Valtrex

Serious side effects may occur. See "Drug Precautions" section.

Common side effects of Valtrex in adults include:

• headache
• nausea
• stomach pain
• vomiting
• dizziness

Side effects in HIV-1-infected adults include:

• headache
• tiredness
• rash

Other less common side effects in adults include:

• painful periods in women
• joint pain
• depression
• low blood cell counts
• changes in tests that measure how well the liver and kidneys work

The most common side effect seen in children aged less than 18 years was headache.

Talk to your healthcare provider if you develop any side effects that concern you.

These are not all the side effects of Valtrex . For more information ask your healthcare provider or pharmacist.

Before taking Valtrex, tell your healthcare provider about all your medical conditions, including:

• if you have had a bone marrow transplant or kidney transplant, or if you have advanced HIV-1 disease or "AIDS". Patients with these conditions may have a higher chance for getting a blood disorder called thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). TTP/HUS can result in death.
• if you have kidney problems. Patients with kidney problems may have a higher chance for getting side effects or more kidney problems with Valtrex. Your healthcare provider may give you a lower dose of Valtrex.
• if you are aged 65 years or older. Elderly patients have a higher chance of certain side effects. Also, elderly patients are more likely to have kidney problems. Your healthcare provider may give you a lower dose of Valtrex.
• if you are pregnant or breastfeeding
• about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Valtrex may affect other medicines, and other medicines may affect Valtrex. It is a good idea to keep a complete list of all the medicines you take. Show this list to your healthcare provider and pharmacist any time you get a new medicine.

Neither valacyclovir nor acyclovir metabolized by CYP isoenzymes.1

Specific Drugs

In the U.S.

• Valtrex

Available Dosage Forms:

• Tablet

Therapeutic Class: Antiviral

Pharmacologic Class: Viral DNA Polymerase Inhibitor

Chemical Class: Guanosine Nucleoside Analog

Valacyclovir works best if it is used within 48 hours after the first symptoms of shingles or genital herpes (e.g., pain, burning, or blisters) begin to appear. For recurrent outbreaks of genital herpes, valacyclovir works best if it is used within 24 hours after the symptoms begin to appear.

If you are taking valacyclovir for the treatment of chickenpox, it is best to start taking valacyclovir as soon as possible after the first sign of the chickenpox rash appears, usually within one day.

Valacyclovir may be taken with meals or on an empty stomach.

If you are using the oral suspension, use a specially marked measuring spoon or other device to measure each dose accurately. The average household teaspoon may not hold the right amount of liquid.

Drink extra fluids so you will pass more urine while you are using this medicine. This will keep your kidneys working well and help prevent kidney problems.

To help clear up your infection, keep taking valacyclovir for the full time of treatment, even if your symptoms begin to clear up after a few days. Do not miss any doses. However, do not use this medicine more often or for a longer time than your doctor ordered.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For treatment of chickenpox:
    • Adults and children below 2 years of age—Use and dose must be determined by your doctor.
    • Children 2 to 18 years of age—Dose is based on body weight and must be determined by your doctor. The usual dose is 20 milligrams (mg) per kilogram (kg) of body weight, taken three times a day for 5 days. However, the dose is usually not more than 1000 mg three times a day.
  • For treatment of cold sores:
    • Adults—2000 milligrams (mg) every 12 hours for one day.
    • Children 12 years of age and above—2000 milligrams (mg) every 12 hours for one day.
    • Children below 12 years of age—Use and dose must be determined by your doctor.
  • For treatment of genital herpes, first outbreak:
    • Adults—1000 milligrams (mg) two times a day for ten days.
    • Children—Use and dose must be determined by your doctor.
  • For treatment of genital herpes, recurrent outbreaks:
    • Adults—500 milligrams (mg) two times a day for three days.
    • Children—Use and dose must be determined by your doctor.
  • To prevent recurrent outbreaks of genital herpes:
    • Adults—500 milligrams (mg) or 1000 mg once a day.
    • Children—Use and dose must be determined by your doctor.
  • For treatment of shingles:
    • Adults—1000 milligrams (mg) three times a day for seven days.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Valtrex is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation [see Adverse Reactions (6.3)].

