Herpiva 500 & 1000 500 mg, 1 g Tablet

HERPIVA is indicated for the:

• treatment of herpes zoster (shingles). HERPIVA reduces the duration of zoster-associated pain, which includes acute and postherpetic neuralgia, thus accelerating resolution of pain. HERPIVA also reduces the proportion of patients with zoster-associated pain.
• episodic treatment of recurrent genital herpes in immunocompetent adult patients.
• prevention (suppression) of recurrent herpes simplex infection of the skin and mucous membrane of the ano-genital area.
• prophylaxis of cytomegalovirus (CMV) infection, CMV disease and other herpes virus infections following organ transplantation, where a special risk exists.

Posology

Dosage in adults:

For treatment of herpes zoster: 1 g of HERPIVA to be taken three times per day for seven days.

Recurrent genital herpes: The recommended dosage for the treatment of recurrent genital herpes is 500 mg twice daily for 5 days. Dosing should begin as early as possible. For recurrent episodes of herpes simplex, this should ideally be during the prodromal period or immediately the first signs or symptoms appear. There are no data on the effectiveness of HERPIVA when initiated more than 24 hours after the onset of signs and symptoms.

For the prevention (suppression) of recurrences of herpes simplex infection:

Immunocompetent patients: 500 mg to be taken once daily. Some patients with very frequent recurrences (e.g. 10 or more per year) may gain additional benefit from the daily dose of 500 mg being taken as a divided dose (250 mg twice daily).

Immunocompromised patients: 500 mg twice daily.

Prophylaxis of cytomegalovirus infection (CMV) and disease: Adults and adolescents (from 12 years of age): 2 g to be taken four times a day. Dosing should be initiated as early as possible post-transplant. This dose should be reduced according to creatinine clearance (see renal impairment below). The duration of treatment will usually be 90 days but may need to be extended in high risk patients.

Special populations

Elderly population: The possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly (see renal impairment below). Adequate hydration should be maintained.

Renal impairment: Caution is advised when administering HERPIVA to patients with impaired renal function. Adequate hydration should be maintained. The dose of HERPIVA should be modified as follows in patients with significantly impaired renal function:

Therapeutic indication

Creatinine Clearance

HERPIVA Dose

Herpes zoster

15 - 30 mL/min

< 15 mL/min

1 g twice a day

1 g once a day

Recurrent genital herpes

> 15 mL/min

0- 15 mL/min

500 mg twice daily

500 mg once daily

Prevention of recurrences

Immunocompetent

15 - 30 mL/min

No dosage adjustment

< 15 mL/min

HERPIVA is not recommended for use, as it does not contain a 250 mg strength in a single dose.

Immunocompromised

15 - 30 mL/min

< 15 mL/min

No dosage adjustment

500 mg once daily

CMV prophylaxis: The dosage of HERPIVA should be adjusted in patients with impaired renal function as shown in the table below:

Creatinine Clearance

HERPIVA Dose

u2265 75 mL/min

2 g four times daily

50 to < 75 mL/min

1 500 mg four times daily

25 to < 50 mL/min

1 500 mg three times daily

10 to < 25 mL/min

1 500 mg twice daily

< 10 mL/min or dialysis **

1 500 mg once daily

** In patients on haemodialysis, the HERPIVA dosage recommended for patients with a creatinine clearance of less than 15 ml/min should be used, but the dose should be administered after the haemodialysis has been performed. HERPIVA is not recommended for use, as it does not contain a 250 mg strength in a single dose. The creatinine clearance should be monitored frequently, especially during periods when renal function is changing rapidly e.g. immediately after transplantation or engraftment. The HERPIVA dosage should be adjusted accordingly.

Hepatic impairment: Dose modification is not required in patients with mild or moderate cirrhosis (hepatic synthetic function maintained). Pharmacokinetic data in patients with advanced cirrhosis (impaired hepatic synthetic function and evidence of portal-systemic shunting) do not indicate the need for dosage adjustment; however, clinical experience is limited. For higher doses (4 g or more) see section 4.8

Paediatric population: No data are available.

Hypersensitivity to valaciclovir or aciclovir or any of the excipients listed in section 6.1.

Drug reaction with eosinophilia and systemic symptoms (DRESS) DRESS, which can be life-threatening or fatal, has been reported in associate with valaciclovir as in HERPIVA treatment. At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of DRESS appear, HERPIVA should be withdrawn immediately, and an alternative treatment considered (as appropriate). If the patient has developed DRESS with the use of HERPIVA, treatment must not be restarted in this patient at any time.

Hydration status: Care should be taken to ensure adequate fluid intake in patients who are at risk of dehydration, particularly the elderly.

Use for HZV treatment: Clinical response should be closely monitored, particularly in immunocompromised patients. Consideration should be given to intravenous antiviral therapy when response to oral therapy is considered insufficient. Patients with complicated herpes zoster, i.e. those with visceral involvement, disseminated zoster, motor neuropathies, encephalitis and cerebrovascular complications should be treated with intravenous antiviral therapy. Moreover, immunocompromised patients with ophthalmic zoster or those with a high risk for disease dissemination and visceral organ involvement should be treated with intravenous antiviral therapy.

Transmission of genital herpes: Patients should be advised to avoid intercourse when symptoms are present even if treatment with an antiviral has been initiated. Continuous therapy with HERPIVA in patients with recurrent genital herpes reduces the risk of transmitting genital herpes. It does not cure genital herpes or completely eliminate the risk of transmission. In addition to therapy with valaciclovir, it is recommended that patients use safer sex practices. As genital herpes is a sexually transmitted infection, patients should, in order to further reduce the risk of infecting partners, avoid contact with lesions, damaged skin/mucosa, and avoid intercourse when lesions and/or symptoms are present. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding; therefore patients should be counselled to use safer sex practices. The effect of HERPIVA on transmission of sexually transmitted infections other than herpes (including HIV, gonorrhoea, syphilis and Chlamydia) is unknown. The efficacy of HERPIVA for reducing transmission of genital herpes has not been established in individuals with multiple partners, non-heterosexual couples and couples not counselled to use safer sex practises.

