Valtrex: composition and pharmaceutical form
One tablet contains 500 mg of valaciclovir as the hydrochloride. It is an antiviral against the herpes group of viruses, and every treatment regimen is built from the number of tablets and how often they are taken.
Valaciclovir is the L-valine ester of aciclovir, that is, a prodrug: in the body it breaks down rapidly and almost completely into aciclovir and valine, most probably with the help of an enzyme called valaciclovir hydrolase. That form exists so that oral dosing delivers markedly more active substance into the blood than aciclovir itself.
How Valtrex works
Aciclovir is an analogue of the purine nucleoside guanine. It selectively suppresses the multiplication of herpes group viruses and in vitro acts on herpes simplex virus types 1 and 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6).
The selectivity comes from the fact that the first step of activation requires a virus-specific enzyme. For HSV, VZV and EBV this is viral thymidine kinase, present only in infected cells; for CMV the specificity of phosphorylation is at least partly provided by a phosphotransferase, the product of the UL97 gene. The conversion from monophosphate to triphosphate is completed by cellular kinases. Aciclovir triphosphate is a competitive inhibitor of viral DNA polymerase, and its incorporation into the DNA molecule terminates chain synthesis: viral DNA is not completed and multiplication stops.
Indications
The first group of indications covers varicella zoster virus infections: treatment of herpes zoster and of its ophthalmic form in adults with normal immunity, and treatment of herpes zoster in adults with mildly or moderately weakened immunity.
The second and third groups concern herpes simplex and cytomegalovirus.
- treatment and containment of skin and mucous membrane infections caused by herpes simplex virus, including the first episode and recurrences of genital herpes in adults and adolescents with normal immunity and in adults with weakened immunity;
- suppression of recurrent genital herpes in the same groups, and treatment and prevention of recurrent ophthalmic herpes;
- prevention of cytomegalovirus infection and disease after organ transplantation in adults and adolescents; no studies have been carried out in HSV-infected patients whose immunity is weakened for reasons other than HIV.
Method of use and dosage
One rule governs everything: the earlier treatment starts, the better the result. In herpes zoster it begins as soon as the diagnosis is made — there are no data on starting later than 72 hours from the appearance of the rash; in recurrent herpes simplex it is better to start in the prodromal period or right after the first lesions, and then the medicine can prevent them developing.
| Indication | Dose |
| Herpes zoster, normal immunity | 1000 mg three times daily for 7 days |
| Herpes zoster, weakened immunity | 1000 mg three times daily for at least 7 days and a further 2 days after the lesions have crusted over; started if no more than a week has passed since the vesicles appeared |
| Herpes simplex, normal immunity, from 12 years | 500 mg twice daily: 3–5 days for a recurrence, up to 10 days for a first episode |
| Cold sores | 2000 mg twice daily for one day only; the second dose is taken about 12 hours later, but no sooner than 6; extending the course brings nothing |
| Herpes simplex, weakened immunity | 1000 mg twice daily for a minimum of 5 days and, for a first episode, which may run a more severe course, up to 10 days; start within 48 hours |
| Prevention of recurrent herpes | with normal immunity 500 mg once daily and, with very frequent recurrences — from 10 episodes a year without treatment — the same 500 mg split into two 250 mg doses; with weakened immunity 500 mg twice daily; treatment is reviewed after 6–12 months |
| Prevention of cytomegalovirus after transplantation | 2000 mg four times daily, starting as soon as possible after the transplant; usually 90 days, longer in high-risk patients |
In every regimen the dose is reduced according to creatinine clearance and the patient is kept adequately hydrated; in older people the likelihood of impaired renal function is taken into account. On intermittent haemodialysis the medicine is given after the session, and clearance is monitored regularly — especially when renal function changes quickly, for example right after a kidney transplant. In mild and moderate hepatic cirrhosis the dose is unchanged; the data in advanced cirrhosis do not require changing it either, though experience here is limited. Safety and efficacy in children under 12 have not been established.
Contraindications
Hypersensitivity to valaciclovir, aciclovir or any excipient. The list ends at that single point, which is unusual for a prescription medicine.
A short list does not mean the medicine can be taken without care: the main restrictions have been moved into the dosing and warnings sections. In almost every regimen the dose depends on renal function, and older patients and those with renal failure carry an increased risk of adverse reactions of the nervous system.
Special warnings and precautions
Aciclovir is cleared by the kidneys, so where their function is impaired the dose of valaciclovir is reduced. In older people such impairment is more likely, and a dose reduction is worth considering there too. Both groups face an increased risk of nervous system reactions: such patients are watched closely, and in the reported cases these reactions resolved after treatment was stopped.
- in herpes zoster and in herpetic eye infections the clinical response is assessed carefully, particularly where immunity is weakened, and if the response to oral treatment is insufficient, intravenous antiviral treatment is used instead;
- intravenous treatment is mandatory in complicated herpes zoster — with organ involvement, disseminated lesions, motor neuropathies, encephalitis and cerebrovascular complications — and also with weakened immunity in the ophthalmic form or with a high risk of dissemination;
- there are no data on doses of 4000 mg a day and above in liver disease and no dedicated studies after liver transplantation, so such doses are used with caution.
Transmission of genital herpes is a subject of its own. While symptoms are present, sexual contact should be avoided even if treatment has begun: preventive dosing substantially reduces how often the virus is shed, but transmission is still possible, so safer sexual behaviour is recommended alongside treatment. Data from about 200 transplant patients at high risk of cytomegalovirus show that valaciclovir is suitable only where safety considerations rule out valganciclovir or ganciclovir, and at high doses central nervous system reactions occur more often. The effect on driving has not been studied.