Mechanism of Action

Valacyclovir is an antiviral drug [see Clinical Pharmacology (12.4)].

Pharmacokinetics

The pharmacokinetics of valacyclovir and acyclovir after oral administration of Valtrex have been investigated in 14 volunteer trials involving 283 adults and in 3 trials involving 112 pediatric subjects aged 1 month to less than 12 years.

Pharmacokinetics in Adults: Absorption and Bioavailability: After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L─valine by first-pass intestinal and/or hepatic metabolism.

The absolute bioavailability of acyclovir after administration of Valtrex is 54.5% ± 9.1% as determined following a 1─gram oral dose of Valtrex and a 350─mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of Valtrex is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat).

Acyclovir pharmacokinetic parameter estimates following administration of Valtrex to healthy adult volunteers are presented in Table 3. There was a less than dose─proportional increase in acyclovir maximum concentration (Cmax) and area under the acyclovir concentration─time curve (AUC) after single─dose and multiple─dose administration (4 times daily) of Valtrex from doses between 250 mg to 1 gram.

There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in adults with normal renal function.

Distribution: The binding of valacyclovir to human plasma proteins ranges from 13.5% to 17.9%. The binding of acyclovir to human plasma proteins ranges from 9% to 33%.

Metabolism: Valacyclovir is converted to acyclovir and L─valine by first─pass intestinal and/or hepatic metabolism. Acyclovir is converted to a small extent to inactive metabolites by aldehyde oxidase and by alcohol and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted valacyclovir are low and transient, generally becoming non-quantifiable by 3 hours after administration. Peak plasma valacyclovir concentrations are generally less than 0.5 mcg/mL at all doses. After single─dose administration of 1 gram of Valtrex, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in subjects with hepatic dysfunction, renal insufficiency, and in healthy subjects who received concomitant cimetidine and probenecid, respectively.

Elimination: The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of a single 1 gram dose of radiolabeled valacyclovir to 4 healthy subjects, 46% and 47% of administered radioactivity was recovered in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1-gram dose of Valtrex to 12 healthy subjects was approximately 255 ± 86 mL/min which represents 42% of total acyclovir apparent plasma clearance.

The plasma elimination half‑life of acyclovir typically averaged 2.5 to 3.3 hours in all trials of Valtrex in subjects with normal renal function.

Specific Populations: Renal Impairment: Reduction in dosage is recommended in patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.5, 8.6)].

Following administration of Valtrex to subjects with ESRD, the average acyclovir half‑life is approximately 14 hours. During hemodialysis, the acyclovir half‑life is approximately 4 hours. Approximately one‑third of acyclovir in the body is removed by dialysis during a 4‑hour hemodialysis session. Apparent plasma clearance of acyclovir in subjects on dialysis was 86.3 ± 21.3 mL/min/1.73 m2 compared with 679.16 ± 162.76 mL/min/1.73 m2 in healthy subjects.

Hepatic Impairment: Administration of Valtrex to subjects with moderate (biopsy─proven cirrhosis) or severe (with and without ascites and biopsy─proven cirrhosis) liver disease indicated that the rate but not the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir half─life is not affected. Dosage modification is not recommended for patients with cirrhosis.

HIV-1 Disease: In 9 subjects with HIV-1 disease and CD4+ cell counts less than 150 cells/mm3 who received Valtrex at a dosage of 1 gram 4 times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different from that observed in healthy subjects.

Geriatrics: After single-dose administration of 1 gram of Valtrex in healthy geriatric subjects, the half‑life of acyclovir was 3.11 ± 0.51 hours, compared with 2.91 ± 0.63 hours in healthy younger adult subjects. The pharmacokinetics of acyclovir following single- and multiple‑dose oral administration of Valtrex in geriatric subjects varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient [see Dosage and Administration (2.4), Use in Specific Populations (8.5. 8.6)].

