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/index.php/Valdecoxib

# Valdecoxib Valdecoxib is a Cyclooxygenase-2 Inhibitor that is FDA approved for the treatment of osteoarthritis, adult rheumatoid arthritis and primary dysmenorrhea. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Abdominal pain, Diarrhea, Flatulence, Indigestion, Nausea, Dizziness, Headache, Rash, Hypertension, Peripheral edema , Backache, Myalgia.

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/index.php/Valerian_(herb)

# Valerian (herb) Valerian (Valeriana officinalis, Valerianaceae) is a hardy perennial flowering plant, with heads of sweetly scented pink or white flowers. This "sweet" smell is quite overpowering when the flower is placed into a vase. The flowers are in bloom from June to September. Valerian was used as a perfume in the sixteenth century. Native to Europe and parts of Asia, Valerian has been introduced into North America. It is consumed as food by the larvae of some Lepidoptera (butterfly and moth) species including Grey Pug. Other names used for this plant include garden valerian (to distinguish it from other Valeriana species), garden heliotrope (although not related to Heliotropium) and all-heal. Valerian, in Pharmacology and Phytotherapic Medicine, is the name of a herb or dietary supplement prepared from roots of the plant, which, after maceration, trituration, dehydration processes, are conveniently packaged, usually into capsules, that may be utilized for certain effects including sedation and anxiolytic effect. Valerian has been used as a medicinal herb since at least the time of ancient Greece and Rome. Hippocrates described its properties, and Galen later prescribed it as a remedy for insomnia. The name Valerian comes from the Latin word valere, meaning "to be strong or healthy", generally thought to refer to its medicinal use, though many references suggest that it also refers to the strong odor. Due to valerian's historical use as a sedative, anti-convulsant, migraine treatment and pain reliever, most basic science research has been directed at the interaction of valerian constituents with the GABA neurotransmitter receptor system. These studies remain inconclusive and all require independent replication. The mechanism of action of valerian in general, as a mild sedative in particular, remains unknown. Valerian extracts appear to have some affinity for the GABAA (benzodiazepine) receptor, but this activity does not appear to be mediated by valerenic acid, but rather by the relatively high content of γ-aminobutyric acid (GABA) itself. The chief constituent of Valerian is a yellowish-green to brownish-yellow oil which is present in the dried root varying from 0.5 to 2 per cent though an average yield rarely exceeds 0.8 per cent. This variation in quantity is partly explained by location: a dry, stony soil, yielding a root richer in oil than one that is moist and fertile. The volatile oils that form the active ingredient are extremely pungent, somewhat reminiscent of well-matured cheese or wet dog. Valerian tea should not be prepared with boiling water, as this may drive off the lighter oils. In the United States Valerian is sold as a nutritional supplement. Therapeutic use has increased as dietary supplements have gained in popularity, especially after the Dietary Supplement Health and Education Act was passed in 1994. This law allowed the distribution of many agents as over-the-counter supplements, and therefore allowed them to bypass the regulatory requirements of the Food and Drug Administration (FDA). Valerian is used against sleeping disorders, restlessness and anxiety, and as a muscle relaxant. Valerian seems only to work when taken over longer periods (several weeks), though many users find that it takes effect immediately. Some studies have demonstrated that valerian extracts interact with the GABA and benzodiazepine receptors. Valerian is also used traditionally to treat gastrointestinal pain and spastic colitis. Long term safety studies are missing. As valepotriates may be potential mutagens, valerian should only be used after consultation with a physician. Valerian medication is sometimes recommended as a first line when benefit-risk analysis dictates. Valerian is often indicated as transition medication during discontinuation processes involving bromazepan, clonazepam and diazepam, among others. Valerian has uses in herbal medicine as a sedative. The main current use of valerian is as a remedy for insomnia, with a recent meta-analysis providing some evidence of effectiveness. It has been recommended for epilepsy but that is not supported by research (although its analogue valproic acid is used as an anticonvulsant and mood-stabilizing drug). Valerian root generally does not lose effectiveness over time. While shown to be an effective remedy for the reduction of anxiety, it has also been reported to cause headaches and night terrors in some individuals. This may be due to the fact that some people lack a digestive conversion property necessary to effectively break down Valerian. In these individuals, Valerian can cause agitation. One study found that valerian tends to sedate the agitated person and stimulate the fatigued person, bringing about a balancing effect on the system. Oral forms are available in both standardized and unstandardized forms. Standardized products may be preferable considering the wide variation of the chemicals in the dried root, as noted above. When standardized it is done so as a percentage of valerenic acid or valeric acid. Physician Formulas makes a 300 mg capsule standardized to 0.8% valerenic acid (2.4mg). Nature's Sunshine Time-Release Valerian tablet contains 500 mg of valerian root extract standardized to 0.8% valerenic acid (4mg). Nature Made makes a 400mg capsule standardized to only 0.28% valerenic acid (0.56mg). Nutraceutical makes two 50mg capsules under the names Solaray and Thompson standardized to 0.8% valeric acid (0.4mg). Dosage is difficult to determine due to the lack of standardization and variability in available forms. Typical dosages of the crude herb vary from 1-10 grams per day. Valerian root is non-toxic but may cause side effects in excessive doses. Few adverse events attributable to valerian have been reported. Large doses or chronic use may result in stomach ache, apathy, and a feeling of mental dullness or mild depression. In some individuals, valerian can cause stomach ache, anxiety, and night terrors (see above). An unusual feature of valerian is that the dried root affects the domestic cat in a similar way as that of catnip. If valerian root is left in a place to which cats have access, they will roll in it, salivate onto it and eat it. Burmese cats are attracted to the dried herb and will deliberately destroy containers to obtain it. However, some cats will not go near valerian root. Valerian is also very attractive to rats, so much so that it has been used to bait traps. Some versions of the legend of the Pied Piper of Hamelin have him using valerian, as well as his pipes, to attract the rats.