Use in ocular HSV infections: Clinical response should be closely monitored in these patients. Consideration should be given to intravenous antiviral therapy when response to oral therapy is unlikely to be sufficient.

Use in CMV infections: Transplant patients (~ 200) at high risk of CMV disease (e.g. donor CMV-positive/recipient CMV negative or use of anti-thymocyte globulin induction therapy) should only use HERPIVA when safety concerns preclude the use of valganciclovir or ganciclovir. High dose HERPIVA as required for CMV prophylaxis may result in more frequent adverse events, including CNS abnormalities, than observed with lower doses administered for other indications (see section 4.8). Patients should be closely monitored for changes in renal function, and doses adjusted accordingly (see section 4.2).

Renal impairment and elderly patients: Aciclovir is eliminated by renal clearance, therefore the dose of HERPIVA must be reduced in patients with renal impairment (see section 4.2). Elderly patients are likely to have reduced renal function and therefore the need for dose reduction 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. These reactions are generally reversible on discontinuation of treatment (see section 4.8).

Use of higher doses of HERPIVA in hepatic impairment and liver transplantation: There are no data available on the use of higher doses of HERPIVA (4000 mg or more per day) in patients with liver disease. Caution should be exercised when administering daily doses greater than 4000 mg to these patients.

Nephrotoxic medicines: The combination of HERPIVA with nephrotoxic medicines should be made with caution, especially in patients with impaired renal function, and warrants regular monitoring of renal function. This applies to concomitant administration with aminoglycosides, organoplatinum compounds, iodinated contrast media, methotrexate, pentamidine, foscarnet, ciclosporin, and tacrolimus.

Active tubular secretion inhibitors or competitors: Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Cimetidine and probenecid taken together with HERPIVA increases aciclovir concentrations. Other medicines (including e.g. tenofovir) administered concurrently that compete with or inhibit active tubular secretion may increase aciclovir concentrations by this mechanism. Similarly, HERPIVA administration may increase plasma concentrations of the concurrently administered substance.

In patients receiving higher aciclovir exposures from HERPIVA (e.g. at doses for zoster treatment or CMV prophylaxis), caution is required during concurrent administration with medicines which inhibit active renal tubular secretion.

Immunosuppressant medicines: Increases in plasma AUCs of aciclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant medicine used in transplant patients, have been shown when the medicines are co-administered.

Pregnancy: Safety in pregnancy has not been established.

Breastfeeding: Following oral administration of a 500 mg dose of HERPIVA, peak acyclovir concentrations (Cmax) in breast milk ranged from 0,5 to 2,3 (median 1,4) times the corresponding maternal acyclovir serum concentrations. Mothers on treatment with HERPIVA should not breastfeed their infants.

Fertility: Aciclovir did not affect fertility in rats dosed by the oral route. At high parenteral doses of aciclovir testicular atrophy and aspermatogenesis have been observed in rats and dogs. No human fertility studies were performed with HERPIVA, but there were no changes in sperm count, motility or morphology in 20 patients after 6 months of daily treatment with 400 to 1 g aciclovir.

HERPIVA may cause dizziness which may influence the ability to drive and use machines. Patients should not drive or operate machines until they know how HERPIVA affects them.

Blood and lymphatic system disorders

Less frequent: Leucopenia, thrombocytopenia

Immune system disorders

Less frequent: Anaphylaxis

Psychiatric and nervous system disorders

Frequent: Dizziness

Less frequent: Confusion, hallucinations, decreased consciousness, tremor, agitation, ataxia, dysarthria, convulsions, encephalopathy, coma, psychotic symptoms, delirium.

Nervous system disorders

Frequent: Headache

Respiratory, thoracic, and mediastinal disorders

Less frequent: Dyspnoea

Gastrointestinal disorders

Frequent: Vomiting, diarrhoea, nausea

Less frequent: Abdominal discomfort

Hepato-biliary disorders

Less frequent: Reversible increases in liver function tests (e.g. bilirubin, liver enzymes).

Skin and subcutaneous tissue disorders

Frequent: Rashes including photosensitivity, pruritus

Less frequent: Urticaria, angioedema

Frequency unknown: Drug reaction with eosinophilia and systemic symptoms (DRESS) (see section 4.4)

Renal and urinary disorders

Less frequent: Renal pain, haematuria (often associated with other renal events). Renal impairment, acute renal failure (especially in elderly patients or in patients with renal impairment receiving higher than the recommended doses).

Additional information on special populations: There have been reports of renal insufficiency, microangiopathic hemolytic anaemia and thrombocytopenia (sometimes in combination) in severely immunocompromised adult patients, particularly those with advanced HIV disease, receiving high doses (8000 mg daily) of valaciclovir for prolonged periods in clinical trials. These findings have also been observed in patients not treated with valaciclovir who have the same underlying or concurrent conditions.

Reporting side effects: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://sahpra.org.za/wp-content/uploads/2020/01/6.04_ARF1_v5.1_27Jan2020.pdf

Symptoms and Signs: Acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, decreased consciousness, and coma, have been reported in patients receiving overdoses of valaciclovir. Nausea and vomiting may also occur. Caution is required to prevent inadvertent overdosing. Many of the reported cases involved renally impaired and elderly patients receiving repeated overdoses, due to lack of appropriate dosage reduction.

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