FILNARINE SR 200 MG PROLONGED-RELEASE FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Filnarine SR 200 mg prolonged release film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Prolonged Release Film-coated Tablet contains:

10 mg morphine sulfate corresponding to 7.5 mg morphine

Excipients with known effect:

Each Prolonged Release Film-coated Tablet contains:

10 7.74 mg lactose monohydrate

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablet.

White to off-white film-coated tablets.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of severe pain, particularly cancer pain and post-operative pain.

4.2 Posology and method of administration

Posology

The treatment is initiated by titration with an immediate release morphine formulation to a morphine dose which gives adequate pain control. Thereafter, the patient is transferred to the same daily dose of Filnarine prolonged release tablets.

Breakthrough pain should be treated with immediate release morphine.

Filnarine prolonged-release tablets should be used at 12-hourly intervals. The dosage is dependent upon the severity of the pain, the patient’s age and previous history of analgesic requirements.

For adults and adolescents from the age of 12 years after initiated treatment with an immediate release morphine formulation:

A patient presenting with severe pain should normally be started on 10–30 mg morphine sulfate 12-hourly, patients with low body-weight requiring a small starting dose.

Patient presenting with severe pain, uncontrolled by weaker opioids (e.g. dihydrocodeine), should normally be started on 30 mg morphine sulfate 12-hourly, patients with low body-weight requiring a small starting dose. However, a starting dose as low as 10 mg bd may be appropriate for the elderly who may be susceptible to morphine and patients with low body-weight requiring a small starting dose, in hypothyroidism and in patients with significantly impaired renal or hepatic function. (see section 4.4 and 5.2)

Increasing severity of pain will require an increased dosage of morphine. An incremental increase of 30%-50% in the daily dose may be appropriate. The correct dosage for any individual patient is that which is sufficient to control pain with no, or tolerable, undesirable effects for a full 12 hours.

Patients receiving Filnarine prolonged release tablets in place of parenteral morphine should be treated cautiously based on individually different sensitivity, that means that the dose requirement per day should not be overestimated. As a result of the replacement, there may be a reduction in the analgesic effect. Normally a dose increase is required of the order of 100% of the parental morphine dose.

It should be emphasised that patients, once titrated to an effective dose of a certain opioid drug, should not be changed to other slow, sustained or controlled release morphine or other narcotic analgesic preparations without retitration and clinical assessment. Otherwise a continuing analgesic action is not ensured.

Paediatric population:

6 years and older: A starting dosage in the range of 0.2 mg – 0.8 mg morphine/kg 12-hourly with dose titration as for adults is recommended.

If it is not possible to give the recommended dosage with this formulation (prolonged-release tablet) another pharmaceutical form should be chosen.

Special populations:

A reduction in dosage may be advisable in older people, in hypothyroidism, and in patients with significantly impaired renal or hepatic function (see section 5.2).

Post operative pain:

Filnarine prolonged-release tablets are not recommended in the first 24 hours post operatively or until normal bowel function has returned. Thereafter it is suggested that the following dosage schedule be observed at the physician’s dis­cretion: – 20 mg 12 hourly to patients under 70 kg – 30 mg 12 hourly to patients over 70 kg

– in elderly patients a reduction in dosage may be advisable

– use in children is not recommended

Discontinuation of therapy

An abstinence syndrome may be precipitated if opioid administration is suddenly discontinued. Therefore the dose should be gradually reduced prior to discontinuation.

Method of administration

The prolonged-release film-coated tablets are for oral use. They should be swallowed completely with some liquid. Filnarine prolonged-release tablets must not be divided or dissolved before administration. Dissolving or parting the Filnarine prolonged-release tablets will damage the sustained release system and lead to rapid release of morphine which may entail substantial undesirable effects.

4.3 Contraindications

– Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

– Children under 6 years of age, because swallowing tablets as a whole requires oro-pharyngeal control.

– Respiratory depression

– Airway obstruction caused by mucus

– Obstructive airways disease

– Convulsive disorders

– Head injury

– Raised intracranial pressure

– Paralytic ileus

– “Acute abdomen”

– Delayed gastric emptying

– Acute hepatic disease

– Post-operative after biliary surgery

– 24 hours before chordotomy

– Concurrent administration of monoamine oxidase inhibitors or within two weeks of discontinuation of their use.

– Concomitant use of morphine agonists/anta­gonists (see section 4.5)

– Agitation states in patients affected by alcohol or hypnotics.

4.4 Special warnings and precautions for use

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs

Concomitant use of Filnarine and 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 Filnarine 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).

Filnarine Prolonged Release Film-coated Tablets should be used with caution in opiatedependent patients and in patients with hypotension with hypovolaemia, disorders of consciousness, diseases of the biliary tract, biliary or urinary colic, pancreatitis, obstructive and inflammatory bowel disorders, prostatic hypertrophy and adrenocortical insufficiency.

Pre-operative administration of Filnarine Prolonged Release Film-coated Tablets is not recommended.

