Cycloviral SEDICO

Cycloviral SEDICO Tablets are indicated for the treatment of herpes simplex virus infections of the skin and mucous membranes including initial and recurrent genital herpes (excluding neonatal HSV and severe HSV infections in immunocompromised children).

Cycloviral SEDICO Tablets are indicated for the suppression (prevention of recurrences) of recurrent herpes simplex infections in immunocompetent patients.

Cycloviral SEDICO Tablets are indicated for the prophylaxis of herpes simplex infections in immunocompromised patients.

Cycloviral SEDICO Tablets are indicated for the treatment of varicella (chickenpox) and herpes zoster (shingles) infections.

Posology

Dosage in adults

Treatment of herpes simplex infections: 200 mg Cycloviral SEDICO should be taken five times daily at approximately four hourly intervals omitting the night time dose. Treatment should continue for 5 days, but in severe initial infections this may have to be extended.

In severely immunocompromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut the dose can be doubled to 400 mg Cycloviral SEDICO, or alternatively, intravenous dosing could be considered.

Dosing should begin as early as possible after the start of an infection; for recurrent episodes this should preferably be during the prodromal period or when lesions first appear.

Suppression of herpes simplex infections in immunocompetent patients: 200 mg Cycloviral SEDICO should be taken four times daily at approximately six-hourly intervals.

Many patients may be conveniently managed on a regimen of 400 mg Cycloviral SEDICO twice daily at approximately twelve-hourly intervals.

Dosage titration down to 200 mg Cycloviral SEDICO taken thrice daily at approximately eight-hourly intervals or even twice daily at approximately twelve-hourly intervals may prove effective.

Some patients may experience break-through infection on total daily doses of 800 mg Cycloviral SEDICO.

Therapy should be interrupted periodically at intervals of six to twelve months, in order to observe possible changes in the natural history of the disease.

Prophylaxis of herpes simplex infections in immunocompromised patients: 200 mg Cycloviral SEDICO should be taken four times daily at approximately six-hourly intervals.

In severely immunocompromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut, the dose can be doubled to 400 mg Cycloviral SEDICO, or alternatively, intravenous dosing could be considered.

The duration of prophylactic administration is determined by the duration of the period at risk.

Treatment of varicella and herpes zoster infections: 800 mg Cycloviral SEDICO should be taken five times daily at approximately four-hourly intervals, omitting the night time dose. Treatment should continue for seven days.

In severely immunocompromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut, consideration should be given to intravenous dosing.

Dosing should begin as early as possible after the start of an infection: Treatment of herpes zoster yields better results if initiated as soon as possible after the onset of the rash. Treatment of chickenpox in immunocompetent patients should begin within 24 hours after onset of the rash.

Paediatric population

Treatment of herpes simplex infections, and prophylaxis of herpes simplex infections in the immunocompromised: Children aged two years and over should be given adult dosages and children below the age of two years should be given half the adult dose.

For treatment on neonatal herpes virus infections, intravenous Cycloviral SEDICO is recommended.

Treatment of varicella infection

6 years and over: 800 mg Cycloviral SEDICO four times daily

2 - 5 years: 400 mg Cycloviral SEDICO four times daily

Under 2 years: 200 mg Cycloviral SEDICO four times daily

Treatment should continue for five days.

Dosing may be more accurately calculated as 20 mg/kg bodyweight (not to exceed 800 mg) Cycloviral SEDICO four times daily.

No specific data are available on the suppression of herpes simplex infections or the treatment of herpes zoster infections in immunocompetent children.

Dosage in the elderly

The possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly (see Dosage in renal impairment below). Adequate hydration of elderly patients taking high oral doses of Cycloviral SEDICO should be maintained.

Dosage in renal impairment

Caution is advised when administering Cycloviral SEDICO to patients with impaired renal function. Adequate hydration should be maintained.

In the management of herpes simplex infections in patients with impaired renal function, the recommended oral doses will not lead to accumulation of Cycloviral SEDICO above levels that have been established safe by intravenous infusion. However for patients with severe renal impairment (creatinine clearance less than 10 ml/minute) an adjustment of dosage to 200 mg Cycloviral SEDICO twice daily at approximately twelve-hourly intervals is recommended.