Interaction with other medicines
Aciclovir is excreted mainly unchanged in the urine by active tubular secretion, and every significant interaction is arranged around that mechanism. Substances that slow secretion in the renal tubules or compete for it raise the plasma concentration of aciclovir and, conversely, taking valaciclovir may raise the concentration of a medicine given alongside it.
- after a 1000 mg dose of valaciclovir, cimetidine and probenecid reduce the renal clearance of aciclovir and increase its area under the curve by about 25% and 45% respectively, and together by about 65%;
- other medicines that slow tubular secretion or compete for it, such as tenofovir, also raise the concentration of aciclovir, and at high doses of valaciclovir such combinations call for caution;
- nephrotoxic medicines are combined cautiously, especially where renal function is impaired, and that function is monitored where necessary: aminoglycosides, organic platinum compounds, iodinated contrast media, methotrexate, pentamidine, foscarnet, ciclosporin and tacrolimus;
- when aciclovir was given together with the inactive metabolite of mycophenolate mofetil, an immunosuppressant used after transplantation, the area under the curve of both rose, although in healthy volunteers the combination of valaciclovir itself with mycophenolate produced no changes.
Clinical experience with that combination is limited. The general rule is simple: any agent that either damages the kidneys or competes with aciclovir for tubular secretion shifts the safety balance — and the more so, the higher the daily dose of valaciclovir.
Pregnancy and breastfeeding
Data on use in pregnancy are limited. They come from pregnancy registries documenting outcomes in women exposed to valaciclovir or to aciclovir orally or intravenously — 111 and 1246 cases, of which 29 and 756 with exposure in the first trimester — and from post-marketing experience. Neither those data nor animal studies point to teratogenicity or toxicity in the fetal and neonatal periods; even so, in pregnancy the medicine is used only where the expected benefit outweighs the potential risk.
Aciclovir, the main metabolite of valaciclovir, passes into breast milk. At therapeutic doses, however, no effect on newborns or infants is expected: the dose the child receives is less than 2% of the intravenous therapeutic dose of aciclovir used to treat neonatal herpes. During breastfeeding the medicine is used with caution and only where there is a clinical indication. Oral valaciclovir did not affect fertility in rats, while parenteral administration of high doses of aciclovir to rats and dogs produced testicular atrophy and impaired spermatogenesis. In humans the effect on fertility has not been studied, but in 20 patients given oral aciclovir at 400 to 1000 mg a day for up to six months no effect on sperm count, morphology or motility was seen.
Adverse reactions
The most common adverse reactions, reported in at least one of the indications, are headache and nausea. The safety database was built from 5855 participants in clinical trials: treatment of herpes zoster, treatment and prevention of genital herpes, and treatment of cold sores.
- very common headache; common nausea, vomiting, diarrhoea, dizziness, rash including photosensitivity rash, and itching;
- uncommon: leukopenia and thrombocytopenia, disorientation, hallucinations, altered consciousness, tremor, agitation, breathlessness, abdominal discomfort, transient rises in liver function parameters, urticaria, kidney pain, haematuria;
- rare: anaphylaxis, ataxia, speech disturbances, seizures, encephalopathy, coma, psychotic symptoms, delirium, angioedema, acute renal failure.
Neurological disturbances, sometimes severe, may be linked to encephalopathy; they are generally transient and usually seen where renal function is impaired or other predisposing factors are present, and after transplantation on 8000 mg a day for cytomegalovirus prevention they occur far more often. Leukopenia was reported mainly where immunity was weakened. Renal failure develops more often in older people and in kidney disease at doses above those recommended; precipitation of aciclovir crystals inside the renal tubules has also been described, so adequate fluid intake matters during treatment. In adults with severe immunodeficiency, particularly in advanced HIV infection, prolonged intake of 8000 mg a day produced renal failure, microangiopathic haemolytic anaemia and thrombocytopenia, sometimes together; the same phenomena were seen in patients with the same underlying conditions who were not taking valaciclovir.
Overdose
In patients given valaciclovir at doses above the therapeutic range, acute renal failure and neurological symptoms were reported: confusion, hallucinations, agitation, disturbed consciousness and coma; nausea and vomiting are also possible. Many of the described cases involved older people and patients with kidney disease who repeatedly received excessive doses because the dose had not been reduced in time.
The main measure, therefore, is to prevent unintentional overdose. If one occurs, the patient is watched for signs of toxicity, and since haemodialysis significantly speeds the removal of aciclovir from the blood, it is considered as a way of managing symptomatic overdose.
How to get a prescription for Valtrex online
The medicine is prescription-only, and the first thing the doctor will establish is what exactly is being treated: herpes zoster, a first episode or a recurrence of herpes, cold sores, prevention of recurrences, or prevention of cytomegalovirus after transplantation. The whole regimen follows from that: the range of doses here is among the widest, from 500 mg once daily to 2000 mg four times daily.
It matters to give the date the first symptoms appeared: in herpes zoster there are no data on starting later than 72 hours, and in a herpes recurrence the gain comes precisely from an early start. Kidney disease with test results, organ transplantation, weakened immunity including HIV infection, pregnancy and breastfeeding are reported separately, along with the medicines being taken — nephrotoxic ones above all. The doctor will assess these circumstances during the online consultation and, if there are no contraindications, will issue an electronic prescription.
