This information is intended for use by health professionals

1. Name of the medicinal product

IMUNOVIR 500 mg Tablets

2. Qualitative and quantitative composition

Each tablet contains 500mg Inosine Acedoben Dimepranol (INN, also known as inosine pranobex*) which is the p-acetamidobenzoic acid salt of N,N-dimethylamino-2-propanol [DIP.PAcBA] and β-inosine in a 3:1 molar ratio.

*British Approved Name (BAN) the non-proprietary designation

Excipient(s) with known effect: each tablet contains 67mg wheat starch.

For the full list of excipients, see section 6.1

3. Pharmaceutical form

White to off-white oblong tablets with a faint amine odour, engraved with a score-line on one side and 'DN' on the other.

The score-line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical particulars
4.1 Therapeutic indications

Imunovir tablets are indicated in the management of:

a) Mucocutaneous infections due to herpes simplex virus (type 1 and/or type II).

b) Genital warts as adjunctive therapy to podophyllin or carbon dioxide laser.

c) Subacute sclerosing panencephalitis (SSPE).

4.2 Posology and method of administration

Posology

Adults and the Elderly:

The recommended dosage is 50mg/kg – 100mg/kg of body weight usually 3g/day up to a maximum of 4g/day, administered orally in 3-4 equally divided doses during waking hours.

Mucocutaneous herpes simplex: 1 g administered orally 4 times daily, for 7 -14 days.

Genital warts: 1g administered orally 3 times daily, for 14-28 days as adjunctive therapy to podophyllin or carbon dioxide laser.

Subacute sclerosing panencephalitis (SSPE): 50-100mg/kg daily, up to a maximum of 3-4 g, in divided doses every 4 hours, with regular monitoring to evaluate patient status and requirement for extended treatment.

The weight of the patient and the severity of the disease are important factors in determining the dosage.

Children:

No information is available in children.

Method of administration

Oral use

To make ingestion easier, the tablets may be crushed and dissolved in a small amount of flavoured liquid at the time of administration.

4.3 Contraindications

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

Imunovir should not be used where the patient is presently suffering from gout or has elevated uric acid blood levels.

4.4 Special warnings and precautions for use

a) Imunovir may cause a transient elevation of baseline serum and urinary uric acid, usually remaining within the normal range (using 8mg % as the upper limit), particularly in males and in the ageing population of both sexes. The elevation of uric acid levels is due to the catabolic metabolism of the inosine moiety in this product in humans to uric acid. It is not due to a fundamental drug-induced alteration of enzyme or renal clearance function. Therefore, Imunovir may be administered with caution in patients with a history of gout, hyperuricaemia, urolithiasis, or to patients with impaired renal function. During treatment, uric acid levels in these patients should be monitored closely.

b) In the case of long term treatment, the serum and/or urine uric acid levels, liver function, blood count and renal functions should be checked on a regular basis in all patients. There is a possibility that ureteric and biliary calculi may occur when patients receive long term treatment.

In some people acute hypersensitivity reactions (urticaria, angioedema, anaphylaxis) may occur. Treatment with Imunovir should be withdrawn in these cases.

Wheat starch in this medicine contains only very low levels of gluten regarded as gluten-free and is very unlikely to cause problems if you have coeliac disease.

One tablet contains no more than 10.5 micrograms of gluten.

If you have a wheat allergy (different from coeliac disease) you should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

The drug should be used with caution with xanthine oxidase inhibitors or uricosuric agents, including diuretics.

Imunovir may be administered after but not concomitantly with immunosuppressive agents, as there may be a pharmacokinetic influence on the desired therapeutic effects.

Concomitant use with AZT increases AZT nucleotide formation through multiple mechanisms involving increased plasma AZT bioavailability and increased intracellular phosphorylation in human blood monocytes.

As a result Imunovir increases the effect of AZT.

4.6 Fertility, pregnancy and lactation

Controlled trials monitoring foetal risk and impairment of fertility in humans are not available. It is not known if Imunovir is excreted in human milk. Therefore, Imunovir should not be administered during pregnancy or lactation unless the physician decides the benefits outweigh the potential risk.

Although animal tests have shown no teratogenic effect, the use of Imunovir in women where pregnancy is suspected or confirmed should be avoided.

4.7 Effects on ability to drive and use machines

Imunovir has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

During treatment with Imunovir, the only consistently observed drug-related side effects in adults as well as paediatric population is a transient elevation (usually remaining within normal range) of urine and serum uric acid levels, which usually return to baseline values a few days after the end of treatment.

Frequency convention (MedDRA)

Very common

≥1/10

Common

≥1/100, <1/10

Uncommon

≥1/1,000, <1/100

Rare

≥1/10,000, <1/1,000

Very rare

<1/10,000, including isolated reports

Not Known

Cannot be estimated from the available data

System Organ Class

Frequency

Adverse Reaction

Immune system disorders:

Not known

Angioedema, Hypersensitivity, Urticaria, Anaphylactic reaction

Psychiatric disorders

Uncommon

Nervousness

Nervous system disorders

Common

Headache, Vertigo

Uncommon

Somnolence, Insomnia

Not Known

Dizziness

Gastrointestinal disorders:

Common

Vomiting, Nausea, Epigastric discomfort

Uncommon

Diarrhoea, Constipation

Not known

Abdominal pain upper

Skin and subcutaneous tissue disorders

Common

Rash, Pruritus

Not known

Erythema

Musculoskeletal and connective tissue disorders

Common

Arthralgia

Renal and urinary disorders

Uncommon

Polyuria

General disorders and administration site conditions

Common

Fatigue, Malaise

Investigations

Very Common

Blood uric acid increased, Urine uric acid increased

Common

Blood urea increased, Transaminases increased, Blood alkaline phosphate increased

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

There has been no experience of overdose with Imunovir. However, serious adverse effects apart from increased levels of uric acid in the body, seem unlikely in view of the animal toxicity studies. Treatment should be restricted to symptomatic and supportive measures.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other antivirals, ATC code: J05AX05

Imunovir is a synthetic purine derivative with immunomodulatory and antiviral properties, which result from an apparent in vivo enhancement of host immune responses due to the drug.

