:
– (past or present) dependence on opioids or other substances (e.g. alcohol, medicinal products)
– impaired consciousness
– glaucoma
– tendency to cerebral convulsions (also in the patient’s history)
– phaeochromocytoma
– cor pulmonale
– acute myocardial infarction (due to increased peripheral resistance)
– hypothyroidism, hyperthyroidism (see section 4.2)
– Addison’s disease (see section 4.2)
– Crohn’s disease, ulcerous colitis
– myxoedema
– disorders of the prostate (see section 4.2) or urethra (risk of urinary retention/obstruction)
– elderly patients and patients with hepatic and/or renal insufficiency
– children and adolescents younger than 16 years (due to the high active substance content, see section 4.2).

If high doses of pethidine are used, facilities for intubation and assisted ventilation must be readily available.

Potential for dependence, withdrawal syndrome
Pethidine has primary dependence potential and may lead to abuse. With longer-term use, tolerance as well as physical and psychological dependence will develop.
There is a cross-tolerance with other opioid substances. Pethidine is therefore not to be used for withdrawal treatment in patients dependent on opiates.
In dependent patients, withdrawal symptoms may occur upon sudden discontinuation of pethidine. Symptoms may include for instance psychiatric disorders such as restlessness, anxiety, irritability, depression, or vegetative symptoms such as sweating, abdominal cramps, vomiting, circulatory collapse etc. Treatment in a hospital is required.

With medicinal products acting on the CNS there is generally a risk of misuse. Before prescribing pethidine to patients who have a history of dependence on, or are currently dependent on alcohol or pharmaceutical substances, or who have a tendency to abuse medicinal products, the indication must therefore be very carefully considered and any use of pethidine must take place under close supervision.

Due to the risk of a serotonin syndrome occurring, pethidine should not be used together with serotonergic medicinal products (see section 4.5).

During pethidine therapy, the consumption of alcohol should be avoided.

If hypersensitivity reactions, convulsions or cardiac arrhythmias occur, treatment with pethidine is to be stopped immediately.

This medicinal product contains less than 1 mmol sodium (23 mg) per ampoule, i.e. it is essentially ‘sodium-free’.

Treatment with Alodan® solution for injection may yield positive results in doping tests.

4.5 Interaction with other medicinal products and other forms of interaction
Pethidine must not be used together with or up to 2 weeks following treatment with MAO inhibitors, since life-threatening effects on the central nervous system as well as on respiratory and circulatory functions have been observed with this combination (see section 4.3).

Combination with other centrally depressant substances, such as narcotics, anaesthetics, antihistaminics, benzodiazepines, sedatives, hypnotics, tricyclic antidepressants, barbiturates, muscle relaxants or alcohol may enhance pethidine’s depressant effect on respiration and its sedative action. 3

Combined use with phenothiazines may lead to a marked fall in blood pressure and increased respiratory depression.

Concomitant administration with cimetidine may inhibit pethidine metabolism and lead to respiratory depression and CNS impairment; pethidine dosage should be reduced.

Combined use with phenytoin or phenobarbital causes increased formation of the toxic metabolite norpethidine.

Concomitant use of pethidine with partial opioid receptor antagonists (naloxone, buprenorphine) may reduce the analgesic effect and cause withdrawal symptoms due to the competitive receptor antagonism.

With concomitant administration of pethidine together with other serotonergic substances such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) or preparations containing St John’s wort (Hypericum perforatum), cases of serotonin syndrome have been reported (see section 4.4).

Ritonavir may raise the plasma levels of the metabolite norpethidine. Caution is therefore required if pethidine and ritonavir are coadministered.

Opioid analgesics such as pethidine slow down gastric emptying and thus produce the following interactions:
– paracetamol: the rate of absorption of paracetamol is slowed down, while total absorption volume remains unaffected
– metoclopramide, domperidone: antagonising effect of opioid analgesics
– anticholinergic substances in general: potentiation of effects and risk of paralytic ileus.

4.6 Fertility, pregnancy and lactation
Pregnancy
Pethidine should not be used during pregnancy, because it may lead to tolerance and subsequently to withdrawal symptoms in the newborn.

Use during childbirth should only be via the intramuscular route and at the lowest possible dosage. Pethidine does not reduce normal uterus contractibility.

If pethidine is used during childbirth,
– respiratory depression, slower heart rate and reduced neuro-behavioural functions including feeding difficulty may occur in the newborn, as pethidine crosses the placenta (this is a dose and time dependent effect),
– behavioural impairment and EEG changes were observed in the newborn for up to 6 days post partum, and
– the survival chance of children at risk may be additionally reduced.