In the treatment of herpes zoster infections it is recommended to adjust the dosage to 800 mg Cycloviral SEDICO twice daily at approximately twelve hourly intervals for patients with severe renal impairment (creatinine clearance less than 10 ml/minute), and to 800 mg Cycloviral SEDICO three times daily at intervals of approximately eight hours for patients with moderate renal impairment (creatinine clearance in the range 10 - 25 ml/minute).

Method of administration:

Oral.

Cycloviral SEDICO tablets may be dispersed in a minimum of 50 ml of water or swallowed whole with a little water. Ensure that patients on high doses of Cycloviral SEDICO are adequately hydrated.

Use in patients with renal impairment and in elderly patients:

Cycloviral SEDICO is eliminated by renal clearance, therefore the dose must be adjusted in patients with renal impairment (see 4.2 Posology and Method of Administration).

Elderly patients are likely to have reduced renal function and therefore the need for dose adjustment must be considered in this group of patients. Both elderly patients and patients with renal impairment are at increased risk of developing neurological side effects and should be closely monitored for evidence of these effects. In the reported cases, these reactions were generally reversible on discontinuation of treatment (see 4.8 Undesirable Effects).

Prolonged or repeated courses of Cycloviral SEDICO in severely immune-compromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued Cycloviral SEDICO treatment.

Hydration status: Care should be taken to maintain adequate hydration in patients receiving high oral doses of Cycloviral SEDICO.

The risk of renal impairment is increased by use with other nephrotoxic drugs.

The data currently available from clinical studies is not sufficient to conclude that treatment with Cycloviral SEDICO reduces the incidence of chickenpox-associated complications in immunocompetent patients.

Paediatric population:

Oral Cycloviral SEDICO should be used in paediatric population mainly for the treatment of non-severe skin and mucosa HSV infections. For the treatment of neonatal HSV and severe HSV infections in immunocompromised children IV Cycloviral SEDICO should be used.

There have been no studies to investigate the effect of Cycloviral SEDICO on driving performance or the ability to operate machinery. A detrimental effect on such activities cannot be predicted from the pharmacology of the active substance, but the adverse event profile should be borne in mind.

Prolonged or repeated courses of Cycloviral SEDICO in severely immune-compromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued Cycloviral SEDICO treatment.

Hydration status: Care should be taken to maintain adequate hydration in patients receiving high oral doses of Cycloviral SEDICO.

The risk of renal impairment is increased by use with other nephrotoxic drugs.

The data currently available from clinical studies is not sufficient to conclude that treatment with Cycloviral SEDICO reduces the incidence of chickenpox-associated complications in immunocompetent patients.

Paediatric population:

Oral Cycloviral SEDICO should be used in paediatric population mainly for the treatment of non-severe skin and mucosa HSV infections. For the treatment of neonatal HSV and severe HSV infections in immunocompromised children IV Cycloviral SEDICO should be used.

Cycloviral SEDICO is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that compete with this mechanism may increase Cycloviral SEDICO plasma concentrations.

Probenecid and cimetidine increase the AUC of Cycloviral SEDICO by this mechanism, and reduce Cycloviral SEDICO renal clearance. Similarly increases in plasma AUCs of Cycloviral SEDICO and of the inactive metabolite of mycophenolate mofetil, an immunosuppresant agent used in transplant patients have been shown when the drugs are co administered. However no dosage adjustment is necessary because of the wide therapeutic index of Cycloviral SEDICO.

An experimental study on five male subjects indicates that concomitant therapy with Cycloviral SEDICO increases AUC of totally administered theophylline with approximately 50%. It is recommended to measure plasma concentrations during concomitant therapy with Cycloviral SEDICO.

Pregnancy

The use of Cycloviral SEDICO should be considered only when the potential benefits outweigh the possibility of unknown risks. A post-marketing Cycloviral SEDICO pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of Cycloviral SEDICO. The registry findings have not shown an increase in the number of birth defects amongst Cycloviral SEDICO exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause. Systemic administration of Cycloviral SEDICO in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rabbits, rats or mice. In a non-standard test in rats, foetal abnormalities were observed but only following such high subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.

Caution should however be exercised by balancing the potential benefits of treatment against any possible hazard.

Breastfeeding

Following oral administration of 200 mg Cycloviral SEDICO five times a day, Cycloviral SEDICO has been detected in breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding plasma levels. These levels would potentially expose nursing infants to Cycloviral SEDICO dosages of up to 0.3 mg/kg/day. Caution is therefore advised if Cycloviral SEDICO is to be administered to a nursing woman.