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.

Oral P2Y12 inhibitor antiplatelet therapy

Within the first day of concomitant P2Y12 inhibitor and morphine treatment, reduced efficacy of P2Y12 inhibitor treatment has been observed (see section 4.5).

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 drug is used, and with higher doses. Symptoms can be minimised with adjustments of dose or dosage form, and gradual withdrawal of morphine. For individual symptoms, see section 4.8.

The effects of morphine have led to its abuse and dependence may develop with regular, inappropriate use. Physical and psychic dependence may develop after administration of therapeutic doses for 1–2 weeks. Daily administration in patients with chronic pain significantly reduces the risk of physical and psychic addiction, and it is not a major concern in the treatment of patients with severe pain. Isolated cases of dependence have been reported even after 2–3 days of therapy. The risk may be reduced by observing an exact timetable of administration. Abrupt withdrawal after long term treatment with morphine may lead to a withdrawal syndrome within a few hours. This syndrome usually reaches its maximum 36 to 72 hours after withdrawal. There is cross-tolerance with other opioids.

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.

Should paralytic ileus be suspected or occur during use, Filnarine Prolonged Release Film-coated Tablets should be discontinued immediately.

As with all morphine preparations, Filnarine Prolonged Release Film-coated Tablets should be used with caution post-operatively and following abdominal surgery as morphine impairs intestinal motility and should not be used until the physician is assured of normal bowel function.

Concomitant use of alcohol and Filnarine prolonged release tablets may increase the undesirable effects of morphine; concomitant use should be avoided, since it may result in the rapid release and absorption of a potentially fatal dose of morphine. Additionally, patients must not use prescription or non-prescription medications containing alcohol while on Filnarine therapy.

A reduction in dosage may be advisable in the elderly, in hypothyroidism and in patients with significantly impaired renal or hepatic function (see section 5.2).

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.

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.

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.

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.

4.5 Interaction with other medicinal products and other forms of interaction

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 depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

Morphine potentiates the effect of tranquillisers, anaesthetics, alcohol, muscle relaxants and antihypertensives. Alcohol may enhance the pharmacodynamic effects of Filnarine Prolonged Release Film-Coated Tablets; concomitant use should be avoided, since it may result in the rapid release and absorption of a potentially fatal dose of morphine.

Cimetidine inhibits the metabolism of morphine. The clinical relevance of the interaction is unknown.

Monoamine oxidase inhibitors are known to interact with narcotic analgesics producing CNS excitation or depression with hyper- or hypotensive crisis.

Rifampicin induces the metabolism of orally administered morphine to a high degree and therefore higher doses may be needed.

Clomipramine and amitriptyline increase the analgesic effects of morphine, which may partly be due to an increased bioavailability. An adjustment of the dose may be necessary.

Combination with morphine agonists/anta­gonists (buprenorphine, nalbuphine, pentazocine) is contraindicated because there is reduction of the analgesic effect by competitive blocking of the receptors, with a risk of occurrence of a withdrawal syndrome (see section 4.3).

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 (see section 4.4). 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Morphine is not recommended during pregnancy because animal experiments indicated damage to offspring and morphine is not recommended during labour due to the risk of neonatal respiratory depression. Filnarine should be used during pregnancy only when the potential benefits justify the possible risks to the foetus.

Newborns whose mothers received opioid analgesics during pregnancy should be monitored for signs of neonatal withdrawal (abstinence) syndrome. Treatment may include an opioid and supportive care.

Breast-feeding

Administration to breast-feeding mothers is not recommended as morphine is excreted in breast milk. Withdrawal symptoms may be observed in the new-born infant of mothers undergoing chronic treatment.

Fertility

Animal studies have shown that morphine may reduce fertility (see 5.3. preclinical safety data).

4.7 Effects on ability to drive and use machines

Morphine has major influence on the ability to drive and use machines. Morphine may reduce attention and reaction time. This should be anticipated particularly at the beginning of treatment, when dosage is increased or when associated with concomitant alcohol or other sedative medicines.

"This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

The medicine is likely to affect your ability to drive,

Do not drive until you know how the medicine affects you

It is an offence to drive while under the influence of this medicine

However, you would not be committing an offence (called ‘statutory defence’) if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely"

4.8 Undesirable effects

Drug dependence and withdrawal (abstinence) syndrome

Use of opioid analgesics may be associated with the development of physical and/or psychological dependence or tolerance. An abstinence syndrome may be precipitated when opioid administration is suddenly discontinued or opioid antagonists administered, or can sometimes be experienced between doses. For management, see 4.4.

Physiological withdrawal symptoms include: Body aches, tremors, restless legs syndrome, diarrhoea, abdominal colic, nausea, flu-like symptoms, tachycardia and mydriasis.

Psychological symptoms include dysphoric mood, anxiety and irritability. In drug dependence, “drug craving” is often involved.

