Valaciclovir 500 / 1000 Unicorn 500 mg / 1000 mg FC tablet

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

Dosage in adults

For treatment of herpes zoster
1 000 mg of VALACICLOVIR UNICORN 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 when treatment is 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.
• Immunocompromised patients: 500 mg twice daily.

Prophylaxis of cytomegalovirus infection (CMV) and disease
Adults and adolescents (from 12 years of age) 2 000 mg 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 Dosage in renal impairment). The duration of treatment will usually be 90 days, but may need to be extended in high risk patients.

Special populations

Dosage in children
No data are available.

Dosage in the elderly
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.

Dosage in renal impairment
Caution is advised when administering VALACICLOVIR UNICORN to patients with impaired renal function. Adequate hydration should be maintained. The dose of VALACICLOVIR UNICORN should be adjusted as follows in patients with significantly impaired renal function:

Therapeutic indication

• Creatinine Clearance
• VALACICLOVIR UNICORN Dose

Herpes zoster

• 15 - 30 ml/min: 1 000 mg twice a day
• <15 ml/min: 1 000 mg once a day

Recurrent genital herpes

• > 15 ml/min: 500 mg twice daily
• Prevention of recurrences
• 0-15 ml/min: 500 mg once daily

Immunocompetent

• 15-30 ml/min: No dosage adjustment
• <15 ml/min: 250 mg* once daily

Immunocompromised

• 15-30 ml/min: No dosage adjustment
• <15 ml/min: 500 mg once daily

* VALACICLOVIR UNICORN 500 is not a scored tablet. In patients on haemodialysis the VALACICLOVIR UNICORN dose 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.

CMV prophylaxis
In patients with impaired renal function, the dosage of VALACICLOVIR UNICORN should be adjusted as shown in the table below:

Creatinine Clearance

• VALACICLOVIR UNICORN Dose

u2265 75 ml/min: 2 000 mg 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 VALACICLOVIR UNICORN dosage should be administered after the haemodialysis has been performed. Creatinine clearance should be monitored frequently, especially during periods when renal function is changing rapidly e.g. immediately after transplantation or engraftment. The dosage of VALACICLOVIR UNICORN should be adjusted accordingly.

Dosage in hepatic impairment
In patients with mild or moderate cirrhosis (hepatic synthetic function maintained) dose modification is not required. 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.

VALACICLOVIR UNICORN is contraindicated in patients known to be hypersensitive to valaciclovir, aciclovir or any of the excipients listed in section 6.1.

In patients with advanced HIV disease and also in bone marrow transplant and renal transplant recipientsu2019 u2018thrombotic, thrombocytopenic purpura/haemolytic uremic syndromeu2019 (in some cases fatal) has been reported. This syndrome has not been observed in immunocompetent patients.

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

Use in patients with renal impairment and in elderly patients
The dose of VALACICLOVIR UNICORN should be adjusted in patients with renal impairment as aciclovir is eliminated by renal clearance (see section 4.2: Dosage in renal impairment). Dose reduction must be considered in the elderly as they are likely to have reduced renal function. Both elderly patients and patients with renal impairment are at increased risk of developing neurological side effects and should be closely monitored. It has been reported that these reactions were generally reversible on discontinuation of treatment (see section 4.8).

Uses of higher doses of VALACICLOVIR UNICORN in hepatic impairment and liver transplantation
There are no data available on the use of high doses of VALACICLOVIR UNICORN (4 g or more per day) in patients with liver disease. Caution should therefore be exercised when administering high doses of VALACICLOVIR UNICORN to these patients.

Use for zoster 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.

Use in genital herpes
Suppressive treatment with VALACICLOVIR UNICORN reduces the risk of transmitting genital herpes. It does not cure genital herpes. The frequency of viral shedding is significantly reduced. However, the risk of transmission is still possible. In addition to therapy with VALACICLOVIR UNICORN, it is recommended that patients use safer sex practices.

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 adequate.

Use in CMV infections
Data on the efficacy of valaciclovir from transplant patients at high risk of CMV disease (e.g. donor CMV-positive/recipient CMV negative or use of anti-thymocyte globulin induction therapy) indicate that valaciclovir should only be used in these patients when safety concerns prohibit the use of valganciclovir or ganciclovir. High dose valaciclovir 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).

The combination of valaciclovir with nephrotoxic medicines should be used with caution, especially in subjects 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, foscamet, ciclosporin, and tacrolimus. Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion.

