SUMMARY OF PRODUCT CHARACTERISTICS
1.
NAME OF THE MEDICINAL PRODUCT
Dolaristo 10 mg tablets
Dolaristo 20 mg tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Dolaristo 10 mg: Each tablet contains 10 mg morphine hydrochloride corresponding to 7.6 mg morphine.
Excipient with known effect: One tablet contains 65.30 mg lactose.
Dolaristo 20 mg: Each tablet contains 20 mg morphine hydrochloride corresponding to 15.2 mg morphine.
Excipient with known effect: One tablet contains 130.60 mg lactose.
For the full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Tablet
10 mg: white, round and flat tablets with a score line on one side, diameter 6.5 mm, embossed with “10”.
The tablet can be divided into equal doses.
20 mg: white, round and flat tablets with a score line on one side, diameter 8.5 mm, embossed with “20”.
The tablet can be divided into equal doses.
4.
CLINICAL PARTICULARS
4.1
Therapeutic indications
Severe opioid-sensitive pain, e.g. cancer pain.
4.2
Posology and method of administration
Due to great inter-patient-variability concerning pharmacokinetics, pain intensity, pain genesis, possible
tolerance and age, the dosage of Dolaristo should be individualised.
The recommended dose when initiating morphine treatment is 5 – 10 mg 4 – 6 times daily.
If this does not produce sufficient pain relief, it may be necessary to increase the dose to 10 – 30 mg 4 – 6
times daily, or even more in exceptional cases. Dosage interval should be 4 – 6 hours.
Dolaristo may also be dissolved in water.
Patients with reduced hepatic or renal function and elderly patients:
Caution should be shown, and the dose should be reduced initially in morphine treatment of elderly patients
and in treatment of patients with impaired hepatic and renal function, see section 5.2.
Treatment control
Constipation and nausea should be prevented by concomitant administration of laxatives or antiemetics,
respectively.
4.3
Contraindications
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Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Stagnation of secretion, respiratory depression, acute hepatic disease, agitation states during effect of alcohol
or hypnotics.
4.4
Special warnings and precautions for use
Addictive agent. Great caution should be shown when prescribing this medicinal product.
The dose may need to be reduced in case of bronchial asthma, upper airway obstruction, head injuries,
peritoneal dialysis, hypotension with hypovolaemia, hypothyroidism, impaired hepatic and renal function,
inflammatory bowel disorders, pancreatitis, bile duct or urinary tract spasm, and in the treatment of elderly
patients.
Morphine should not be used in idiopathic or psychopathological pain conditions.
Treatment with MAO inhibitors, see section 4.5 “Interaction with other medicinal products and other forms
of interaction”.
There is an increased risk of respiratory depression when treating elderly patients.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5
Interaction with other medicinal products and other forms of interaction
Combinations to be avoided
Small amount of alcohol
Small amounts of alcohol may dramatically enhance the weak respiratory depressant effect of morphine. The
combination should therefore be avoided.
Barbiturates
Barbiturates enhance the respiratory depressant effect of opiates and opioids. The combination should
therefore be avoided.
Antacids
Concomitant administration may result in a more rapid release of morphine. Thus, the substances should be
administered with an interval of at least two hours.
MAO inhibitors
MAO inhibitors may potentiate the effect of morphine (respiratory depression and hypotension).
Serotonergic syndrome has been reported in concomitant treatment with petidine and MAO inhibitors and
cannot be excluded when combining morphine and MAO inhibitors.
Combinations requiring dose adjustment
Rifampicin
Rifampicin reduces the plasma concentration of oral morphine to such extent that higher doses than usual are
required for analgesic effect.
Gabapentin
The risk of CNS symptoms should be considered in choice of treatment. During concomitant administration
of the two medicinal products, dose reduction of gabapentin should be considered. Patients should therefore
be monitored closely for signs of CNS depression such as somnolence, and the dose of gabapentin- or
morphine should be reduced accordingly.
Amitriptyline, clomipramine and nortriptyline
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Amitriptyline, clomipramine and nortriptyline enhance the analgesic effect of morphine. Dose adjustment
may be necessary.
Combined morphine agonists/antagonists
Combined morphine agonists/antagonists (buprenorphine, nalbuphine, pentazocine) reduce the analgesic
effect by competitive blocking of receptors and thereby increase the risk of withdrawal symptoms.
Combinations for which the clinical effect is unclear
Baclofen
The combination of morphine and intrathecal Lioresal caused hypotension in one patient. The risk of apnoea
or other CNS symptoms cannot be excluded with this combination.
Benzodiazepines
Combined use may increase sedation of the patient. Benzodiazepines may enhance the respiratory depressant
effect of opiates. This should be taken into consideration.
Hydroxizine
Concomitant administration of hydroxyzine and morphine may cause an additive effect and thus increase
CNS depression and somnolence. Changing to other non-sedative antihistamine should be considered.
