Valacyclovir Side Effects

Brand Names: Valtrex

Please note - some side effects for Valacyclovir may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Valacyclovir - for the Consumer

Valacyclovir

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Valacyclovir:

Dizziness; headache; nausea; stomach pain; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Valacyclovir:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); agitation; aggressive behavior; bloody or dark urine; change in the amount of urine produced; confusion; depression; fatigue; fever; hallucinations; joint pain; lower back pain; painful menstrual periods; pale skin; pinpoint bruises; seizures; severe abdominal pain; severe or persistent headache; shaky movements; speech problems; swelling of the face, hands, feet, or entire body; unsteady movement; unusual bruising or bleeding; weakness; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Valacyclovir Side Effects - for the Professional

Valacyclovir

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome [seeWarnings and Precautions (5.1)].
• Acute Renal Failure [seeWarnings and Precautions (5.2)].
• Central Nervous System Effects [seeWarnings and Precautions (5.3)].

The most common adverse reactions reported in at least 1 indication by > 10% of adult patients treated with Valacyclovir hydrochloride and observed more frequently with Valacyclovir hydrochloride compared to placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in > 10% of pediatric patients < 18 years of age was headache.

Clinical Trials Experience in Adult Patients

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Cold Sores (Herpes Labialis): In clinical studies for the treatment of cold sores, the adverse reactions reported by patients receiving Valacyclovir hydrochloride 2 grams twice daily (n = 609) or placebo (n = 609) for 1 day, respectively, included headache (14%, 10%) and dizziness (2%, 1%). The frequencies of abnormal ALT (> 2 x ULN) were 1.8% for patients receiving Valacyclovir hydrochloride compared with 0.8% for placebo. Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase, and serum creatinine) occurred with similar frequencies in the 2 groups.

Genital Herpes:Initial Episode: In a clinical study for the treatment of initial episodes of genital herpes, the adverse reactions reported by ≥ 5% of patients receiving Valacyclovir hydrochloride 1 gram twice daily for 10 days (n = 318) or oral acyclovir 200 mg 5 times daily for 10 days (n = 318), respectively, included headache (13%, 10%) and nausea (6%, 6%). For the incidence of laboratory abnormalities see Table 2.

Recurrent Episodes: In 3 clinical studies for the episodic treatment of recurrent genital herpes, the adverse reactions reported by ≥ 5% of patients receiving Valacyclovir hydrochloride 500 mg twice daily for 3 days (n = 402), Valacyclovir hydrochloride 500 mg twice daily for 5 days (n = 1,136) or placebo (n = 259), respectively, included headache (16%, 11%, 14%) and nausea (5%, 4%, 5%). For the incidence of laboratory abnormalities see Table 2.

Suppressive Therapy: Suppression of Recurrent Genital Herpes in Immunocompetent Adults: In a clinical study for the suppression of recurrent genital herpes infections, the adverse reactions reported by patients receiving Valacyclovir hydrochloride 1 gram once daily (n = 269), Valacyclovir hydrochloride 500 mg once daily (n = 266), or placebo (n = 134), respectively, included headache (35%, 38%; 34%), nausea (11%, 11%, 8%), abdominal pain (11%, 9%, 6%), dysmenorrhea (8%, 5%, 4%), depression (7%, 5%, 5%), arthralgia (6%, 5%, 4%), vomiting (3%, 3%, 2%), and dizziness (4%, 2%, 1%). For the incidence of laboratory abnormalities see Table 2.

Suppression of Recurrent Genital Herpes in HIV-Infected Patients: In HIV-infected patients, frequently reported adverse reactions for Valacyclovir hydrochloride (500 mg twice daily; n = 194, median days on therapy = 172) and placebo (n = 99, median days on therapy = 59), respectively, included headache (13%, 8%), fatigue (8%, 5%), and rash (8%, 1%). Post-randomization laboratory abnormalities that were reported more frequently in Valacyclovir subjects versus placebo included elevated alkaline phosphatase (4%, 2%), elevated ALT (14%, 10%), elevated AST (16%, 11%), decreased neutrophil counts (18%, 10%), and decreased platelet counts (3%, 0%), respectively.

Reduction of Transmission: In a clinical study for the reduction of transmission of genital herpes, the adverse reactions reported by patients receiving Valacyclovir hydrochloride 500 mg once daily (n = 743) or placebo once daily (n = 741), respectively, included headache (29%, 26%), nasopharyngitis (16%, 15%), and upper respiratory tract infection (9%, 10%).

