Valproate Sodium (Page 4 of 10)

5.9 Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use

Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see WARNINGS AND PRECAUTIONS (5.10)]. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.8)].

5.10 Hypothermia

Hypothermia, defined as an unintentional drop in body core temperature to < 35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see DRUG INTERACTIONS (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

5.11 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-organ Hypersensitivity Reactions

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multi-organ Hypersensitivity, has been reported in patients taking valproate. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Valproate should be discontinued and not be resumed if an alternative etiology for the signs or symptoms cannot be established.

5.12 Interaction with Carbapenem Antibiotics

Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see DRUG INTERACTIONS (7.1)].

5.13 Somnolence in the Elderly

In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see DOSAGE AND ADMINISTRATION (2.2)].

5.14 Post-traumatic Seizures

A study was conducted to evaluate the effect of IV valproate in the prevention of post-traumatic seizures in patients with acute head injuries. Patients were randomly assigned to receive either IV valproate given for one week (followed by oral valproate products for either one or six months per random treatment assignment) or IV phenytoin given for one week (followed by placebo). In this study, the incidence of death was found to be higher in the two groups assigned to valproate treatment compared to the rate in those assigned to the IV phenytoin treatment group (13% vs. 8.5%, respectively). Many of these patients were critically ill with multiple and/or severe injuries, and evaluation of the causes of death did not suggest any specific drug-related causation. Further, in the absence of a concurrent placebo control during the initial week of intravenous therapy, it is impossible to determine if the mortality rate in the patients treated with valproate was greater or less than that expected in a similar group not treated with valproate, or whether the rate seen in the IV phenytoin treated patients was lower than would be expected. Nonetheless, until further information is available, it seems prudent not to use valproate sodium injection in patients with acute head trauma for the prophylaxis of post-traumatic seizures.

5.15 Monitoring: Drug Plasma Concentration

Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see DRUG INTERACTIONS (7)].

5.16 Effect on Ketone and Thyroid Function Tests

Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test.

There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown.

5.17 Effect on HIV and CMV Viruses Replication

There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

  • Hepatic failure [see Warnings and Precautions (5.1) ]
  • Birth defects [see Warnings and Precautions (5.2) ]
  • Decreased IQ following in utero exposure [see Warnings and Precautions (5.3) ]
  • Pancreatitis [see Warnings and Precautions (5.5) ]
  • Hyperammonemic encephalopathy [see Warnings and Precautions (5.6, 5.8, 5.9)]
  • Bleeding and other hematopoietic disorders [see Warnings and Precautions (5.7) ]
  • Hypothermia [see Warnings and Precautions (5.10)]
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-organ hypersensitivity reactions [see Warnings and Precautions (5.11) ]
  • Somnolence in the elderly [see Warnings and Precautions (5.13) ]

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

The adverse reactions that can result from valproate sodium injection use include all of those associated with oral forms of valproate. The following describes experience specifically with valproate sodium injection. Valproate sodium injection has been generally well tolerated in clinical trials involving 111 healthy adult male volunteers and 352 patients with epilepsy, given at doses of 125 to 6,000 mg (total daily dose). A total of 2% of patients discontinued treatment with valproate sodium injection due to adverse reactions. The most common adverse reactions leading to discontinuation were 2 cases each of nausea/vomiting and elevated amylase. Other adverse reactions leading to discontinuation were hallucinations, pneumonia, headache, injection site reaction, and abnormal gait. Dizziness and injection site pain were observed more frequently at a 100 mg/min infusion rate than at rates up to 33 mg/min. At a 200 mg/min rate, dizziness and taste perversion occurred more frequently than at a 100 mg/min rate. The maximum rate of infusion studied was 200 mg/min.

Adverse reactions reported by at least 0.5% of all subjects/patients in clinical trials of valproate sodium injection are summarized in Table 1.

Table 1. Adverse Reactions Reported During Studies of Valproate Sodium Injection
Body System/Reaction N = 463
Body as a Whole
Chest Pain 1.7%
Headache 4.3%
Injection Site Inflammation 0.6%
Injection Site Pain 2.6%
Injection Site Reaction 2.4%
Pain (unspecified) 1.3%
Cardiovascular
Vasodilation 0.9%
Dermatologic
Sweating 0.9%
Digestive System
Abdominal Pain 1.1%
Diarrhea 0.9%
Nausea 3.2%
Vomiting 1.3%
Nervous System
Dizziness 5.2%
Euphoria 0.9%
Hypesthesia 0.6%
Nervousness 0.9%
Paresthesia 0.9%
Somnolence 1.7%
Tremor 0.6%
Respiratory
Pharyngitis 0.6%
Special Senses
Taste Perversion 1.9%

In a separate clinical safety trial, 112 patients with epilepsy were given infusions of valproate sodium injection (up to 15 mg/kg) over 5 to 10 minutes (1.5 — 3 mg/kg/min). The common adverse reactions (> 2%) were somnolence (10.7%), dizziness (7.1%), paresthesia (7.1%), asthenia (7.1%), nausea (6.3%), and headache (2.7%). While the incidence of these adverse reactions was generally higher than in Table 1 (experience encompassing the standard, much slower infusion rates), e.g., somnolence (1.7%), dizziness (5.2%), paresthesia (0.9%), asthenia (0%), nausea (3.2%), and headache (4.3%), a direct comparison between the incidence of adverse reactions in the 2 cohorts cannot be made because of differences in patient populations and study designs.

Ammonia levels have not been systematically studied after IV valproate, so that an estimate of the incidence of hyperammonemia after IV valproate sodium injection cannot be provided. Hyperammonemia with encephalopathy has been reported in 2 patients after infusions of valproate sodium injection.

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