Oramorph Oral 20 Mg Solution

For the relief of severe pain in adults.

Posology
The dosage of Oramorph u00ae Oral Drops 20mg/ml must be adapted to the severity of pain and to the individual sensitivity of the patient. The recommended range of the single and daily doses is stated in the following table based on a single dose of 0,2 to 0,3 mg morphine sulphate/kg body weight.

Age
Single dose
Total daily dose
Adults
0,5-3 ml, i.e. 8-48 drops of Oramorph u00ae Oral Drops
Up to 18 ml, i.e. 288 drops of Oramorph u00ae Oral Drops

20mg/ml, corresponding to 10-60 mg morphine sulphate
20mg/ml, corresponding up to 360 mg morphine sulphate
The dose is removed from the 20 ml bottle by counting the drops (1 drop = 1,25 mg morphine sulphate). In case of decreasing effect, the single doses can be repeated after 4-6 hours. The maximum daily doses should not exceed the single doses by more than 4 to 6-fold. If higher daily doses are required, other suitable active ingredient strengths may be used alternatively or in combination with Oramorph u00ae Oral Drops 20 mg/ml.

Special populations
Renal or hepatic impairment
In patients with impaired liver or kidney function and in those with suspected delayed gastrointestinal passage Oramorph u00ae Oral Drops 20mg/ml should be dosed with special caution.

Elderly patients
Elderly patients (usually 75 years and older) and patients with poor overall physical condition may be more sensitive to morphine. Therefore, the adjustment of dose must be done more carefully and/or the dosage intervals must be extended. As appropriate, lower dosage strengths must be given instead.

Special recommendations concerning dose adjustment
For initial dose adjustment, pharmaceutical forms with lower active ingredient content may be applied, possibly also in addition to an existing therapy with prolonged-release tablets. In principle, the administered dose should be sufficiently high and at the same time the lowest dose needed for pain relief in the individual case should be aimed at. For treatment of chronic pain dosing following a fixed time schedule is preferred. In patients receiving another additional analgesic treatment (e. g. surgery, plexus blockage) the dose should be readjusted following the respective measure.

Method of administration
For oral use. The oral drops solution is administered with a sufficient quantity of liquid. The medication can be taken independently of meals. The medical practitioner decides about the duration of the treatment dependent on the pain. Oramorph u00ae Oral Drops 20mg/ml should not be given longer than absolutely necessary. If prolonged analgesic treatment with Oramorph u00ae Oral Drops 20mg/ml appears necessary based on the nature and severity of the disease, careful and regular monitoring within short time intervals should be installed (if required by means of temporary suspension of the medication) to evaluate if and to what extent the therapeutic necessity persists. If needed, more suitable pharmaceutical forms should be applied instead. In case of chronic pain conditions, a fixed dosage regimen is preferred.

Discontinuation of therapy
Since the risk of occurrence of withdrawal symptoms is increased in case of abrupt discontinuation of therapy the dose should be reduced stepwise after termination of treatment.

Oramorph u00ae Oral Drops 20mg/ml is contraindicated in:

• patients known to be hypersensitive to morphine or to any of the excipients listed in section 6.1
• ileus
• acute abdomen
• head injury or raised intracranial pressure with a decrease in the level of consciousness, unless ventilation is performed
• patients with compromised airways
• pregnancy and lactation

Careful monitoring by the medical practitioner and possibly dose reduction is needed in case of:

• opioid dependence
• impaired consciousness from any cause
• conditions associated with a disturbance of the respiratory centre and of the respiratory function or where such disturbances must be avoided
• cor pulmonale
• conditions with increased intracranial pressure unless ventilation is performed
• hypotension in the setting of hypovolaemia
• prostatic hyperplasia with residual urine (risk of bladder rupture due to urinary retention)
• obstruction or spasms of urinary tracts
• diseases of biliary ducts
• obstructive and inflammatory bowel diseases
• phaeochromocytoma
• pancreatitis
• hypothyroidism
• epilepsy or increased propensity to seizures.

In case of an opioid overdose, respiratory depression is the most important risk (see section 4.9).

Dependence and withdrawal (abstinence) syndrome
Use of opioid analgesics may be associated with the development of physical and/or psychological dependence or tolerance. The risk increases with the time the medicine is used, and with higher doses. Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. Symptoms can be minimised with adjustments of dose or dosage form, and gradual withdrawal of morphine. For individual symptoms (see section 4.8).