Fertility

There is no information on the effect of Cycloviral SEDICO on human female fertility.

In a study of 20 male patients with normal sperm count, oral Cycloviral SEDICO administered at doses of up to 1g per day for up to six months has been shown to have no clinically significant effect on sperm count, motility or morphology.

There have been no studies to investigate the effect of Cycloviral SEDICO on driving performance or the ability to operate machinery. A detrimental effect on such activities cannot be predicted from the pharmacology of the active substance, but the adverse event profile should be borne in mind.

The frequency categories associated with the adverse events below are estimates. For most events, suitable data for estimating incidence were not available. In addition, adverse events may vary in their incidence depending on the indication.

The following convention has been used for the classification of undesirable effects in terms of frequency: Very common > 1/10, common > 1/100 and < 1/10, uncommon > 1/1000 and < 1/100, rare > 1/10,000 and < 1/1000, very rare < 1/10,000

Blood and the lymphatic system disorders:

Very rare: Anaemia, leukopenia, thrombocytopenia.

Immune system disorders:

Rare: Anaphylaxis.

Psychiatric and nervous system disorders:

Common: Headache, dizziness.

Very rare: Agitation, confusion, tremor, ataxia, dysarthria, hallucinations, psychotic symptoms, convulsions, somnolence, encephalopathy, coma.

The above events are generally reversible and usually reported in patients with renal impairment or with other predisposing factors (see 4.4 Special Warnings and Precautions for Use).

Respiratory, thoracic and mediastinal disorders:

Rare: Dyspnoea.

Gastrointestinal disorders:

Common: Nausea, vomiting, diarrhoea, abdominal pains.

Hepato-biliary disorders:

Rare: Reversible rises in bilirubin and liver related enzymes.

Very rare: Hepatitis, jaundice.

Skin and subcutaneous tissue disorders:

Common: Pruritus, rashes (including photosensitivity).

Uncommon: Urticaria. Accelerated diffuse hair loss. Accelerated diffuse hair loss has been associated with a wide variety of disease processes and medicines, the relationship of the event to Cycloviral SEDICO therapy is uncertain.

Rare: Angioedema.

Renal and urinary disorders:

Rare: Increases in blood urea and creatinine.

Very rare: Acute renal failure, renal pain.

Renal pain may be associated with renal failure and crystalluria.

General disorders and administration site conditions:

Common: fatigue, fever.

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.

Symptoms and signs

Cycloviral SEDICO is only partly absorbed in the gastrointestinal tract. Patients have ingested overdoses of up to 20g Cycloviral SEDICO on a single occasion, usually without toxic effects. Accidental, repeated overdoses of oral Cycloviral SEDICO over several days have been associated with gastrointestinal effects (such as nausea and vomiting) and neurological effects (headache and confusion).

Overdosage of intravenous Cycloviral SEDICO has resulted in elevations of serum creatinine, blood urea nitrogen and subsequent renal failure. Neurological effects including confusion, hallucinations, agitation, seizures and coma have been described in association with intravenous overdosage.

Management

Patients should be observed closely for signs of toxicity. Haemodialysis significantly enhances the removal of Cycloviral SEDICO from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.

Pharmacotherapeutic group: Direct acting antivirals, Nucleosides and nucleotides excl. reverse transcriptase inhibitors.

ATC code: J05AB01

Cycloviral SEDICO is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including herpes simplex virus (HSV) types I and II and varicella zoster virus (VZV).

The inhibitory activity of Cycloviral SEDICO for HSV I, HSV II and VZV is highly selective. The enzyme thymidine kinase (TK) of normal, uninfected cells does not use Cycloviral SEDICO effectively as a substrate, hence toxicity of mammalian host cells is low; however, TK encoded by HSV and VZV converts Cycloviral SEDICO to Cycloviral SEDICO monophosphate, a nucleoside analogue which is further converted to the diphosphate and finally to the triphosphate by cellular enzymes. Cycloviral SEDICO triphosphate interferes with the viral DNA polymerase and inhibits viral DNA replication with resultant chain termination following its incorporation into the viral DNA.

