Mebendazole Tablets 100mg

Document: spc-doc_PL 40147-0054 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains mebendazole Ph. Eur. 100mg

3 PHARMACEUTICAL FORM

Tablet

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the treatment of threadworm (Enterobius vermicularis) infestation

4.2 Posology and method of administration

Adults, the elderly and children over 2 years:

A single dose of 1 tablet to be chewed or swallowed whole. The dose may be repeated after 2 weeks if re-infestation occurs.

Children under 2 years:

Not recommended.

Care should be taken to avoid re-infestation and it is recommended that the whole family be treated simultaneously.

Method of administration: Oral

4.3 Contraindications

Mebendazole is contraindicated in pregnant women and in individuals with hypersensitivity to the product or any of the excipients listed in section 6.1

4.4 Special warnings and precautions for use

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine

If symptoms do not disappear within a few days, consult your doctor.

Not recommended in the treatment of children under 2 years.

A case-control study of a single outbreak of Stevens-Johnson syndrome /toxic epidermal necrolysis (SJS/TEN) suggested a possible association with the concomitant use of metronidazole with mebendazole. Although there are no additional data on this potential interaction, concomitant use of Mebendazole and metronidazole should be avoided.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant treatment with cimetidine may inhibit the metabolism of mebendazole in the liver, resulting in increased plasma concentrations of the drug.

Concomitant use of mebendazole and metronidazole should be avoided (see section 4.4)

4.6 Fertility, Pregnancy and lactation

Use in pregnancy

Since Mebedazole is contra-indicated in pregnancy patients who think they are or may be pregnant should not take this preparation.

Use in lactation

As limited information is available on the excretion of mebendazole in human milk, it is not advisable to breastfeed following administration of mebendazole.

4.7 Effects on ability to drive and use machines

None known

4.8 Undesirable effects

Throughout this section adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of Mebendazole based on the comprehensive assessment of the available adverse event information. A causal relationship with Mebendazole cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

At the recommended dose, Mebendazole is generally well tolerated. However, patients with high parasitic burdens when treated with Mebendazole have manifested diarrhoea and abdominal pain

The safety of mebendazole was evaluated in 6276 subjects who participated in 39 clinical trials for the treatment of single or mixed parasitic infestations of the gastrointestinal tract. In these 39 clinical trials, no adverse drug reactions (ADRs) occurred in 1% of mebendazole-treated subjects.

ADRs identified from clinical trials and post-marketing experience with mebendazole are included in Table 1. The displayed frequency categories use the following convention:

Very common Common Uncommon Rare Very rare

(> 1/10)

(> 1/100 and < 1/10)

(> 1/1000 and < 1/100)

(> 1/10,000 and < 1/1000) (<1/10,000)

Not known (cannot be estimated from the available date).

Table 1: Adverse drug Reactions

System Organ Class	Adverse Drug Reactions
System Organ Class	Frequency Category
	Common	Uncommon	Rare
	(> 1/100 to < 1/10)	(> 1/1000 to < 1/100)	(> 1/10,000 and < 1/1000)
Blood and lymphatic system			Neutropenia^b

disorders
Immune system disorders			Hypersensitivity including anaphylactic reaction and anaphylactoid reaction^b
Nervous system disorders			Convulsions^b Dizziness^a
Gastrointestinal disorders	Abdominal pain^a	Abdominal discomfort^a; Diarrhoea^a; Flatulence^a
Hepatobiliary disorders			Hepatitis^b; Abnormal liver function tests^b
Skin and subcutaneous tissue disorders			Rash^a Toxic epidermal necrolysis^b; Stevens-Johnson syndrome^b; Exanthema^b; Angioedema^b; Urticaria^b; Alopecia^b

a ADR frequency data derived from Clinical Trials or Epidemiological Studies b Adverse reactions reported during post-marketing surveillance.