Herpes Zoster: In 2 clinical studies for the treatment of herpes zoster, the adverse reactions reported by patients receiving Valacyclovir hydrochloride 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities see Table 2.

Table 2. Incidence (%) of Laboratory Abnormalities in Herpes Zoster and Genital Herpes Study Populations

*Data were not collected prospectively. LLN = Lower limit of normal. ULN = Upper limit of normal.
Laboratory Abnormality	Herpes Zoster		Genital Herpes Treatment			Genital Herpes Suppression
	Valacyclovir hydrochloride 1 gram 3 times daily (n = 967)	Placebo (n = 195)	Valacyclovir hydrochloride 1 gram twice daily (n = 1,194)	Valacyclovir hydrochloride 500 mg twice daily (n = 1,159)	Placebo (n = 439)	Valacyclovir hydrochloride 1 gram once daily (n = 269)	Valacyclovirhydrochloride 500 mg once daily (n = 266)	Placebo (n = 134)
Hemoglobin (< 0.8 x LLN)	0.8%	0%	0.3%	0.2%	0%	0%	0.8%	0.8%
White blood cells (< 0.75 x LLN)	1.3%	0.6%	0.7%	0.6%	0.2%	0.7%	0.8%	1.5%
Platelet count (< 100,000/mm3)	1%	1.2%	0.3%	0.1%	0.7%	0.4%	1.1%	1.5%
AST (SGOT) (> 2 x ULN)	1%	0%	1%	*	0.5%	4.1%	3.8%	3%
Serum creatinine (> 1.5 x ULN)	0.2%	0%	0.7%	0%	0%	0%	0%	0%

Clinical Trials Experience in Pediatric Patients

Sixty-five of these pediatric patients, 12 to < 18 years of age, received oral tablets for 1 to 2 days for treatment of cold sores. The frequency, intensity, and nature of clinical adverse reactions and laboratory abnormalities were similar to those seen in adults.

Pediatric Patients 12 to < 18 Years of Age (Cold Sores): In clinical studies for the treatment of cold sores, the adverse reactions reported by adolescent patients receiving Valacyclovir hydrochloride 2 grams twice daily for 1 day, or Valacyclovir hydrochloride 2 grams twice daily for 1 day followed by 1 gram twice daily for 1 day (n = 65, across both dosing groups), or placebo (n = 30), respectively, included headache (17%, 3%) and nausea (8%, 0%).

Labeling describing additional clinical trial adverse reactions in pediatric patients (ages of 1 month to ≤ 12 years) is approved for GlaxoSmithKline’s Valtrex® Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of those adverse reactions is not approved for this Valacyclovir HCL tablet product.

Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of Valacyclovir hydrochloride. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Valacyclovir hydrochloride.

General: Facial edema, hypertension, tachycardia.

Allergic: Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria [see Contraindications (4)].

CNS Symptoms: Aggressive behavior; agitation; ataxia; coma; confusion; decreased consciousness; dysarthria; encephalopathy; mania; and psychosis, including auditory and visual hallucinations, seizures, tremors [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), (8.6)].

Eye: Visual abnormalities.

Gastrointestinal: Diarrhea.

Hepatobiliary Tract and Pancreas: Liver enzyme abnormalities, hepatitis.

Renal: Renal failure, renal pain (may be associated with renal failure) [see Warnings and Precautions (5.2), Use in Specific Populations (8.5), (8.6)].

Hematologic: Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS [see Warnings and Precautions (5.1)].

Skin: Erythema multiforme, rashes including photosensitivity, alopecia.

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Side Effects by Body System - for Healthcare Professionals

Gastrointestinal

Gastrointestinal side effects have included nausea (up to 15%), abdominal pain (up to 11%), and vomiting (up to 6%). Constipation, anorexia, diarrhea, elevated amylase, and elevated serum lipase have been reported. Diarrhea has been reported during postmarketing experience. In clinical trials of otherwise healthy individuals, frequencies were higher for patients over 50 years of age than for younger patients.