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/index.php/Valganciclovir

# Valganciclovir hydrochloride Valganciclovir hydrochloride is an antiviral agent that is FDA approved for the treatment of cytomegalovirus (CMV) retinitis; prevention of CMV disease in adults and children. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, pyrexia, nausea, tremor, neutropenia, anemia, graft rejection, thrombocytopenia, hypertension, upper respiratory tract infection, cough, vomiting, constipation.

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/index.php/Validation_therapy

# Validation therapy Validation therapy was developed by Naomi Feil for older people with cognitive impairments and dementia. Feil's own approach classifies individuals with cognitive impairment as having one of four stages in a continuum of dementia. These stages are: The basic principle of the therapy is the concept of validation or the reciprocated communication of respect which communicates that the other's opinions are acknowledged, respected, heard, and (regardless whether or not the listener actually agrees with the content), they are being treated with genuine respect as a legitimate expression of their feelings, rather than marginalized or dismissed. Validation therapy uses different specific techniques, and it has attracted criticism from researchers who dispute the evidence for some of the beliefs and values of validation therapy, and the appropriateness of the techniques; as there are not enough quality evidences proving the efficacy of such method for people with dementia.

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/index.php/Valinomycin

# Valinomycin It is a member of the group of natural neutral ionophores because it doesn't have a residual charge. It consists of enantiomeres D-Valine and L-Valine, D-Hydroxyvaleric acid and L-Lactic acid. Structures are alternated bound via amide and ester bridges. Valinomycin is highly selective for potassium ions over sodium ions within the cell membrane. It functions as a potassium-specific transporter and facilitates the movement of potassium ions through lipid membranes "down" an electrochemical potential gradient. The stability constant K for the potassium-valinomycin complex is 106 and for the sodium-valinomycin complex only 10. This difference is important for maintaining the selectivity of valinomycin for the transport of potassium ions (and not sodium ions) in biological systems. From the chemical structure it can be seen that there are some prevailing features. The 12 carbonyl groups are essential for the binding of metal ions, and also for solvatation in polar solvent. The isopropyl groups and methyl groups are responsible for solvatation in nonpolar solvents. Along with its shape and size this molecular duality is the main reason for its binding properties. For polar solvents valinomycin will mainly expose the carbonyls to the solvent and in nonpolar solvents the iso-propyl groups are located predominantly on the exterior of the molecule. This conformation changes when valinomycin is bound to a potassium ion. The molecule is "locked" into a conformation where the exterior is made up of the isopropyl groups. It is not actually locked into configuration because the size of the molecule makes it highly flexible, but the potassium gives some degree of coordination to the macromolecule.