Methylphenidate
Methylphenidate may enhance the analgesic effect of morphine. In case of concomitant treatment dosage
reduction of morphine should be considered.
Nimodipine
Nimodipine may enhance the analgesic effect of morphine. Dosage reduction of morphine should be
considered in case of concomitant treatment.
Ritonavir
Morphine levels may be reduced due to induction of glucuronidation of concomitantly administered ritonavir
dosed as an antiretroviral substance or pharmacokinetic enhancer (booster) of other protease inhibitors.
4.6
Fertility, pregnancy and lactation
Pregnancy
In humans, there are no adequate data available to allow an evaluation of any potential teratogenic risk.
There have been reports of a possible link to an increased incident of inguinal hernias. Morphine crosses the
placental barrier. Animal studies showed a potential for damage in offspring throughout the entire duration
of gestation (see section 5.3). For this reason, morphine must only be used during pregnancy in cases where
the maternal benefit clearly outweighs the risk for the child.
Due to the mutagenic properties of morphine, it should not be administered to men and women of childproducing/child bearing potential unless effective contraception is assured.
Withdrawal symptoms have been described in neonates after prolonged morphine use during pregnancy.
Parturition
Morphine can prolong or shorten the duration of labour. Neonates, whose mothers are given opioid
analgesics during childbirth, should be monitored for signs of respiratory depression or withdrawal syndrome
and (if necessary), treated with a specific opioid antagonist.
Breast-feeding
Morphine is excreted into breast milk, where it reaches higher concentrations than in maternal plasma. As
clinically relevant concentrations may be reached in nursing infants, breast-feeding is not advised.
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Fertility
Morphine had adverse effects on animal fertility (see section 5.3).
4.7
Effects on ability to drive and use machines
Dolaristo has major influence on the ability to drive and use machines. Reactivity may be impaired during
treatment with Dolaristo. This should be taken into consideration when increased alertness is required, e.g.
when driving.
4.8
Undesirable effects
The most common side effects are constipation and nausea and also sedation. Constipation occurs in almost
all patients, nausea in approximately 30 % of outpatients. The table below list all undesirable effects by
system organ class and frequency.
Organ system
Common
(1/100, <1/10)
Endocrine disorders
Increased release
of ADH
Psychiatric disorders
Uncommon
(1/1 000, <1/100)
Dysphoria
Nervous system
disorders
Sedation
Eye disorders
Cardiac disorders
Miosis
Not known
(cannot be
estimated from
the available data)
Euphoria, sleep-,
memory- and
concentration
disorders
Seizures
Respiratory
depression,
dizziness,
disorientation
Palpitations,
tachycardia,
syncope
Orthostatic
hypotension,
hypertension,
hypotension,
peripheral oedema
Vascular disorders
Respiratory, thoracic
and mediastinal
disorders
Gastrointestinal
disorders
Hepatobiliary
disorders
Skin and
subcutaneous tissue
disorders
Musculoskeletal and
connective tissue
disorders
Renal and urinary
disorders
General disorders
and administration
Rare
(1/10 000,
<1/1 000)
Bronchoconstriction
Constipation,
nausea, vomiting
Dry mouth
Bile duct spasms
Pruritus
Urticaria
Myoclonia
Urinary retention
Urinary tract spasms
Lightheadedness
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site conditions
Sedation usually declines after a few days of administration. Nausea and vomiting usually decline during
long-term use. Spasms in bile duct and urinary tract may occur in predisposed subjects. The respiratory
depressant effect is dose-dependent and rarely a clinical problem. Habituation and tolerance do not usually
cause any problems in the treatment of severe cancer pain.
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 listed in Appendix V.
4.9
Overdose
Symptoms of overdose:
Typical symptoms: impaired consciousness, severe respiratory depression, maximum miotic pupils.
Hypotension. Pale, damp skin. Following high doses: cyanosis, areflexia, apnoea, coma, circulatory shock,
pulmonary oedema. Acidosis, convulsions (primarily in children), possibly hypokalaemia and
hypocalcaemia. Nausea, vomiting, constipation. In case of serious intoxication: risk of myocardial damage,
rhabdomyolysis and renal failure.
Treatment of overdose:
If necessary gastric lavage, charcoal, laxatives.
Respiratory depression related to morphine intoxication can be reversed by naloxone, initially 0.4 mg in
adults (children 0.01 mg/kg) by slow intravenous administration; the dose may be increased gradually, if
necessary. Continuous infusion of naloxone may occasionally be a practical alternative. Respiratory
treatment on indication (with PEEP in pulmonary oedema). Naloxone cannot replace respiratory treatment in
serious intoxication. Intravenous fluid (electrolyte solution, glucose), blood gas control, correction of
acidosis. Symptomatic treatment.
Toxicity:
The toxic dose for adults (without development of tolerance) is usually within a range of 40 – 60 mg orally.
Scopolamine, hypnotics and alcohol potentiate the toxic effects.