Immune system disorders

Morphine has histamine-releasing effects which may be responsible in part for reactions such as urticaria and pruritus.

Gastrointestinal disorders

If nausea and vomiting occur with Filnarine prolonged release tablets, the tablets can be combined with an anti-emetic if required. Constipation may be treated with appropriate laxatives.

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 Yellow Card Scheme: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store).

4.9 Overdose

Signs of morphine toxicity and overdose are pin-point pupils, respiratory depression and hypotension. Circulatory failure and deepening coma may occur in more severe cases. In addition tachycardia, vertigo, dropping of body temperature, relaxation of skeletal muscles, Pneumonia aspiration; in children general convulsions were observed.

Death may occur from respiratory failure.

Treatment of morphine overdose:

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.

In the case of massive overdose the intravenous administration of naloxone is recommended. Intravenous administration of 0,4–0,8 mg naloxone is recommended. Administration should be repeated at 2 to 3 minute intervals as necessary, or by infusion of 2 mg in 500 ml of sodium chloride 0.9 mg/ml (0.9%) solution or 0.004 mg/ml glucose (5%). The infusion should be run at a rate related to the previous bolus dose administered and should be in accordance with the patient’s response. However, because the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. Filnarine SR prolonged release tablets will continue to release and add to the morphine load for up to 12 hours after administration and the management of morphine overdose should be modified accordingly.

Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on morphine. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

Gastric contents may need to be emptied as this can be useful in removing unabsorbed active substance, particularly when a modified release formulation has been taken.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Opioids, natural opium alkaloids

ATC-code: NO2AA01

Morphine acts as an agonist at opiate receptors in the CNS particularly li and to a lesser extent k receptors. li receptors are thought to mediate supraspinal analgesia, respiratory depression and euphoria, and k receptors spinal analgesia, miosis and sedation. Morphine also has a direct action on the bowel wall nerve plexuses causing constipation.

In elderly patients, the analgesic effect of morphine is increased.

Other effects of morphine on the central nervous system are nausea, vomiting and release of antidiuretic hormone.

The respiratory depressive effect of morphine can lead to respiratory insufficiency in patients with decreased ventilation capacity due to pulmonary disease or due to effects of other medicinal products.

The effects of morphine may be increased in patients with encephalitis.

5.2 Pharmacokinetic properties

Absorption and distribution

The maximum peak concentration is reached approximately 2 hours after dosing. After oral administration morphine is subject to a high and variable first-pass metabolism. The bioavailability of morphine is 30%, with a range between 10 and 50%. The bioavailability of morphine may be increased in patients with liver cancer. When the prolonged release tablets were taken with food, tmax of morphine was not changed. Cmax of morphine was slightly raised after the prolonged release tablets were taken with food (from 9.73 to 10.0 ng/ml).

Circa 20–30% of morphine is bound to plasma proteins. The volume of distribution is 1–3.8 l/kg.

Morphine-6-glucuronide passes the blood-brain barrier.

Morphine passes the placenta and is excreted into breastmilk.

Biotransformation and elimination

Morphine is eliminated mainly by metabolism. In the liver morphine is metabolised to the inactive morphine-3-glucuronide and to the active morphine-6-glucuronide. This metabolite is more potent than morphine itself.

The metabolites are mainly excreted in the urine (90% in 24 hours). Morphine and its metabolites are recirculated interohepatically. About 7–10% is excreted through the bile in the faeces. The half-life is about 3 hours. The pharmacokinetics of morphine is independent of dose. The plasma levels of the active morphine-6-glucuronide may be markedly increased in patients with decreased renal function.

5.3 Preclinical safety data

Experimental studies have shown that morphine sulfate induces chromosome damage in animals in somatic and germ cells. A genotoxic potential for humans may be expected. Long term animal studies on the carcinogenic potential of morphine have not been conducted. Several studies show that morphine can enhance tumor growth.

In male rats, reduced fertility and chromosomal damage in gametes have been reported.

In animal studies morphine showed a teratogenic potential and neurobehavioural deficiencies in the developing organism, while data in humans do not show evidence of malformations or fetotoxic effects of morphine.

6.1

Tablet core:

Hypromellose

Stearic acid

Magnesium stearate

Colloidal anhydrous silica

Tablet coating:

Hypromellose

Macrogol 400

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Keep blister card in the outer carton in order to protect from light.

6.5 Nature and contents of container

PVC/PVDC/Al blisters containing 5, 7 and 10 prolonged release film-coated tablets.

Pack sizes:

Blisters of 10, 14, 20, 25, 28, 30, 50, 56, 60 or 100 prolonged release film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Not applicable

7 MARKETING AUTHORISATION HOLDER

TEVA UK Limited

Brampton Road, Hampden Park

Eastbourne, East Sussex, BN22 9AG

Trading address:

Leeds, LS27 0JG

8 MARKETING AUTHORISATION NUMBER(S)

PL 00289/1019

9 DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE

19/07/2007 / 20/06/2010