Oramorph®

/ BioAvenir

The dosage has to be adapted to the severity of pain and to the individual sensitivity of the patient.
The recommended range of the single and daily doses for children and adults is stated in the following table based on a single dose of 0.2 to 0.3 mg morphine sulphate/kg body weight.
Children under 3 years contra indicated.
Children 3-5 years (12.5 – 18 kg): 0.125-0.25 ml, i. e. 2-4 drops, corresponding to 2.5-5 mg morphine sulphate, every 4-6 hours.
Children 6-12 years (20 – 40 kg): 0.25-0.5 ml, i. e. 4-8 drops, corresponding to 5-10 mg morphine sulphate, every 4-6 hours.
Adolescents 13-18 years / Adults (40-50 kg):  0.5-1.0 ml, i. e. 8-16 drops, corresponding to 10-20 mg morphine sulphate, every 4-6 hours.
Adults: 0.5-3 ml, i. e. 8-48 drops, corresponding to 10-60 mg morphine sulphate, every 4-6 hours.
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 needed other appropriate dosage strengths have to be considered alternatively or in combination with Oramorph.
When patients are transferred from other morphine preparations to Oramorph oral solution dosage titration may be appropriate.
A calibrated oral dosing pipette is supplied with this dosage form for accurate and convenient dose adjustment. The required dose may be added to a soft drink immediately prior to administration.
Morphine Sulphate is readily absorbed from the gastro-intestinal tract following oral administration. However, when Oramorph oral solution is used in place of parenteral morphine, a 50 % to 100 % increase in dosage is usually required in order to achieve the same level of analgesia. 
Renal or hepatic impairment
In patients with impaired liver or kidney function and in those with suspected delayed gastrointestinal passage Oramorph 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 has to be done more carefully and / or the dosage intervals have to be extended. As appropriate, lower dosage strengths have to 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 and duration of administration
The oral drops, solution are administered with a sufficient quantity of liquid. The medication can be taken independently of meals. The physician decides about the duration of the treatment in dependence on the pain.
By no means Oramorph be given longer than absolutely necessary. If prolonged analgesic treatment with Oramorph 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.
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.

For the relief of moderate to severe pain.  

Patients with:
– hypersensitivity to morphine or to any of the excipients of Oramorph.
– paralytic ileus
– acute abdomen.
– respiratory depression
– obstructive airways disease
– head injuries
– delayed gastric emptying
– acute hepatic disease
– Acute alcoholism
– Coma
– Convulsive disoreders
– Raised intracranial pressure
Concomitant use with MAO’s inhibitors or within two weeks of dicontinuation of their use.
Morphine and some other opioids can induce the release of endogenous histamine and thereby stimulate catecholamine release making them unsuitable for use in patients with phaeochromocytoma.
Patients with  acute asthma exacerbations.
Pregnancy and lactation.