5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Natural opium alkaloids, ATC code: N02AA01
Mechanism of action
Morphine is an opioid analgesic with strong analgesic effect. The analgesic effect is partly due to alteration
of perceptionof pain and partly due to an increase in pain threshold. Morphine probably exerts its analgesic
effect on different levels within CNS.
In elderly patients the analgetic effect of morphine is increased. The CNS effects of morphine also include
respiratory depression, psychiatric symptoms, nausea and vomiting, miosis and secretion of antidiuretic
hormone.
Pharmacodynamic effects
Morphine is metabolised via conjugation to the 2 major metabolites morphine-6-glucuronide (M6G) and
morphine-3-glucuronide (M3G). Small amounts of morphine-3,6-diglucuronide may also be formed. M3G
has low affinity to opioid receptors, thus no documented analgesic effect, but may contribute to excitatory
effect. M6G is twice as potent as morphine in systemic administration, and the pharmacological effects of
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M6G cannot be distinguished from the effects of morphine. In chronic administration it is a significant part
of the analgesic effects of morphine.
Clinical efficacy and safety
The respiratory depressant effect of morphine is attributed to inhibition of the stimulating effect of carbon
dioxide on the respiratory centre in the medulla oblongata. This effect may lead to respiratory insufficiency
in patients with reduced ventilation capacity due to lung disease or effects of other pharmaceuticals. There is
an increased risk of respiratory depression when treating elderly patients.
Following encephalitis the effects of morphine may be enhanced. Morphine intoxication requires supportive
respiratory treatment and administration of an antidote.
Nausea and vomiting may occur due to stimulation of dopamine receptors in the “trigger zone” in medulla
oblongata. The increased secretion of antidiuretic hormone contributes to reduced urine volumes during
morphine treatment. Morphine increases the tonus of smooth muscles in the gastrointestinal tract. This leads
to constipation due to slower passage of food through the gastrointestinal tract. Furthermore, the pressure in
biliary and urinary tract is increased, making morphine less suitable in patients with bile duct- or urinary
tract spasms.
Morphine has addictive properties and tolerance to the effects of morphine may develop. However, this
usually does not lead to any problems in the treatment of severe pain associated with cancer.
5.2
Pharmacokinetic properties
The kinetics of morphine is not dose dependant.
Absorption
Maximum analgesic effect is obtained within 1-2 hours.
Morphine is well absorbed from the gastrointestinal tract but undergoes extensive and variable first pass
metabolism. The bioavailability of oral morphine preparations is approximately 30 % but usually varies
between 10 and 50 %. Bioavailability may be increased in patients with hepatic cancer.
Distribution
The volume of distribution is approximately 3 L/kg with a plasma protein binding of approximately 35 %.
Clearance is approximately 24 mL/min per kg.
Biotransformation
Morphine is metabolised in the liver to the two major metabolites morphine-3-glucuronide (no analgesic
effect but may contribute to excitatory effects) and morphine-6-glucuronide (M6G) (more potent than
morphine itself). Small amounts of morphine-3,6-diglucuronide may also be formed. Morphine and its
metabolites undergo enterohepatic circulation.
Elimination
The elimination of morphine is primarily via glucuronidation, and the excretion of unchanged morphine in
urine isr < 0.1 %. M6G is excreted via urine, leading to accumulation of M6G in patients with impaired renal
function. Impaired hepatic and renal function have an impact on elimination of the substance.
5.3
Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology
and repeated dose toxicity. Effects in non-clinical studies were observed for genotoxicity, and toxicity to
reproduction and development.
Mutagenic and tumorigenic potential
There are clearly positive findings available with regards to mutagenicity, which indicate that morphine has a
clastogenic effect and that, furthermore, this effect exerts an influence on gametes. Thus, morphine is to be
regarded as a mutagenic substance and such an effect may also be assumed in humans.
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There have been no long-term animal studies on the tumorigenic potential of morphine.
Reproductive toxicity
Animal studies showed a potential for damage in offspring throughout the entire duration of gestation (CNS
malformations, growth retardation, testicular atrophy, changes in neurotransmitter systems and behavioural
patterns, dependence). In addition, morphine had an effect on male sexual behaviour and fertility in various
animal species.
6.
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Lactose monohydrate
Maize starch
Gelatine
Magnesium stearate (E470b)
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
2 years
6.4
Special precautions for storage
Do not store above 30 °C.
6.5
Nature and contents of container
10 mg:
Blister (PVC/Alu): 25, 50 and 100 tablets.
Bottle (HDPE): 100 tablets.
20 mg:
Blister (PVC/Alu): 25, 50 and 100 tablets.
Bottle (HDPE): 100 tablets.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
No special requirements.
7.
MARKETING AUTHORISATION HOLDER
[To be completed nationally]
8.
MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
7
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
[To be completed nationally]
10.
DATE OF REVISION OF THE TEXT
20 November 2015
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