Neonates therefore have to be closely monitored until no significant impairment of breathing is to be expected (for at least 6 hours in any case). Depending on the clinical status (and above all taking into account reduced respiratory function after birth), administration of an opiate antagonist (e.g. naloxone) to the neonate is recommended.

Breast-feeding
Pethidine and its metabolite norpethidine are excreted in breast milk. If single doses of pethidine are administered, breast-feeding usually does not have to be interrupted. During repeated use, however, breast-feeding is not recommended because breast-fed infants may develop serious adverse effects, which may also occur with some delay and may persist for days or weeks. It is therefore to be decided after consideration of the benefit both of breast-feeding for the infant and of the treatment for the mother whether lactation should be stopped or pethidine treatment is to be abandoned.

4.7 Effects on ability to drive and use machines
Pethidine has major influence on the ability to drive and use machines. Out-patients should be cautioned against driving.

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4.8 Undesirable effects
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
Frequency not known: cannot be estimated from the available data

Immune system disorders
Rare: Outbreaks of sweat, heat sensation (especially with rapid i.v. administration)
Frequency not known: Shock, allergic/anaphylactic reaction, flush

Endocrine disorders
Frequency not known: Weight gain

Psychiatric disorders
Very rare: Psychoses

Nervous system disorders
Common: Vertigo, euphoria/dysphoria, tiredness, confusion
Frequency not known: Anxiety, nervousness, sleep disorders, depression, drowsiness, delirium, weakness, changes of cognitive and sensory performance – disturbances of consciousness, of thinking and concentration (e.g. with regard to decision making as well as perception, hallucinations), paradoxical agitation, disorientation, impaired reactivity, disturbed coordination, headache, convulsions, rigor, tremor, loss of libido, hyperreflexia, serotonin syndrome

Eye disorders
Common: Miosis (particularly after rapid i.v. administration)
Frequency not known: Disturbed vision, nystagmus

Cardiac disorders
Common: Bradycardia
Frequency not known: Pallor, hypotension, tachycardia, ECG changes (prolongation of QT), cardiovascular collapse

Vascular disorders
Frequency not known: Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders
Common: Respiratory depression: At equianalgesic doses, pethidine frequently causes respiratory depression of about the same intensity as morphine (also in newborns). This may lead to elevated CO
2 concentrations with a subsequent increase in cerebral pressure.
Frequency not known: Disturbances of breathing due to inhibition of the respiratory centre, dose-dependent, more frequent and more severe after i.v. injection: apnoea, dyspnoea, impaired nasal breathing, rhinitis, bronchospasm (a possible suppression of the cough reflex must be borne in mind), pulmonary oedema

Gastrointestinal disorders
Common: Gastrointestinal disturbances, constipation
Frequency not known: Dry mouth, anorexia; nausea, vomiting, hiccups (after rapid i.v. administration); increased tonus of gastrointestinal smooth muscle: spastic constipation, ileus

Hepatobiliary disorders
Uncommon: Increases in amylase and lipase levels, increase in hepatic transaminases
Frequency not known: Spasms of the biliary and pancreatic ducts

Skin and subcutaneous tissue disorders
Uncommon: Skin reactions (e.g. rash, urticaria, pruritus), hypersensitivity reactions (exanthema)

Musculoskeletal and connective tissue disorders
Rare: Rhabdomyolysis
Frequency not known: Muscular twitching (more frequent after parenteral administration and high doses)

Renal and urinary disorders
Frequency not known: Micturition disturbances: urinary retention (particularly in patients with prostatic hyperplasia), myoglobinuria, oliguria

Reproductive system and breast disorders
Frequency not known: Impotence

General disorders and administration site conditions
Common: Malaise
Frequency not known: After i.v. injection: pain, reddening and wealing along the affected vein After i.m. injection: muscular necrosis, nerve damage Tachyphylaxis (with longer-term use)

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 national reporting system.

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4.9. Overdose
Symptoms
Typical symptoms include miosis, respiratory depression or even respiratory arrest.
Moreover, impaired consciousness (in severe cases coma), hypotension, tachycardia, vertigo, muscular tremor, rises in temperature, and with increasing hypoxaemia also mydriasis. Massive overdoses, particularly after i.v. administration, may lead to respiratory arrest, circulatory arrest and death.