Therapeutic administration in patients with chronic pain is associated with a markedly reduced risk of psychological dependence and must be assessed carefully. Morphine has an abuse potential similar to other strong agonist opioids, and should be used with particular caution in patients with a history of alcohol or drug abuse.

Post-operative treatment
Compared to patients not undergoing surgery, the use of Oramorph u00ae Oral Drops 20mg/ml solution is associated with an increased risk of ileus or respiratory depression during the postoperative phase and should therefore be administered with caution in patients before and after surgery. Due to the analgesic effect of morphine serious intra-abdominal complications such as bowel perforation can be masked.

Adrenal insufficiency
Opioid analgesics may cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency may include e.g. nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure. In case of pre-existing adrenocortical insufficiency (e.g. Morbus Addison), plasma concentrations of cortisol should be monitored and possibly corticoids should be substituted.

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.

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.

Women of childbearing potential / Contraception in males and females
Due to its mutagenic properties, morphine should be given to males with procreative potential and to females with childbearing potential only if effective contraceptive measures are guaranteed (see section 4.6).

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.

Risk from concomitant use of sedative medicines such as benzodiazepines or related medicines
Concomitant use of Oramorph u00ae Oral Drops 20mg/ml and sedative medicines such as benzodiazepines or related medicines may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Oramorph u00ae Oral Drops 20mg/ml concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Use with rifampicin
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.

Drug testing
The use of Oramorph u00ae Oral Drops 20mg/ml can lead to positive results of doping control or drug testing.

Paediatric population
Oramorph u00ae Oral Drops 20mg/ml is not recommended for use in children.

The following interactions of this medicinal product must be considered:

Concomitant application of morphine and other medicines with centrally sedating effects such as tranquilisers, anaesthetics, hypnotics and sedatives, neuroleptics, barbiturates, antidepressants, antihistamines or antiemetics, and other opioids or alcohol can result in an increase of the adverse effects of morphine at the usually recommended dose. This applies especially to the possibility of respiratory depression, sedation, hypotension and even coma.

Sedative medicines such as benzodiazepines or related medicines
The concomitant use of opioids with sedative medicines such as benzodiazepines or related medicines 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).

Anticholinergics
Medicines with anticholinergic effect (e.g. psychotropic medicines, antihistamines, antiemetics, medicines for the treatment of Morbus Parkinson) can enhance anticholinergic adverse effects of opioids (e.g. constipation, dry mouth or disturbances of micturition).

Cimetidine
Cimetidine and other medicines impairing liver metabolism can lead to higher morphine plasma concentrations due to the inhibition of its metabolism.

Muscle relaxants
Morphine can enhance the effect of muscle relaxants.

Monoamine oxidase inhibitors
In patients pre-treated with certain antidepressants (MAO inhibitors) within 14 days prior to initiation of opioids life-threatening interactions affecting the central nervous system, the respiratory and the circulatory function have been observed in relation to pethidine. Comparable effects related to morphine cannot be excluded.

Rifampicin
Concomitant application of rifampicin can lead to a decrease in the effect of morphine.

Paediatric population
The similarity of interactions to adults has not been established.

Women of childbearing potential / Contraception in males and females
Due to its mutagenic properties, morphine should be given to males with procreative potential and to females with childbearing potential only if effective contraceptive measures are guaranteed (see section 4.4).

Pregnancy
The use of Oramorphu00ae Oral Drops 20mg/ml is contraindicated during pregnancy (see section 4.3). Infants born to mothers taking Oramorphu00ae Oral Drops 20mg/ml may suffer withdrawal reactions.

Breastfeeding
The use of Oramorphu00ae Oral Drops 20mg/ml is contraindicated during lactation (see section 4.3). Since clinically relevant concentrations can be reached in infants, mothers taking Oramorphu00ae Oral Drops 20 mg/ml should not breastfeed their infants.

Fertility
Animal studies have shown that morphine may reduce fertility (see section 5.3).