Prolonged or repeated courses of Cycloviral SEDICO in severely immuno-compromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued Cycloviral SEDICO treatment. Most of the clinical isolates with reduced sensitivity have been relatively deficient in viral TK, however, strains with altered viral TK or viral DNA polymerase have also been reported. In vitro exposure of HSV isolates to Cycloviral SEDICO can also lead to the emergence of less sensitive strains. The relationship between the in vitro-determined sensitivity of HSV isolates and clinical response to Cycloviral SEDICO therapy is not clear.

Cycloviral SEDICO is only partially absorbed from the gut. Mean steady state peak plasma concentrations (C^ssmax) following doses of 200 mg administered four-hourly were 3.1 microMol (0.7 micrograms/ml) and equivalent trough plasma levels (C^ssmin) were 1.8 microMol (0.4 micrograms/ml). Corresponding C^ssmax levels following doses of 400 mg and 800 mg administered four-hourly were 5.3 microMol (1.2 micrograms/ml) and 8 microMol (1.8 micrograms/ml) respectively and equivalent C^ssmin levels were 2.7 microMol (0.6 micrograms/ml) and 4 microMol (0.9 micrograms/ml).

In adults the terminal plasma half-life of Cycloviral SEDICO after administration of intravenous Cycloviral SEDICO is about 2.9 hours. Most of the drug is excreted unchanged by the kidney. Renal clearance of Cycloviral SEDICO is substantially greater than creatinine clearance, indicating that tubular secretion, in addition to glomerular filtration contributes to the renal elimination of the drug. 9-carboxymethoxymethylguanine is the only significant metabolite of Cycloviral SEDICO, and accounts for approximately 10 - 15% of the administered dose recovered from the urine. When Cycloviral SEDICO is given one hour after 1 gram of probenecid the terminal half-life and the area under the plasma concentration time curve is extended by 18% and 40% respectively.

In adults, mean steady state peak plasma concentrations (C^ssmax) following a one hour infusion of 2.5 mg/kg, 5 mg/kg and 10 mg/kg were 22.7 microMol (5.1 micrograms/ml), 43.6 microMol (9.8 micrograms/ml) and 92 microMol (20.7 micrograms/ml), respectively. The corresponding trough levels (C^ssmin) 7 hours later were 2.2 microMol (0.5 micrograms/ml), 3.1 microMol (0.7 micrograms/ml), and 10.2 microMol (2.3 micrograms/ml), respectively.

In children over 1 year of age similar mean peak (C^ssmax) and trough (C^ssmin) levels were observed when a dose of 250 mg/m² was substituted for 5 mg/kg and a dose of 500 mg/m² was substituted for 10 mg/kg. In neonates and young infants (0 to 3 months of age) treated with doses of 10 mg/kg administered by infusion over a one-hour period every 8 hours the C^ssmax was found to be 61.2 microMol (13.8 micrograms/ml) and C^ssmin to be 10.1 microMol (2.3 micrograms/ml). The terminal plasma half-life in these patients was 3.8 hours. A separate group of neonates treated with 15 mg/kg every 8 hours showed approximate dose proportional increases, with a Cmax of 83.5 micromolar (18.8 microgram/ml) and Cmin of 14.1 micromolar (3.2 microgram/ml).

In the elderly, total body clearance falls with increasing age associated with decreases in creatinine clearance although there is little change in the terminal plasma half-life.

In patients with chronic renal failure the mean terminal half-life was found to be 19.5 hours. The mean Cycloviral SEDICO half-life during haemodialysis was 5.7 hours. Plasma Cycloviral SEDICO levels dropped approximately 60% during dialysis.

Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels. Plasma protein binding is relatively low (9 to 33%) and drug interactions involving binding site displacement are not anticipated.

Mutagenicity:

The results of a wide range of mutagenicity tests in vitro and in vivo indicate that Cycloviral SEDICO is unlikely to pose a genetic risk to man.

Carcinogenicity:

Cycloviral SEDICO was not found to be carcinogenic in long term studies in the rat and the mouse.

Teratogenicity:

Systemic administration of Cycloviral SEDICO in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rats, rabbits or mice.

In a non-standard test in rats, foetal abnormalities were observed, but only following such high subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.

Fertility:

Largely reversible adverse effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported only at doses of Cycloviral SEDICO greatly in excess of those employed therapeutically. Two generation studies in mice did not reveal any effect of Cycloviral SEDICO on fertility.

Not applicable.

Not applicable.