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 at: www.mhra.gov.uk/yellowcard

4.9 Overdose

In patients treated at dosages substantially higher than recommended or for prolonged periods of time, the following adverse reactions have been reported rarely: alopecia, reversible liver function disturbances, hepatitis, agranulocytosis, neutropenia and glomerulonephritis. With the exception of agranulocytosis and glomerulonephritis, these also have been reported in patients who were treated with mebendazole at standard dosages (see section 4.8).

Signs and Symptoms

In the event of accidental overdosage, abdominal cramps, nausea, vomiting and diarrhoea may occur.

Treatment

There is no specific antidote. Activated charcoal may be given if considered appropriate.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: anthelmintic for oral administration, benzimidazole derivatives; ATC code: P02CA01

In vitro and in vivo work suggests that mebendazole blocks the uptake of glucose by adult and larval forms of helminths, in a selective and irreversible manner. Inhibition of glucose uptake appears to lead to endogenous depletion of glycogen stores within the helminth. Lack of glycogen leads to decreased formation of ATP and ultrastructural changes in the cells.

There is no evidence that mebendazole is effective in the treatment of cysticercosis.

5.2 Pharmacokinetic properties

Absorption

Following oral administration, approximately <10% of the dose reaches the systemic circulation, due to incomplete absorption and to extensive presystemic metabolism (first-pass effect). Maximum plasma concentrations are generally seen 2 to 4 hours after administration. Dosing with a high fat meal leads to a modest increase in the bioavailability of mebendazole.

Distribution

The plasma protein binding of mebendazole is 90 to 95%. The volume of distribution is 1 to 2 L/kg, indicating that mebendazole penetrates areas outside the vascular space. This is supported by data in patients on chronic mebendazole therapy (e.g., 40 mg/kg/day for 3-21 months) that show drug levels in tissue.

Metabolism

Orally administered mebendazole is extensively metabolized primarily by the liver. Plasma concentrations of its major metabolites (amino and hydroxylated amino forms of mebendazole) are substantially higher than those of mebendazole. Impaired hepatic function, impaired metabolism, or impaired biliary elimination may lead to higher plasma levels of mebendazole.

Elimination

Mebendazole, the conjugated forms of mebendazole, and its metabolites likely undergo some degree of enterohepatic recirculation and are excreted in the urine and bile. The apparent elimination half-life after an oral dose ranges from 3 to 6 hours in most patients.

Steady-state Pharmacokinetics

During chronic dosing (e.g., 40 mg/kg/day for 3-21 months), plasma concentrations of mebendazole and its major metabolites increase, resulting in approximately 3-fold higher exposure at steady-state compared to single dosing.

5.3 Preclinical safety data

Acute oral toxicity of mebendazole in a number of species is low with a large margin of safety. Chronic oral toxicity studies in rats at 40 mg/kg/day and above, showed altered liver weights with some slight centrilobular swelling and hepatocellular vacuolation, and altered testicular weights with some tubular degeneration, desquamation and marked inhibition of spermatogenic activity.

In genotoxicity studies mebendazole was aneugenic in mammalian somatic cells above a threshold plasma concentration of 115 ng/mL, but had no mutagenic or clastogenic activity. In limited long term studies in mice and rats no carcinogenic effects were seen.

Mebendazole has shown embryotoxic and teratogenic activity in pregnant rats and mice at oral doses of 10 mg/kg/day and above and in rats at a single dose of 10 mg/kg, approximately equivalent to the human dose of 100 mg on a body surface area (mg/m2) basis.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose, maize starch, pregelled starch, sunset yellow (E110), sodium saccharin, sodium lauryl sulphate, natural orange flavour, sodium starch glycollate, microcrystalline cellulose and magnesium stearate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 25 °C.

6.5 Nature and contents of container

Blister packs

Pack size: 1, 2, 4, 6 and 8 tablets.

6.6 Special precautions for disposal

None stated.

7 MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited Unit G4,

Riverside Industrial Estate,

Riverside Way,

Dartford DA1 5BS UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 40147/0054

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

6^th August 1999

10 DATE OF REVISION OF THE TEXT

17/09/2015