Nervous system

Nervous system side effects have included headache (up to 38%) and dizziness (up to 4%). Central nervous system effects including agitation, seizures, and encephalopathy have been reported. Choreiform movements, myoclonus, vasculitic mononeuritis multiplex, somnolence, and Cotard's syndrome have been reported. Agitation, ataxia, coma, decreased consciousness, dysarthria, encephalopathy, seizures, and tremors have been reported during postmarketing experience. Neurotoxicity has been most commonly reported in patients with renal failure, the elderly, and in patients following bone marrow transplant, and is associated with high serum concentrations of acyclovir.

Acyclovir neurotoxicity is almost exclusively seen in patients with renal failure. These patients may have longstanding chronic renal failure, or acute failure which may be attributed to acyclovir. One group of six bone marrow transplant patients exhibited abnormal EEGs with diffuse slowing. Although more commonly seen with intravenous administration of higher doses, neurotoxicity has also been reported in patients receiving oral doses of acyclovir. Following discontinuation of therapy, mental status recovered within about a week. Several patients with chronic renal failure exhibiting neurotoxicity improved dramatically following hemodialysis.

Although there have been no similar reports in clinical trials of valacyclovir completed to date, the assumption may be made that neurotoxicity can also occur with valacyclovir based on the fact that plasma acyclovir concentrations from oral valacyclovir administration tend to be much higher than those obtained with oral acyclovir.

Psychiatric

Psychiatric side effects have included depression (up to 7%) and disorientation. Central nervous system effects including hallucinations, confusion, and delirium have been reported. Aggressive behavior, confusion, mania, and psychosis (including auditory and visual hallucinations) have been reported during postmarketing experience.

Renal

Renal side effects have included acute renal failure, elevated serum creatinine (up to 0.7%), renal toxicity, and renal failure (presenting as an increase in serum creatinine and blood urea nitrogen). Renal failure and renal pain (may be associated with renal failure) have been reported during postmarketing experience. Renal effects are transient and resolve over several days following discontinuation of therapy. Renal damage is most likely due to crystallization of acyclovir in the renal tubules. Patients with preexisting renal insufficiency are at greater risk for developing neurotoxicity and further deterioration in renal function.

Transient renal dysfunction has been reported with both oral and intravenous administration of acyclovir. Crystallization of the drug in the renal tubules is thought to be the mechanism for the development of renal dysfunction based on findings of crystalluria in several case reports and at least one prospective study. Inadequate hydration of the patient and rapid administration of the drug may contribute to the development of crystalluria. Acute tubular necrosis and interstitial nephritis have also been reported in association with acyclovir therapy. Although there have been no similar reports in clinical trials of valacyclovir completed to date, the assumption may be made that renal toxicity can also occur with valacyclovir based on the fact that plasma acyclovir concentrations from oral valacyclovir administration tend to be much higher than those obtained with oral acyclovir.

Hematologic

TTP/HUS, including some fatalities, has been reported during clinical trials in patients with advanced HIV disease and in allogeneic bone marrow transplant and renal transplant recipients, who were receiving 8 g valacyclovir per day.

Hematologic side effects have included thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), and decreased neutrophil counts (18%), platelet counts (up to 3%), hemoglobin (up to 0.8%), and white blood cells (up to 1.3%). Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, and TTP/HUS have been reported during postmarketing experience.

Hepatic

Hepatic side effects have included elevated AST (up to 16%), ALT (up to 14%), and bilirubin. Liver enzyme abnormalities and hepatitis have been reported during postmarketing experience.

Hypersensitivity

Hypersensitivity side effects have included acute hypersensitivity reactions (including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria) during postmarketing experience. Stevens-Johnson syndrome has been reported.

Dermatologic

Dermatologic side effects have included rash (8%). Erythema multiforme, rashes including photosensitivity, and alopecia have been reported during postmarketing experience.

Cardiovascular

Cardiovascular side effects have included hypertension and tachycardia during postmarketing experience.

Ocular

Ocular side effects have included visual abnormalities during postmarketing experience.

Respiratory

Respiratory side effects have included nasopharyngitis (16%) and upper respiratory tract infection (9%).

Musculoskeletal

Musculoskeletal side effects have included arthralgia (up to 6%).

Genitourinary

Genitourinary side effects have included dysmenorrhea (up to 8%).

Other

Other side effects have included fatigue (8%). Facial edema has been reported during postmarketing experience.

Metabolic

Metabolic side effects have included elevated alkaline phosphatase (4%) and hypoglycemia.

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