In clinical studies Imunovir has been shown to normalise (to the patient's baseline) a deficient or dysfunctional cell-mediated immunity by evoking a Th1 type response which initiates T lymphocyte maturation and differentiation and potentiation of induced lymphoproliferative responses, in mitogen or antigen-activated cells. Similarly, the drug has been shown to modulate T lymphocyte and natural killer cell cytotoxicity, T8 suppressor and T4 helper cell functions and also to increase the number of IgG and complement surface markers.

Imunovir increases cytokine IL-1 production and enhances IL-2 production, upregulating the expression of the IL-2 receptor in vitro. It significantly increases endogenous IFN -γ secretion and decreases the IL-4 production in vivo. It has also been shown to potentiate neutrophil, monocyte and macrophage chemotaxis and phagocytosis.

In vivo, inosine acedoben dimeparanol enhances potentiation of depressed lymphocytic mRNA protein synthesis and translational ability while inhibiting viral RNA synthesis achieved by yet-to-be-clarified degrees of (1) incorporation of inosine-mediated orotic acid into polyribosomes; (2) inhibition of polyadenylic acid attachment to viral messenger RNA and (3) molecular reorganisation of lymphocyte intramembrane plasma particles (IMP) that results in a nearly threefold increase in density.

Imunovir inhibits cGMP phosphodiesterase only at high concentrations in vitro and at levels not involved in the in vivo immunopharmacological effects.

5.2 Pharmacokinetic properties

Each moiety of the drug exhibits separate pharmacological properties

Absorption: When administered orally in man, Imunovir is rapidly and completely absorbed (≥ 90%) from the gastrointestinal tract and appears in the blood. Similarly, 94-100% of IV values of DIP [N,N-dimethylamino-2-propanol] and PacBA [p-acetamidobenzoic acid] components are recovered in urine after oral administration in Rhesus monkeys.

Distribution: Radiolabelled material was found in the following tissues in order of decreasing specific activity when drug was administered to monkeys: kidneys, lung, liver, heart, spleen, testes, pancreas, brain and skeletal muscle

Metabolism: In human subjects following a 1 g oral dose of Imunovir, the following plasma levels were found for DIP and PAcBA, respectively: 3.7μg/ml (2 hours) and 9.4μg/ml (1 hour). In human dose tolerance studies, peak post-dose elevation of uric acid levels as a measurement of drug-derived inosine are not linear and can vary + 10% between 1-3 hours.

Excretion: The 24-hour urinary excretion of PAcBA and its major metabolite under steady-state conditions at 4g per day amounted to approximately 85% of the administered dose. 95% of the DIP-derived radioactivity in urine was recovered as unchanged DIP and DIP N-oxide. The elimination half-life is 3.5 hours for DIP and 50 minutes for PAcBA. The major metabolites in humans are the N-oxide for DIP and the o-acylglucuronide for PAcBA. Because the inosine moiety is degraded by the purine degradation pathway to uric acid, radiolabelled experiments in humans are inappropriate. In animals up to about 70% of the administered inosine can be recovered as urinary uric acid following oral tablet administration and the remainder as the normal metabolites, xanthine and hypoxanthine.

Bioavailability/AUC: Urinary recoveries under steady state conditions of the PAcBA moiety and its metabolite were found to be > 90% of the expected value from solution. The recovery of the DIP moiety and its metabolite was >76%. The plasma AUC was >88% for DIP and > 77% for PAcBA.

5.3 Preclinical safety data

Imunovir showed a low toxicity profile in multivariate acute, subacute and chronic toxicology in mice, rats, dogs, cats and monkeys in doses up to 1500mg/kg/day and produced the lowest acute oral LD50 at 50 times the maximum therapeutic dosage level of 100mg/kg/day.

Long-term toxicology studies in mice and rats have shown no indication of carcinogenic potential.

Standard mutagenicity assays and in vivo studies in mice and rats and in vitro studies in human peripheral blood lymphocytes revealed no aberrant properties.

No evidence of perinatal toxicity, embryotoxicity, teratogenicity or impaired reproductive function in mice, rats and rabbits could be demonstrated in studies with continuous parental dosing of up to 20 times the maximum therapeutically recommended human dose (100 mg/kg/day) (See also item 4.6 for usage recommendations in pregnancy.)

6. Pharmaceutical particulars
6.1 List of excipients

Povidone, Mannitol, Wheat Starch, Magnesium Stearate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

5 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

100 (5 x 20) tablets in transparent, colourless PVC/PVDC blister packs sealed with aluminium foil.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Kora Corporation Ltd. (trading as Kora Healthcare)

Swords Business Park,

Swords, Co. Dublin

Ireland.

8. Marketing authorisation number(s)

PL 39972/0001

9. Date of first authorisation/renewal of the authorisation

15th November 1983/ 29th September 2009

10. Date of revision of the text

06/11/2019