Therapy
− Cautious administration of the opiate antagonist naloxone at repeated low doses because it has a shorter duration of action than pethidine (caution: in cases of physical pethidine dependence, withdrawal symptoms will occur upon administration of the antagonist!)
− In case of overdose by s.c. injection: immediately inject 1 mg of adrenalin in a diluted solution (20 ml physiological saline solution) around the pethidine injection site.
− In case of overdose following oral ingestion: primary detoxification by gastric lavage and reduction of absorption by means of active charcoal
− Intensive care measures: electrolyte infusions, intubation and artificial respiration
− Measures for prevention of hypothermia and for volume substitution.

The possibility of multiple substance intoxication should always be borne in mind (alcohol, psychoactive substances), e.g. in suicide attempts.

Pethidine and its active metabolite norpethidine can be largely eliminated by haemodialysis.

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5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics, opioids, phenylpiperidine derivatives
ATC code: N02AB02

Mechanism of action
Pethidine is a highly effective analgesic. Analgesia is mainly achieved via the central nervous system. The active substance, a phenylpiperidine derivative, binds to specific opiate receptors in brain and spinal cord, thus inhibiting transmission of impulses along the polysynaptic pathways of the nociceptive system.
70-100 mg of pethidine correspond to an equianalgesic dose of 10 mg of morphine.
Beside its desired CNS-directed analgesic effect, pethidine has sedative-hypnotic action and a depressing effect on the respiratory system which are less pronounced than those of morphine. Pethidine leads to only a slight increase in visceral muscle tone and has a spasmolytic effect on vascular smooth muscle. This may cause a reduction in blood pressure and an increase in heart rate.
Uterine contractility remains largely unaffected.
In addition, pethidine causes histamine release and has antitussive and mild anticholinergic properties.

5.2. Pharmacokinetic properties
Distribution, biotransformation
Following intravenous administration of 25 mg pethidine hydrochloride, maximum plasma concentrations of 100 to 200 ng/ml were reached; comparable maximum plasma concentrations were achieved within 15 minutes after intramuscular administration. The absorption half-life was 7-18 minutes and bioavailability was in the range of 93 to 98%.
Analgesia sets in within 10 to 15 minutes after subcutaneous or intramuscular injection, reaches its maximum after ½-1 hour and persists for about 2-4 hours.
Pethidine quite freely passes the placental barrier and is also excreted into breast milk.

Elimination
Pethidine is metabolised in the liver, its primary metabolite being the pharmacologically active norpethidine. The plasma half-life of pethidine is about 4 hours, that of norpethidine approximately 8 (to 12) hours. Pethidine and its metabolites are excreted in the form of glucuronides mainly via the kidneys.
In the presence of severe hepatic impairment, plasma clearance is reduced by up to 25%.
If renal function is impaired, norpethidine may cumulate and cause serious side effects (convulsions). Plasma clearance may be reduced by up to 67%.
Plasma half-lives measured in neonates were between 6.5 and 39 hours, which is 2 to 7 times the half-life seen in adults.

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5.3. Preclinical safety data
Mutagenic and carcinogenic potential
There are no studies on potential mutagenic effects. In-vivo tests have yielded clear evidence of chromosomal break induction by pethidine. It is therefore suspected that it may have mutagenic effects in humans. No long-term animal studies regarding a carcinogenic potential are available.

Reproduction toxicity
In hamsters, single injection of pethidine during early gestation has resulted in malformations of the skull (cranioschisis) from the lowest tested dose of 127 mg/kg.
Experience with human pregnancies to date (approximately 270 patients exposed during the first trimester of pregnancy) has not yielded any evidence of a teratogenic risk. A possible association with the occurrence of inguinal hernia cannot be ruled out.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients
Water for injections
Hydrochloric acid and/or sodium hydroxide solution for pH adjustment

6.2. Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3. Shelf life
5 years

6.4. Special precautions for storage
Do not store above 25°C.
Store in the original package in order to protect from light.

6.5. Nature and contents of container
Clear glass ampoules. Packs of 5 or 50 ampoules.
Not all pack sizes may be marketed.

6.6. Special precautions for disposal and other handling
If required, the solution for injection may be mixed with 10% dextrose solution or physiological saline solution.

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

7. MARKETING AUTHORISATION HOLDER
G.L. Pharma GmbH, Austria

8. MARKETING AUTHORISATION NUMBER
1228026966

9. DATE OF FIRST AUTHORISATION OF THE AUTHORISATION
1st August 2009
10. DATE OF REVISION OF THE TEXT
March 2017