Lovrak tablets 800mg are indicated for the treatment of varicella (chickenpox) and herpes zoster (shingles) infections (excluding neonatal HSV and severe HSV infections in immunocompromised children).

Lovrak is recommended in children over the age of 6.

Dosage in adults:

Treatment of varicella and herpes zoster infections: 

800 mg Lovrak 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 the onset of the rash.

Dosage in children:

Treatment of varicella infections:

6 years and over: 800mg Lovrak four times daily.

Treatment should continue for five days.

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

For treatment of neonatal herpes virus infections, intravenous acyclovir is recommended.

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 acyclovir should be maintained.

Dosage in renal impairment:

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

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

Administration

Lovrak tablets are for oral administration, swallowed whole with a little water. Ensure that patients on high doses of acyclovir are adequately hydrated.

Use in patients with renal impairment and in elderly patients:

Acyclovir 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 acyclovir in severely immune-compromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued acyclovir treatment (see section 5.1).

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

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 acyclovir reduces the incidence of chickenpox-associated complications in immunocompetent patients.

Acyclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that compete with this mechanism may increase acyclovir plasma concentrations. Probenecid and cimetidine increase the AUC of acyclovir by this mechanism, and reduce acyclovir renal clearance. Similarly increases in plasma AUCs of acyclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppresant agent used in transplant patients have been shown when the drugs are coadministered. However no dosage adjustment is necessary because of the wide therapeutic index of acyclovir.

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

Pregnancy:

The use of acyclovir should be considered only when the potential benefits outweigh the possibility of unknown risks.

A post-marketing acyclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of Acyclovir. The registry findings have not shown an increase in the number of birth defects amongst Acyclovir 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 acyclovir 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. Findings from reproduction toxicology studies are included in Section 5.3.

Breast-feeding:

Following oral administration of 200 mg Acyclovir five times a day, Acyclovir 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 Acyclovir dosages of up to 0.3 mg/kg/day. Caution is therefore advised if Acyclovir is to be administered to a nursing woman.

Fertility:

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

In a study of 20 male patients with normal sperm count, oral acyclovir 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.

See clinical studies in section 5.2

There have been no studies to investigate the effect of acyclovir 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 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 acyclovir 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.

To report any side effect(s):

§ Saudi Arabia:

  The National Pharmacovigilance Centre (NPC):

-  Fax: +966-11-205-7662

-  SFDA Call Centre: 19999

-  E-mail: npc.drug@sfda.gov.sa

-  Website: https://ade.sfda.gov.sa

§ Other GCC States:

-  Please contact the relevant competent authority.

Acyclovir is only partly absorbed in the gastrointestinal tract.

Patients have ingested overdoses of up to 20g acyclovir on a single occasion, usually without toxic effects. Accidental, repeated overdoses of oral acyclovir over several days have been associated with gastrointestinal effects (such as nausea and vomiting) and neurological effects (headache and confusion).

Overdosage of intravenous acyclovir 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 acyclovir 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.

Acyclovir 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 Acyclovir for HSV I and HSV II and VZV is highly selective. The enzyme thymidine kinase (TK) of normal, uninfected cells does not use Acyclovir effectively as a substrate, hence toxicity to mammalian host cells is low; however, TK encoded by HSV and VZV converts Acyclovir to Acyclovir monophosphate, a nucleoside analogue which is further converted to the diphosphate and finally to the triphosphate by cellular enzymes. Acyclovir 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 Acyclovir in severely immuno-compromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued Acyclovir 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 Acyclovir 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 Acyclovir therapy is not clear.

Absorption

acyclovir is only partially absorbed from the gut. The average oral bioavailability varies between 10 and 20%. Under fasting conditions, mean peak concentrations (Cmax) of 0.4 microgram/ml are achieved at approximately 1.6 hours after a 200 mg dose administered as oral suspension or capsule. Mean peak plasma concentrations (C_ssmax) increase to 0.7 microgram/ml (3.1 micromoles) at steady state following doses of 200 mg administered every four hours. A less than proportional increase is observed for C_ssmax concentration following doses of 400 mg and 800 mg administered fourhourly, with values reaching 1.2 and 1.8 microgram/ml (5.3 and 8 micromoles), respectively.

Distribution

The mean volume of distribution of 26 L indicates that acyclovir is distributed within total body water. Apparent values after oral administration (Vd/F) ranged from 2.3 to 17.8 L/kg. As plasma protein binding is relatively low (9 to 33%), drug interactions involving binding site displacement are not anticipated. Cerebrospinal fluid concentration are approximately 50% of corresponding plasma concentration at steady-state.

Metabolism

acyclovir is predominantly excreted unchanged by the kidney. The only significant urinary metabolite is 9- [(carboxymethoxy) methyl guanine, and accounts for 10-15% of the dose excreted in the urine.

Elimination

In adults mean systemic exposure (AUC0-∞) to acyclovir ranges between 1.9 and 2.2 microgram*h/mL after a 200 mg dose. At this dose, the mean terminal plasma half-life after oral administration has been shown to vary between 2.8 and 4.1 hours.

Renal clearance of acyclovir (CLr= 14.3 L/h) is substantially greater than creatinine clearance, indicating that tubular secretion, in addition to glomerular filtration, contributes to the renal elimination of the drug. The half-life and total clearance of acyclovir are dependent on renal function. Therefore, dosage adjustment is recommended for renally impaired patients.

There are no pharmacokinetic data for the oral formulation in neonates. The only available pharmacokinetic data are for the IV formulation in this age group.

Special patient populations

Elderly

In the elderly patients with normal renal function total clearance falls with increasing age due to decreases in creatinine clearance. However, the possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly.

Renal impairment

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

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

Carcinogenicity: Acyclovir was not found to be carcinogenic in long term studies in the rat and the mouse.

Teratogenicity: Systemic administration of acyclovir 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 acyclovir greatly in excess of those employed therapeutically. Two generation studies in mice did not reveal any effect of acyclovir on fertility.

Inactive Ingredients:

1. Microcrystalline Cellulose (Avicel PH - 102)

2. Sodium Starch Glycolate (Premojel)

3. Maize Starch

4. Magnesium Stearate

5. Purified Water*

Coating Materials:

1. Hydroxypropyl methylcellulose (hypromellose)

2. Polyethylene Glycol - 6000

3. Talc Fine Powder

4. Titanium Dioxide

5. Purified Water*

6. Ethanol 95%*

*Evaporates during manufacturing process and does not appear in the final product.

Note: Quantity of microcrystalline cellulose (Avicel PH - 102) may vary to adjust the potency of Acyclovir.

There are no special requirements for use on handling of this product.

Store below 30˚C.

2x10's tablets in aluminium-PVC blister strips, packed in a printed carton along with a leaflet.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.