Morphine can impair the attentiveness and the capability to react to such an extent that the ability to drive or to use machines is impaired. This is to be expected especially upon initiation of treatment, dose increase and change in medication as well as in combination with alcohol or the use of sedatives. The assessment of the individual situation in each case must be done by the treating medical practitioner. During a stable therapeutic regimen driving is not prohibited generally.

a) Summary of the safety profile
Data from clinical trials are not available. Therefore, except where stated all frequencies of the undesirable effects are unknown. In normal doses, the commonest side effects of morphine sulphate are nausea, vomiting, constipation, drowsiness and confusion. If constipation occurs, this may be treated with appropriate laxatives. The effects of morphine have led to its abuse and misuse. Dependence and addiction may develop with regular use.

b) Tabulated summary of adverse reactions
SYSTEM ORGAN CLASS
FREQUENCY
ADVERSE REACTIONS
Immune system disorders
Frequency unknown
Anaphylactic and anaphylactoid responses
Endocrine disorders
Less frequent
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders
Frequent
Anorexia
Psychiatric disorders
Frequent
Emotional and mood disturbances not elsewhere classified (NEC)
Frequent
Agitation
Insomnia
Cognitive and attention disorders and disturbances
Less frequent
Drug dependence
Libido decreased
Potency disturbance
Nervous system disorders
Frequent
Sedation
Headache
Dizziness
Taste alteration
Less frequent
Tremor
Muscle contractions involuntary
Epileptic seizure
Frequency unknown
Allodynia
Hyperalgesia
Eye disorders
Less frequent
Blurred vision
Diplopia
Nystagmus
Miosis
Cardiac disorders
Less frequent
Blood pressure increased
Heart rate increased
Palpitations
Cardiac failure
Less frequent
Dyspnoea
Vascular disorders
Frequency unknown
Non-cardiogenic pulmonary oedema
Respiratory, thoracic and mediastinal disorders
Less frequent
Bronchospasm
Gastrointestinal disorders
Frequent
Nausea
Dry mouth
Obstipation
Frequent
Vomiting
Dyspepsia
Less frequent
Pancreatitis
Less frequent
Ileus
Abdominal pain
Hepato-biliary disorders
Less frequent
Colic biliary
Less frequent
Hepatic enzymes increased
Skin and subcutaneous tissue disorders
Frequent
Urticaria
Pruritis
Less frequent
Exanthema
Peripheral oedema
Musculoskeletal and connective tissue disorders
Less frequent
Muscle cramps
Muscle rigidity
Chills
Renal and urinary disorders
Frequent
Micturition disorder
Less frequent
Renal colic
Reproductive system and breast disorders
Less frequent
Amenorrhoea
General disorders and administration site
Less frequent
Facial flushing
Weakness generalised

Symptoms of intoxication
The sensitivity towards morphine varies greatly from patient to patient. Therefore, symptoms of intoxication can occur in adults after application of single doses which correspond to a subcutaneous and intravenous dose of about 30 mg. In patients with carcinoma these doses are frequently exceeded without provoking serious adverse reactions. The manifestation of an opioid intoxication comprises the triad of miosis, respiratory depression and coma. At first pinpoint pupils are observed; however, in case of marked hypoxia the pupils are dilated.

Respiration is markedly reduced (breath rate of 2-4 per minute). The patient becomes cyanotic. Morphine overdosage leads to giddiness and stupor up to coma. The blood pressure remains normal initially but decreases markedly with progression of intoxication. Persistent decrease in blood pressure can result in shock. Tachycardia, bradycardia and rhabdomyolysis can occur. The body temperature decreases. The skeletal muscles relax; occasionally generalised seizures can develop, especially in children. Death may occur from respiratory failure. Death occurs mostly due to respiratory insufficiency or due to complications such as pulmonary oedema. Aspiration pneumonia can develop.

Therapy of intoxication
In unconscious patients with respiratory arrest ventilation, intubation, and intravenous administration of opioid antagonists (e. g. 0,4 mg naloxone intravenously) are indicated. In case of persistent respiratory insufficiency, the single dose has to be repeated 1 to 3 times in 3-minute intervals until the respiratory rate is back to normal and the patient responds to painful stimuli. The patient must be strictly monitored (at least for 24 hours) since the duration of action of the opioid antagonist is shorter compared to that of morphine so that recurrence of the respiratory insufficiency has to be expected. The single dose of the opioid antagonist is 0,01 mg per kg body weight in children. Additionally, measures to prevent a decrease in body temperature and to supplement volume may be necessary.