Loperamide Galpharm 2 Mg Capsules Hard
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Loperamide Galpharm 2mg Capsules, Hard
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Loperamide Hydrochloride 2 mg.
Lactose Monohydrate 146 mg per capsule.
For full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Capsule, hard [Capsule].
Opaque blue cap and grey body, hard gelatin capsule containing white powder.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For symptomatic treatment of acute diarrhoea in adults and children aged 12 years and over.
4.2 Posology and method of administration
For oral use.
Adults, the elderly and children over 12 years of age:
Two capsules to be taken initially, followed by one capsule after each loose motion, up to a maximum of six capsules in any 24 hours.
Children under 12 years of age: Not recommended
Renal impairment
No dose adjustment is required for patients with renal impairment.
Hepatic impairment
Although no pharmacokinetic data are available in patients with hepatic impairment Loperamide Galpharm 2mg Capsules should be used with caution in such patients beacuase of reduced first pass metabolism (see section 4.4 Special warnings and precautions for use).
4.3 Contraindications
Patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients.
When inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon, toxic megacolon and certain poisonings in particular:
• When ileus or constipation are present or when abdominal distension develops, particularly in severely dehydrated children.
• In patients with acute ulcerative colitis.
• In patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella, and Campylobacter.
• In patients with pseudomembranous colitis associated with the use of broad-spectrum antibiotics.
Loperamide hydrochloride should not be used alone in acute dysentery, which is characterised by blood in stools and elevated body temperatures.
Loperamide Hydrochloride should not be used in children under 2 years of age.
4.4 Special warnings and precautions for use
Treatment of diarrhoea with loperamide is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate.
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 loperamide hydrochloride does not preclude the administration of appropriate fluid and electrolyte replacement therapy.
Since persistent diarrhoea can be an indicator of potentially more serious conditions, loperamide hydrochloride should not be used for prolonged periods until the underlying cause of the diarrhoea has been investigated.
loperamide hydrochloride must be used with caution when the hepatic function necessary for the drug's metabolism is defective (eg in cases of severe hepatic disturbance), as this might result in a relative overdose leading to CNS toxicity.
Patients with AIDS treated with loperamide hydrochloride 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.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine because it contains lactose.
When no clinical change is observed in the acute diarrhoea within 48 hours, the administration of loperamide must be interrupted and the patient must be advised to consult his doctor.
Loperamide Galpharm 2mg Capsules should not be used in chronic diarrhoea, which requires follow-up by a physician.
Treatment with Loperamide Galpharm 2mg Capsules must be interrupted immediately when obstipation, abdomnial distension or subileus develops.
Children between 2 and 12 years should only be treated after consulting a doctor. The current formulation is not suitable for use in children below 8 years given the strength of the active substance in the capsule.
4.5 Interaction with other medicinal products and other forms of interaction
Non-clinical data have shown that loperamide hydrochloride is a P-glycoprotein substrate. Furthermore, loperamide is mainly metabolisedby CYP3A4 and CYP2C8.
Concomitant administration of loperamide (16 mg single dose) with quinidine, or ritonavir, which are both P-glycoprotein inhibitors, resulted in a 2 to 3-fold increase in loperamide plasma levels.
The results of one published pharmacokinetic study suggested that the concomitant administration of loperamide with oral desmopressin may result in a 3-fold increase of desmopressin plasma concentrations although no clinical effects were reported.
Possible interactions may occur with drugs that delay intestinal peristalsis (for instance anti-cholinergic drugs) because the effects of loperamide could be enhanced.
Administration of itraconazole with loperamide (4 mg single dose) increased loperamide plasma levels 3- to 4-fold. In addition, gemfibrozil, a CYP2C8 inhibitor, increased the AUC of loperamide 2-fold. Concomitant use of itraconazole and gemfibrozil with loperamide raised the mean Cmax and AUC of loperamide about 2-and 13-fold, respectively. This increase did not lead to measurable CNS effects.
The concomitant administration of loperamide (16mg single dose) and ketoconazole, an inhibitor of CYP3A4 and p-glycoprotein, resulted in a 5-fold increase in loperamide plasma concentrations. This increase was not associated with increased pharmacodynamic effects as measured by pupillometry.
The clinical relevance of these pharmacokinetic interactions, when loperamide is given at recommended dosages (2 mg, up to 12 mg maximum daily dose), is unknown.
4.6 Fertility, pregnancy and lactation
Pregnancy
A limited amount of data from the use of loperamide in pregnant women is available. In one of two epidemiological studies the use of loperamide during early pregnancy suggested a possible moderate increased risk for hypospadia, however, an increased risk for major malformations could not be identified. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
If possible the use of loperamide should be avoided during the first trimester of pregnancy, however, it may be used during the second and third trimester of pregnancy
Lactation
Only very small amounts of loperamide hydrochloride may appear in human breast milk. Therefore, Loperamide Galpharm 2mg Capsules may be used during breast feeding when dietary measures are insufficient and a drug-induced inhibition of intestinal motility is indicated.
Fertility
Only high doses of loperamide hydrochloride affected female fertility in non-clinical studies (see section 5.3).
