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4.4 Special warnings and special

precautions for use

Treatment of diarrhoea with loperamide HCl is

only symptomatic. Whenever an underlying

etiology can be determined, specific treatment

should be given when appropriate.

Antimotility agents such as loperamide may

precipitate ileus and toxic megacolon in patients

with ulcerative colitis, or pseudomembranous

colitis associated with broad

 

‐spectrum

 

antibiotics and should be avoided in severe

acute attacks. It may be used cautiously in mild

or less severe attacks as an adjunct to other

measures, but should be discontinued should

abdominal distention or other untoward

symptoms occur.

The priority in acute diarrhoea is the prevention

or reversal of fluid and electrolyte depletion.

This is particularly important in young children

and in frail and elderly patients with acute

diarrhoea. Use of this medicine does not

preclude the administration of appropriate fluid

and electrolyte replacement therapy.

Since persistent diarrhoea can be an indicator of

potentially more serious conditions, this

medicine should not be used for prolonged

periods until the underlying cause of the

diarrhoea has been investigated.

This medicine must be used with caution when

the hepatic function necessary for the drug's

metabolism is defective (e.g. in cases of severe

hepatic disturbance), as this might result in a

relative overdose leading to CNS toxicity.

Patients with AIDS treated with this medicine for

diarrhoea should have therapy stopped at the

earliest signs of abdominal distension. There

have been isolated reports of toxic megacolon in

AIDS patients with infectious colitis from both

viral and bacterial pathogens treated with

loperamide hydrochloride.

In cases of acute diarrhoea, if symptoms persist

for more than 24 hours, patients should be

advised to consult their physician.

Consult your doctor if you develop new

symptoms, or if your symptoms worsen, or your

symptoms have not improved over two weeks.

Cardiac events including QT prolongation and

Torsades de Pointes have been reported in

association with overdose. Some cases had a

fatal outcome (see section 4.9). Patients should

not exceed the recommended dose and/or the

recommended duration of treatment.Abuse and

misuse of loperamide, as an opioid substitute,

have been described in individuals with opioid

addiction (see section 4.9 Overdose).

4.9 Overdose

Signs and symptoms:

In case of overdose (including relative overdose

due to hepatic dysfunction), CNS depression

(stupor, coordination abnormality, somnolence,

miosis, muscular hypertonia and respiratory

depression), constipation, urinary retention and

ileus may occur. Children, and patients with

hepatic dysfunction, may be more sensitive to

CNS effects.

In individuals who have ingested overdoses of

loperamide HCl, cardiac events such as QT

interval prolongation, Torsades de Pointes, other

serious ventricular arrhythmias, cardiac arrest

and syncope have been observed (see section

4.4). Fatal cases have also been reported.In

individuals who have intentionally ingested

overdoses (reported in doses from 40 mg up to

792 mg per day) of loperamide HCl, QT interval

prolongation and or serious ventricular

arrhythmias, have been observed (see section

4.4 Warnings and Precautions). Fatal cases have

also been reported.

Treatment:

In cases of overdose, ECG monitoring for QT

interval prolongation should be initiated.

If CNS symptoms of overdose occur, naloxone

may be given as an antidote. Since the duration

of action of loperamide is longer than that of

naloxone 1 to 3 hrs), repeated treatment with

naloxone might be indicated. Therefore, the

patient should be monitored closely for at least

48 hours in order to detect possible CNS

depression.

5.3 Preclinical safety data

Non

 

 

‐clinical in vitro and in vivo evaluation of

 

loperamide indicates no significant cardiac

electrophysiological effects within its

therapeutically relevant concentration range and

at significant multiples of this range (up to 47

 

 

‐

 

fold). However, at extremely high concentrations

associated with overdoses (see section 4.4

Warnings and Precautions), loperamide has

cardiac electrophysiological actions consisting of

inhibition of potassium (hERG) and sodium

currents, and arrhythmias. Within its

therapeutically relevant concentration range and

at significant multiples of this range (up to 47

 

 

‐

 

fold), loperamide has no significant cardiac

electrophysiological effects. However, at

extremely high concentrations associated with

intentional overdose (see section 4.4 Warnings

and Precautions), loperamide has cardiac

electrophysiological actions consisting of

inhibition of potassium (hERG) and sodium

currents, and arrhythmias in in vitro and in vivo

animal models.

This was for a Renewal, therefor the only change has been to the date of the revision of the text

Text that has been added has been highlighted and underlined, text that has been removed has been struck through:

4.4 Special warnings and precautions for use

Treatment of diarrhoea with loperamide HCl is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate.

Antimotility agents such as loperamide may precipitate ileus and toxic megacolon in patients with ulcerative colitis, or pseudomembranous colitis associated with broad-spectrum antibiotics and should be avoided in severe acute attacks. It may be used cautiously in mild or less severe attacks as an adjunct to other measures, but should be discontinued should abdominal distention or other untoward symptoms occur.

The priority in acute diarrhoea is the prevention or reversal of fluid and electrolyte depletion.  This is particularly important in young children and in frail and elderly patients with acute diarrhoea.  Use of this medicine does not preclude the administration of appropriate fluid and electrolyte replacement therapy.