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/index.php/Valley_Forge_General_Hospital

# Valley Forge General Hospital Valley Forge General Hospital is a former military hospital in Phoenixville, Pennsylvania. The hospital is near both Philadelphia, Pennsylvania and Valley Forge. It was the only United States Army General Hospital named for a place. The hospital was built in 1942, and opened on Washington's Birthday in 1943 to care for the wounded of World War II. It became the largest military hospital in the United States. Eventually, the hospital had well over 3,000 patients and over 100 separate buildings. One feature of the hospital was its design of primarily two story buildings, interconnected by corridors. There were very long ramps leading from one floor to the other, to facilitate movement of wheelchairs, gurneys, and so on. The exterior was all red brick, and looked like a New England College Campus. The interior was all wood, like virtually any military building built during World War II. It was a maze of corridors, and newly assigned personnel regularly became lost. The Army planned to shut down V.F.G.H. in 1950, but the Korean War began, and it stayed open. The final closing came in 1975, although it had stopped functioning as a hospital the previous year. Many of the techniques used in rehabilitating blinded persons were first developed and used at Valley Forge. It was one of the foremost medical units in rehabilitation of blinded personnel in the world. The Acrylic Eye (for people who had lost an eyeball) was invented by one of the dentists at Valley Forge. it is still in use today. The Department of Psychiatry and Neurology was among the world leaders in Psychiatric treatments. Many new medications were first utilized there, and many treatment techniques were developed there. The physicians, nurses and the neuropsychiatric technicians sent tens of thousands of cured personnel back to duty. The return to duty rate following treatment was much higher than in the vast majority of civilian hospitals. In the late 1960s, Valley Forge General Hospital became the home of a "Clinical Specialist" training program (military MOS 91C). At that time, a person had to have been a medic for at least two years, and have a minimum of two years remaining on their enlistment after completing the school, in order to be accepted. This was advanced training for nine months, on top of all previous training and experience. It was intense, and very, very comprehensive. That training enabled graduates to challenge the R.N. boards after I left the Army. The personnel stationed at Valley Forge General Hospital had no married housing available to them. As a result, they rented housing in Phoenixville, Norristown, Pottstown and virtually all of the other local communities. Many of the personnel joined local groups. Each of the enlisted personnel assigned to Valley Forge General Hospital had to undergo basic fire training. They were trained in how to use fire hoses and various nozzles, how to drive fire trucks, and how to use a wide variety of fire equipment. As the entire interior of the hospital was wood, and most of the buildings were interconnected, this training was essential. Many of the married enlisted personnel also joined local volunteer fire departments, where that training paid off. Valley Forge General Hospital was extensively upgraded in the late 1960s, at a cost of millions of dollars. Then, the new Surgeon General of the United States Army decided that it was no longer needed, and it was closed down. It was a huge loss to the military, and to the local community.

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/index.php/Valnoctamide

# Valnoctamide Valnoctamide (INN, USAN) has been used in France as an sedative-hypnotic since 1964. It is a structural isomer of valpromide, a valproic acid prodrug; unlike valpromide, however, valnoctamide is not transformed into its homologous acid, valnoctic acid, in vivo. In addition to being a sedative, valnoctamide has been investigated for use in epilepsy since 1969 and was still being investigated in 2000 and 2003. It was studied for neuropathic pain in 2005 by Winkler et al, with good results: it had minimal effects on motor coordination and alertness at effective doses, and appeared to be equally effective as gabapentin. RH Belmaker, Yuly Bersudsky and Alex Mishory started a clinical trial of valnoctamide for prophylaxis of mania in lieu of the much more teratogenic valproic acid or its salts. Valnoctamide is a racemic compound with four stereoisomers, all of which were shown to be more effective than valproic acid in animal models of epilepsy and one of which ((2S,3S)-valnoctamide) was considered to be a good candidate by Isoherranen, et al for an anticonvulsant in August of 2003.

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/index.php/Valofane

# Valofane Valofane is a sedative drug structurally related to the barbiturates and similar drugs such as primidone. It is metabolised once inside the body to form the barbiturate proxibarbal and is thus a prodrug.

