Imodium Instants 2mg Orodispersible Tablets

Legal Entity Transfer from McNeil Healthcare (Ireland) Ltd to Johnson & Johnson (Ireland) Ltd:

 

Product name: Imodium Instants 2 mg Orodispersible Tablets

New PA Number: PA 330/45/1

Old PA Number:  PA 823/56/2

Added text has been highlighted and underlined, removed text has been highlighted and struck through:

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Loperamide hydrochloride 2 mg per tablet.

Excipients: Each tablet contains 750 micrograms of Aspartame (E951) and the Mint flavouring contains traces of Sulphites.

For a full list of excipients see section 6.1.

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.

 

Imodium is not a substitute for rehydration therapy.  In addition to taking Imodium, the patient should be advised to drink plenty of fluids such as water, clear soup and squash.

 

Patients should be advised to consult their doctor if diarrhoea persists for more than 24 hours.

 

Loperamide should be used with caution when hepatic function, necessary for the drug’s metabolism, is defective as this may result in relative overdose leading to CNS toxicity.

 

Patients with AIDS treated with Imodium Instants 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.

 

Antimotility agents such as loperamide may precipitate ileus and toxic megacolon in patients with ulcerative colitis, 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 promptly should abdominal distension or other untoward symptoms occur.

 

The stated dose should not be exceeded.

 

 

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).

 

The package leaflet contains the following information:

·      Aspartame (E951) contains a source of phenylalanine which may be harmful for people with phenylketonuria.

·      Mint flavour contains traces of sulphites. This may rarely cause severe hypersensitivity reactions and bronchospasm.

 

Sulphites can cause allergy like reactions, most commonly asthma symptoms in those with underlying asthma. Allergic rhinitis like reactions, urticaria and anaphylaxis might be observed.

4.6 Fertility, pPregnancy and lactation

 

Pregnancy

The safety of loperamide in human pregnancy has not been established. 

 

Breast-Feeding

Small amounts of loperamide may appear in human breast milk.  Therefore, loperamide 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.

4.8 Undesirable effects

 

Adults and children aged ≥ 12 years

The safety of loperamide HCl was evaluated in 2755 adults and children aged ≥ 12 years who participated in 26 controlled and uncontrolled clinical trials of loperamide HCl used for the treatment of acute diarrhoea.

The most commonly reported (i.e. ≥ 1% incidence) adverse drug reactions (ADRs) in clinical trials with loperamide HCl in acute diarrhoea were: constipation (2.7%), flatulence (1.7%), headache (1.2%) and nausea (1.1%).

Table 1 displays ADRs that have been reported with the use of loperamide HCl from either clinical trial (acute diarrhoea) or post marketing experience.

The frequency categories use the following convention: very common (³1/10); common (³1/100 to <1/10); uncommon (³1/1,000 to <1/100); rare (³1/10,000 to <1/1,000); and very rare (<1/10,000).

Table 1:            Adverse Drug Reactions

System Organ Class	Indication
	Common	Uncommon	Rare
Immune System Disorders			Hypersensitivity reactiona Anaphylactic reaction (including Anaphylactic shock)a Anaphylactoid reactiona
Nervous System Disorders	Headache	Dizziness Somnolencea	Loss of consciousnessa Stupora Depressed level of consciousnessa Hypertoniaa Coordination abnormalitya
Eye Disorders			Miosisa
Gastrointestinal Disorders	Constipation Nausea Flatulence	Abdominal pain Abdominal discomfort Dry mouth Abdominal pain upper Vomiting Dyspepsiaa	Ileusa (including paralytic ileus) Megacolona (including toxic megacolonb) Abdominal distension Glossodynia
Skin and Subcutaneous Tissue Disorders		Rash	Bullous eruptiona (including Stevens‑Johnson syndrome, Toxic epidermal necrolysis and Erythema multiforme) Angioedemaa Urticariaa Pruritusa
Renal and Urinary Disorders			Urinary retentiona
General Disorders and Administration Site Conditions			Fatiguea
a:             Inclusion of this term is based on post‑marketing reports for loperamide HCl. As the process for determining post marketing ADRs did not differentiate between chronic and acute indications or adults and children, the frequency is estimated from all clinical trials with loperamide HCl (acute and chronic), including trials in children ≤ 12 years (N=3683). b:             See section 4.4 Special Warnings and Special Precautions for use.

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.

4.9.      Overdose

Signs and symptoms:

 

Overdose (relative or absolute) may lead to constipation, urinary retention, ileus and central nervous system depression (miosis, muscular hypertonia, somnolence and bradypnoea). 

Naloxone may be given as an antidote, repeated as necessary over an observation period of at least 48 hours.

 

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 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 hours), 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.

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.

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.

6.4.      Special precautions for storage

Store in the original container. This medicine does not require any special storage conditions.

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.

PA holder changed to: McNeil Healthcare (Ireland) Ltd.
New PA number: PA 823/56/2

1.

NAME OF THE MEDICINAL PRODUCT

Pharmaceutical form detailed

 

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Quantitative composition of an excipient added

 

5.1

Pharmacodynamic properties

ATC code added

 

 

7.

MARKETING AUTHORISATION HOLDER

Address changed

 

 

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Renewal date changed

 

10.

DATE OF REVISION OF THE TEXT

Changed to 12 June 2009

 

Change to section 4.8 – Undesirable effects	Update to MedDRA and addition of ‘Very rare: Loss of consciousness, depressed level of consciousness’
Change to section 10 – Date of revision of text	August 2008

Change to section 2 – quantitative and qualitative composition	Update QRD
Change to section 4.1 – Therapeutic Indications	Update QRD
Change to section 4.2 – Posology and |Method of Administration	Update QRD
Change to section 4.3 – Contra-indications	Update QRD Lactose
Change to section 4.4 – Special Warnings and Precautions for Use	Update QRD
Change to section 4.5 –Interaction with other medicinal products and other forms of interaction	Update QRD
Change to section 4.6 – Pregnancy and Lactation	Update QRD
Change to section 4.7 - Effects on Ability to Drive and Use Machines	Update QRD
Change to section 4.8 – Undesirable effects	Update to MedDRA and Loss of consciousness, depressed level of consciousness,
Change to section 5.1 - Pharmacodynamic properties	ATC code
Change to section 5.2 - Pharmacokinetic properties	Update to QRD
Change to section 5.3 - Preclinical Safety Data	Update to QRD
Change to section 6.1 – List of Excipients	Update to QRD
Change to section 6.6 –  Instructions for use, handling and disposal	Update to QRD
Change to section 10 – Date of revision of text	August 2008