4.7 Effects on ability to drive and use machines
Loss of conciousness, depressed level of conciousness, tiredness, dizziness or drowsiness may occur when diarrhoea is treated with Loperamide Galpharm 2mg Capsules. Therefore, it is advisable to use caution when driving or opearating machinery. (See section 4.8 Undesirable effects).
4.8 Undesirable effects
Adults and children aged > 12 years
The safety of loperamide hydrochloride was evaluated in 2755 adults and children aged > 12 years who participated in 26 controlled and uncontrolled clinical trials of loperamide hydrochoride used for the treatment of acute diarrhoea.
The most commonly reported (i.e. >1% incidence) adverse drug reactions (ADRs) in clinical trials with loperamide hydrochoride 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 hydrochoride from either clinical trial (acute diarrhoea) or post-marketing experience.
The frequency categories use the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); and very rare (<1/10,000).
|
System Organ Class |
Indication | ||
|
Common |
Uncommon |
Rare | |
|
Immune System Disorders |
Hypersensitivity reactiona Anaphylactic reaction (including Anaphylactic shock)*1 Anaphylactoid reactiona | ||
|
Nervous System Disorders |
Headache Dizziness |
Somnolence3 |
Loss of consciousnessa Stupora Depressed level of consciousness*1 Hypertoniaa Coordination abnormality*1 |
|
Eye Disorders |
Miosis*1 | ||
|
Gastrointestinal Disorders |
Constipation Nausea Flatulence |
Abdominal pain Abdominal discomfort Dry mouth Abdominal pain upper Vomiting Dyspepsiaa |
Ileus*1 (including paralytic ileus) Megacolona (including toxic megacolonb) Glossodyniaa Abdominal distension |
|
Skin and Subcutaneous Tissue Disorders |
Rash |
Bullous eruption*1 (including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme) Angioedemaa Urticaria*1 Pruritus*1 | |
|
System Organ Class |
Indication | ||
|
Common |
Uncommon |
Rare | |
|
Renal and Urinary Disorders |
Urinary retention3 | ||
|
General Disorders and Administration Site Conditions |
Fatigue3 | ||
a: Inclusion of this term is based on post-marketing reports for loperamide hydrochoride. 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 hydrochoride (acute and chronic), including trials in children < 12 years (N=3683).
b: See section 4.4 Special Warnings and Special Precautions for use.
4.9 Overdose
Symptoms
In case of overdose (including relative overdose due to hepatic dysfunction) CNS depression (stupor, coordination abnormality, somnolence, miosis, muscular hypertonia and respiratory depression), urinary retention and ileuss may occur. Children may be more sensitive to CNS effects than adults.
Management
If symptoms of overdose occur, naloxone can be given as an antidote. Since the duration of action of loperamide is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone might be indicated. Therefore, the patient should be monitored closely for at least 48 hours in order to detect any possible CNS depression.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Antipropulsives;
ATC code: A07DA03
Loperamide hydrochloride is a synthetic opioid which inhibits gut motility by binding to opiate receptors in the gut wall and may also reduce gastrointestinal secretions, resulting in improvement in diarrhoea symptoms.
Loperamide also increases the tone of the anal sphincter. Onset of antidiarrhoeal effect occurred as soon as one hour after intake of a 4 mg dose of loperamide.
In a double blind randomised clinical trial in 56 patients with acute diarrhoea receiving loperamide, onset of anti-diarrhoeal action was observed within one hour following a single 4 mg dose. Clinical comparisons with other antidiarrhoeal drugs confirmed this exceptionally rapid onset of action of loperamide.
5.2 Pharmacokinetic properties
Loperamide hydrochloride is well absorbed from the gut. 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 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 hydrochloride reaches the systemic circulation.
The half-life of loperamide hydrochloride in man is about 11 hours with a range of 9 -14 hours. Excretion takes place mainly via faeces.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
Acute and chronic studies on loperamide showed no specific toxicity.
Loperamide had no effect on fertility in male rats when administered orally prior to mating at doses up to approximately 40 mg/kg. No pregnancy occurred in females dosed with approximately 40 mg/kg. Lower doses (approximately 10 and 2.5mg/kg) did not affect female fertility. In rabbits no differences in pregnancy rate were observed when females were administered orally up to 40mg/kg.
No malformations of offspring were noted in rats and rabbits dosed up to 40 mg/kg. Loperamide did no show genotoxic potential.
In an 18-month carcinogenicity study in rats, with doses up to 100 times the maximum human dose no evidence of carcinogenesis was found.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose Maize Starch Talc
Magnesium Stearate Gelatin
Quinoline Yellow Erythrosine Patent Blue Titanium Dioxide
6.2 Incompatibilities
None.
6.3 Shelf life
36 Months.
6.4 Special precautions for storage
This product requires no special storage precautions.
6.5 Nature and contents of container
Blister strips comprising 20 micron printed aluminium foil and 250 micron clear PVC / 40gsm PVdC film. The blister strips are enclosed in a printed cardboard carton with a patient information leaflet.
Pack Sizes of 6, 8, 10, 12 or 20 capsules. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
7. MARKETING AUTHORISATION HOLDER
Galpharm Healthcare Limited
Wrafton
Braunton
Devon
EX33 2DL
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 16028/0150
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
24/05/2012
10 DATE OF REVISION OF THE TEXT
14/07/2016