Since persistent diarrhoea can be an indicator of potentially more serious conditions, This medicine should not be used for prolonged periods until the underlying cause of the diarrhoea has been investigated.

This medicine must be used with caution when the hepatic function necessary for the drug's metabolism is defective (e.g. in cases of severe hepatic disturbance), as this might result in a relative overdose leading to CNS toxicity.

Patients with AIDS treated with this medicine for diarrhoea should have therapy stopped at the earliest signs of abdominal distension.  There have been isolated reports of toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with loperamide hydrochloride.

In cases of acute diarrhoea, if symptoms persist for more than 24 hours, patients should be advised to consult their physician.

Consult your doctor if you develop new symptoms, or if your symptoms worsen, or your symptoms have not improved over two weeks.

Abuse and misuse of loperamide, as an opioid substitute, have been described in individuals with opioid addiction (see section 4.9 Overdose).

4.6 Fertility, pPregnancy and lactation

 

Pregnancy

Safety in human pregnancy has not been established although studies in animals have not demonstrated any teratogenic effects.  As with other drugs, it is not advisable to administer this medicine in pregnancy.

 

Breast-Feeding

Small amounts of loperamide may appear in human breast milk.  Therefore, this medicine is not recommended during breast-feeding.

Women who are pregnant or breast feeding infants should therefore be advised to consult their doctor for appropriate treatment.

 

Fertility

The effect on human fertility has not been evaluated.

4.9.      Overdose

In case of overdose the following effects may be observed: constipation, urinary retention, ileus and neurological symptoms (miosis, muscular hypertonia, somnolence and bradypnoea).  If intoxication is suspected, naloxone may be given as an antidote.  Since the duration of action of loperamide is longer than that of naloxone, the patient should be kept under constant observation for at least 48 hours in order to detect any possible depression of the central nervous system.  Children, and patients with hepatic dysfunction, may be more sensitive to CNS effects.  Gastric lavage, or induced emesis and or enema or laxatives may be recommended.

Signs and symptoms:

In case of overdose (including relative overdose due to hepatic dysfunction), CNS depression (stupor, coordination abnormality, somnolence, miosis, muscular hypertonia and respiratory depression), constipation, urinary retention and ileus may occur. Children, and patients with hepatic dysfunction, may be more sensitive to CNS effects.

 

In individuals who have intentionally ingested overdoses (reported in doses from 40 mg up to

792 mg per day) of loperamide HCl, QT interval prolongation and or serious ventricular arrhythmias, have been observed (see section 4.4 Warnings and Precautions). Fatal cases have also been reported.

 

Treatment:

In cases of overdose, ECG monitoring for QT interval prolongation should be initiated.

 

If CNS symptoms of overdose occur, naloxone may be given as an antidote.  Since the duration of action of loperamide is longer than that of naloxone 1 to 3 hrs), repeated treatment with naloxone might be indicated. Therefore, the patient should be monitored closely for at least 48 hours in order to detect possible CNS depression.

5.2.      Pharmacokinetic properties

 

The half-life of loperamide in man is 10.8 hours with a range of 9 to 14 hours.  Studies on distribution in rats show high affinity for the gut wall with preference for binding to the receptors in the longitudinal muscle layer.  Loperamide is well absorbed from the gut, but is almost completely extracted and metabolised by the liver where it is conjugated and excreted via the bile.  Due to its high affinity for the gut wall and its high first pass metabolism, very little loperamide reaches the systemic circulation.

Absorption:  Most ingested loperamide is absorbed from the gut, but as a result of significant first pass metabolism, systemic bioavailability is only approximately 0.3%.

 

Distribution: Studies on distribution in rats show a high affinity for the gut wall with a preference for binding to receptors of the longitudinal muscle layer.  The plasma protein binding of loperamide is 95%, mainly to albumin.  Non-clinical data have shown that loperamide is a P-glycoprotein substrate.

 

Metabolism: Loperamide is almost completely extracted by the liver, where it is predominantly metabolized, conjugated and excreted via the bile.  Oxidative N-demethylation is the main metabolic pathway

for loperamide, and is mediated mainly through CYP3A4 and CYP2C8.  Due to this very high first pass effect, plasma concentrations of unchanged drug remain extremely low.

 

Elimination: The half-life of loperamide in man is about 11 hours with a range of 9-14 hours.  Excretion of the unchanged loperamide and the metabolites mainly occurs through the faeces.

5.3.  Preclinical safety data

No relevant information additional to that contained elsewhere in the Summary of Product Characteristics.

Within its therapeutically relevant concentration range and at significant multiples of this range (up to 47-fold), loperamide has no significant cardiac electrophysiological effects. However, at extremely high concentrations associated with intentional overdose (see section 4.4 Warnings and Precautions), loperamide has cardiac electrophysiological actions consisting of inhibition of potassium (hERG) and sodium currents, and arrhythmias in in vitro and in vivo animal models.

10      DATE OF REVISION OF THE TEXT

16 November 2016

Addition of the following text to Section 4.8

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Section 4 of the SPC has been updated in line with the Core Data Sheet.

Change to storage conditions.

None provided