Following 1000 mg valaciclovir, cimetidine and probenecid reduce aciclovir renal clearance and increase the AUC of aciclovir by inhibition of the active renal secretion of aciclovir. Cimetidine and probenecid taken together with valaciclovir increased aciclovir AUC; however no dosage adjustment is necessary because of the wide therapeutic index of aciclovir. Other medicines (including e.g. tenofovir) administered concurrently that compete with or inhibit active tubular secretion may increase aciclovir concentrations by this mechanism. Similarly, valaciclovir administration may increase plasma concentrations of the concurrently administered substance. In patients receiving high doses of VALACICLOVIR UNICORN (8 g/day) for CMV prophylaxis, caution is required during concurrent administration with medicines which compete with aciclovir for elimination, because of the potential for increased plasma levels of one or both medicines or their metabolites. 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. There is limited clinical experience with the use of this combination. No significant increase in toxicity was noted when zidovudine and aciclovir is administered concomitantly.

Pregnancy
Safety in pregnancy has not been established.

Lactation
Aciclovir, the principle metabolite of valaciclovir, is excreted in breast milk. Mothers on treatment with VALACICLOVIR UNICORN should not breastfeed their infants.

Fertility
No human fertility studies were performed with valaciclovir, but no changes in sperm count, motility or morphology were reported in 20 patients after 6 months of daily treatment with 400 to 1000 mg aciclovir.

No studies on the effects on the ability to drive and use machines have been performed. The clinical status of the patient and the undesirable effects of VALACICLOVIR UNICORN should be borne in mind when considering the patient's ability to drive or operate machinery. Further, a detrimental effect on such activities cannot be predicted from the pharmacology of the active substance.

Adverse reactions reported from clinical trials

Nervous system disorders: Frequent: Headache

Gastrointestinal disorders: Frequent: Nausea

Tabulated summary of adverse reactions reported post-marketing

System Organ Class Frequency Side effect

Blood and the lymphatic system disorders Less frequent Aplastic anaemia, thrombocytopenia, thrombotic

Frequency unknown thrombocytopenia, purpura, haemolytic uraemic syndrome, and leukopenia (mainly reported in immunocompromised patients). Microangiopathic haemolytic anaemia.

Immune system disorders Less frequent Anaphylaxis.

Psychiatric disorders Less frequent Agitation, somnolence, psychotic symptoms, delirium and hallucinations. Frequency unknown Aggressive behaviour

Nervous system disorders Frequent Less frequent Dizziness. Confusion, decreased consciousness, tremor, convulsions, ataxia, dysarthria, convulsions, encephalopathy and coma.

Cardiac disorders Frequency unknown Tachycardia

Vascular disorders Frequency unknown Hypertension

Respiratory, thoracic and mediastinal disorders Less frequent Dyspnoea

Gastrointestinal disorders Frequent Less frequent Vomiting and diarrhoea. Abdominal discomfort.

Hepato - biliary disorders Less frequent Reversible increases in liver function tests (e.g. bilirubin, liver enzymes), occasionally described as hepatitis.

Skin and subcutaneous tissue disorders Frequent Less frequent Rashes including photosensitivity and pruritus. Urticaria and angioedema.

Musculoskeletal and connective tissue disorders Frequency unknown Arthralgia

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).

Neurological disorders (sometimes severe) may be related to encephalopathy and include confusion, agitation, convulsions, hallucinations, coma. These adverse events are generally reversible and usually seen in patients with renal impairment or with other predisposing factors (see section 4.4). In organ transplant patients receiving high doses (8 g daily) of valaciclovir for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses used for other indications.

Renal pain may be associated with renal failure. Intratubular precipitation of aciclovir crystals in the kidney has also been reported. Adequate fluid intake should be ensured during treatment (see section 4.4).

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the 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://www.sahpra.org.za/Publications/Index/8. Adverse reactions must also be reported to Unicorn Pharmaceuticals (Pty) Ltd to [email protected]

Symptoms and signs
There have been reported cases of acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, decreased consciousness and coma. Nausea and vomiting may also occur. Many of these reported cases involved renally impaired and elderly patients receiving repeated overdoses, due to lack of appropriate dosage reduction.

Management of overdose
Treatment is symptomatic and supportive. Patients should be observed closely for signs of toxicity. In the event of a symptomatic VALACICLOVIR UNICORN overdose occurring, aciclovir is removable by haemodialysis.