Pediatrics: Acyclovir pharmacokinetics have been evaluated in a total of 98 pediatric subjects (aged 1 month to less than 12 years) following administration of the first dose of an extemporaneous oral suspension of valacyclovir [see Adverse Reactions (6.2), Use in Specific Populations (8.4)]. Acyclovir pharmacokinetic parameter estimates following a 20─mg/kg dose are provided in Table 4.

Drug Interactions: When Valtrex is coadministered with antacids, cimetidine and/or probenicid, digoxin, or thiazide diuretics in patients with normal renal function, the effects are not considered to be of clinical significance (see below). Therefore, when Valtrex is coadministered with these drugs in patients with normal renal function, no dosage adjustment is recommended.

Antacids: The pharmacokinetics of acyclovir after a single dose of Valtrex (1 gram) were unchanged by coadministration of a single dose of antacids (Al3+ or Mg++).

Cimetidine: Acyclovir Cmax and AUC following a single dose of Valtrex (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg).

Cimetidine Plus Probenecid: Acyclovir Cmax and AUC following a single dose of Valtrex (1 gram) increased by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir.

Digoxin: The pharmacokinetics of digoxin were not affected by coadministration of Valtrex 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of Valtrex (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).

Probenecid: Acyclovir Cmax and AUC following a single dose of Valtrex (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram).

Thiazide Diuretics: The pharmacokinetics of acyclovir after a single dose of Valtrex (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics.

Microbiology

Mechanism of Action: Valacyclovir is a nucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against HSV types 1 (HSV─1) and 2 (HSV─2) and VZV both in cell culture and in vivo.

The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.

Antiviral Activities: The quantitative relationship between the cell culture susceptibility of herpesviruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the EC50 values against herpes simplex virus isolates range from 0.09 to 60 μM (0.02 to 13.5 mcg/mL) for HSV─1 and from 0.04 to 44 µM (0.01 to 9.9 mcg/mL) for HSV─2. The EC50 values for acyclovir against most laboratory strains and clinical isolates of VZV range from 0.53 to 48 µM (0.12 to 10.8 mcg/mL). Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean EC50 of 6 µM (1.35 mcg/mL).

Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to acyclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered.

Resistance of HSV and VZV to acyclovir occurs by the same mechanisms. While most of the acyclovir─resistant mutants isolated thus far from immunocompromised patients have been found to be TK─deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK─negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valacyclovir (and therefore, to acyclovir) should be considered in patients who show poor clinical response during therapy.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The data presented below include references to the steady─state acyclovir AUC observed in humans treated with 1 gram Valtrex given orally 3 times a day to treat herpes zoster. Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir [see Clinical Pharmacology (12.3)].

Valacyclovir was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gavage) of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. There was no significant difference in the incidence of tumors between treated and control animals, nor did valacyclovir shorten the latency of tumors.

Valacyclovir was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. Also negative were an in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study.

In the mouse lymphoma assay, valacyclovir was not mutagenic in the absence of metabolic activation. In the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic.

Valacyclovir was mutagenic in a mouse micronucleus assay.

Valacyclovir did not impair fertility or reproduction in rats at 6 times human plasma levels.

Taking this medicine will not prevent you from passing genital herpes to other people. Herpes infections are contagious and you can infect other people even while you are taking with Valtrex.

Avoid sexual intercourse or use a latex condom to help keep you from spreading the virus to others. Avoid letting infected areas come into contact with other people. Avoid touching an infected area and then touching your eyes. Wash your hands frequently to prevent the spread of infection.

Do not share this medicine with another person, even if they have the same symptoms you have.

Valtrex can harm your kidneys. This effect is increased when you also use certain other medicines, including: antivirals, chemotherapy, injected antibiotics, medicine for bowel disorders, medicine to prevent organ transplant rejection, injectable osteoporosis medication, and some pain or arthritis medicines (including aspirin, Tylenol, Advil, and Aleve).

Other drugs may interact with valacyclovir, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.