Especially careful monitoring by the physician and possibly dose reduction is needed in case of:
– opioid dependence
– disturbances of consciousness
– conditions associated with a disturbance of the respiratory centre and of the respiratory function or where there is reduced respiratory reserve (such as kyphoscoliosis, emphysema and severe obesity)
– 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 (paralytic ileus)
– chronic hepatic and renal disease
– myxoedema
– adrenocortical insufficiency
– phaeochromocytoma
– pancreatitis
– hypothyroidism
– epilepsia or increased propensity to seizures.
In case of an opioid overdose respiratory depression is the most important risk.
Abrupt discontinuation after repeated use or application of an opioid antagonist can provoke typical signs of withdrawal (withdrawal syndrome).
This medicinal product must not be used in children under 3 years of age.
Opioid Use Disorder (abuse and dependence) and withdrawal (abstinence) syndrome
Tolerance and physical and/or psychological dependence may develop upon repeated administration of opioids.
Repeated use of this drug can lead to Opioid Use Disorder (OUD). A higher dose and longer duration of opioid treatment, can increase the risk of developing OUD. Abuse or intentional misuse of this drug may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (eg. major depression, anxiety and personality disorders).
Patients will require monitoring for signs of drug-seeking behavior (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.
Symptoms can be minimised with adjustments of dose or dosage form, and gradual withdrawal of morphine.
Therapeutic administration in patients with chronic pain is associated with a markedly reduced risk of psychological dependence and has to be assessed in a different light.
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.
Compared to patients not undergoing surgery the use of this drug 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 intraabdominal 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. 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.
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 drugs
Concomitant use with sedative medicines such as benzodiazepines or related drugs 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 morphine 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.
Sleep-related breathing disorders
Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
Severe cutaneous adverse reactions (SCARs)
Acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, has been reported in association with morphine treatment. Most of these reactions occurred within the first 10 days of treatment. If signs and symptoms suggestive of these skin reactions appear, morphine should be withdrawn and an alternative treatment considered.
Hepatobiliary disorders
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.
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.
Within the first day of concomitant P2Y12 inhibitor and morphine treatment, reduced efficacy of P2Y12 inhibitor treatment has been observed.
The use of morphine can lead to positive results of doping tests.
See prescribing information for full details.

Very common: Mood changes (mostly euphoria but also dysphoria).  Common: Headache, dizziness, changes in activity (mostly sedation, but also enhanced activity or agitation), insomnia, alterations of cognitive and sensory functions (e. g. disturbances in thinking, altered apprehensiveness/ hallucinations, confusion), vomiting (especially at the beginning of therapy), anorexia, dyspepsia and taste alterations, disturbances of micturition, sweating, hypersensitivity reactions such as urticaria, pruritus.
See prescribing information for full details.

The following interactions of this medicinal product have to be considered:
– Concomitant application of morphine and other medicines with centrally sedating effects such as tranquilisers, anaesthetics, hypnotics and sedatives, neuroleptics, barbiturates, antidepressants, antihistamines / antiemetics, and other opioids, gabapentin or pregabalin 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 drugs
The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS
– Medicines with anticholinergic effect (e. g. psychotropic drugs, antihistamines, antiemetics, drugs for the treatment of Morbus Parkinson) can enhance anticholinergic adverse effects of opioids (e. g. constipation, dry mouth or disturbances of micturition).
– Cimetidine and other drugs impairing liver metabolism can lead to higher morphine plasma concentrations due to the inhibition of its metabolism
– Morphine can enhance the effect of muscle relaxants.
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.
– Concomitant application of rifampicin can lead to a decrease in the effect of morphine.
– 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 unknown, but data indicate the potential for reduced P2Y12 inhibitor efficacy in patients co- administered morphine and a P2Y12 inhibitor. In patients with acute coronary syndrome, in whom morphine cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12 inhibitor may be considered.

Pregnancy
Morphine may be used during pregnancy only if the benefit for the mother clearly outweighs the risk for the foetus.
Withdrawal symptoms have been reported in neonates following prolonged morphine application during pregnancy. See prescribing information for full details.
Lactation
Morphine is excreted in human milk where concentrations higher than in maternal plasma are reached. Since clinically relevant concentrations can be reached in infants breast feeding is discouraged. See prescribing information for full details.

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 over dosage 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 occurs mostly due to respiratory insufficiency or due to complications such as pulmonary oedema.
Therapy of intoxication
In unconscious patients with respiratory arrest ventilation, intubation and intravenous administration of opioid antagonists (e. g. 0.4- 2 mg naloxon 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 has to be strictly monitored (at least for 24 hours) since the duration of action of the opioid antagonist is shorter (naloxone 2-3 hours) 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.

Effects on ability to drive and use machines
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 or inexistent.
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 has to be done by the treating physician. During a stable therapeutic regimen driving is not prohibited generally.
Shelf life
The shelf life is 3 years.
After opening of the bottle Oramorph  is stable for 90 days.
Storage
Do not store above 25°C. Store the bottle in the outer carton in order to protect from light.