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/index.php/Valproate

# Valproate Valproate, an acidic chemical compound, has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches. VPA is a liquid at room temperature, but it can be reacted with a base such as sodium hydroxide to form the salt sodium valproate, which is a solid. The acid, salt, or a mixture of the two (valproate semisodium) are marketed under the various brand names Depakote, Depakote ER, Depakene, Depakine, Depakine Crono (extended release in Spain), Depacon, Dépakine, Valparin, and Stavzor. Approved uses of the various formulations vary by country; e.g., valproate semisodium is used as a mood stabilizer and also in the US as an anticonvulsant. As an anticonvulsant, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, juvenile myoclonic epilepsy, and the seizures associated with Lennox-Gastaut syndrome. It is also used in treatment of myoclonus. In some countries, parenteral preparations of valproate are used also as second-line treatment of status epilepticus, as an alternative to phenytoin. Valproate is one of the most common drugs used to treat post-traumatic epilepsy. It is more recently being used to treat neuropathic pain, as a second-line agent, particularly lancinating pain from A delta fibers. In the United States, valproic acid is approved by the Food and Drug Administration only for the treatment of manic episodes associated with bipolar disorder, adjunctive therapy in multiple seizure types (including epilepsy), and prophylaxis of migraine headaches. Some randomized controlled studies have repeatedly indicated that sodium valproate and valproic acid, in borderline personality disorder and antisocial personality disorder, may have some slight to moderate mood-stabilizing advantage over no drug treatment or placebo. This is because it is believed to help reduce impulsive aggressive behavioral episodes and improving interpersonal sensitivity. These improvements would likely be somewhat better when used along with the standard psychotherapeutic regimen for these disorders- which often incorporates, among other elements, individual intensive one-on-one cognitive behavioral therapy, perhaps in a secure setting. However, these two personality disorders are widely known to still normally be lifelong and quite treatment-resistant, with a significant recidivism rate. The enzyme histone deacetylase 1 (HDAC1) is needed for HIV to remain latent, or dormant, in infected cells. When the virus is latent, it cannot be destroyed by anti-HIV drugs. A study published in August 2005 found that three of four patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a mean 75% reduction in latent HIV infection. The idea was that valproic acid, by inhibiting HDAC1, forced HIV out of latency (reactivation) and into its replicative cycle. The highly active antiretroviral drugs could then stop the virus, whilst the immune system could destroy the infected cell. Flushing out all latent virus in this manner would potentially cure HIV patients. Subsequent trials, however, found no long-term benefits of valproic acid in HIV infection. Three distinct formulations of valproic acid have been investigated in clinical trials for the treatment of colorectal polyps in familial adenomatous polyposis patients; treatment of hyperproliferative skin diseases (e.g., basal cell carcinoma); and treatment of inflammatory skin diseases (e.g., acne) by TopoTarget. The current names for these therapeutics are Savicol, Baceca and Avugane, respectively. Valproic acid's function as an HDAC inhibitor has also led to its use in direct reprogramming in generation of induced pluripotent stem (iPS) cells, where it has been shown that addition of VPA allows for reprogramming of human fibroblasts to iPS cells without addition of genetic factors Klf4 and c-myc. This function has also been investigated as an epigenetic therapy for treatment of lupus. In a single small study, adult men who took valproate learned to identify pitch better than those taking placebo. It is believed that the drug affects the "plasticity" of the human brain, though the mechanisms of how are not fully understood. Valproic acid was first synthesized in 1882 by B.S. Burton as an analogue of valeric acid, found naturally in valerian. It has two propyl groups, hence the name "val.pro~ic". Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented pentylenetetrazol-induced convulsions in laboratory rats. It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide. Valproic acid has also been used for migraine prophylaxis and bipolar disorder. Valproate is believed to affect the function of the neurotransmitter GABA in the human brain, making it an alternative to lithium salts in treatment of bipolar disorder. Its mechanism of action includes enhanced neurotransmission of GABA (by inhibiting GABA transaminase, which breaks down GABA). However, several other mechanisms of action in neuropsychiatric disorders have been proposed for valproic acid in recent years. Dosing depends on which disease is being treated and whether valproic acid is being treated for maintenance or acute application. For maintenance of bipolar disorder type 1 the dose range can be tested through blood serum testing or by mg per kilogram of weight: minimum of 250 mg a day of Depakote up to 3000 mg a day. For acute treatment of bipolar type 1 the minimum dose would be 1000 mg a day. Valproic acid or valproate are synergistic with lithium, with combination therapy proving more efficacious than monotherapy with valproic acid or valproate alone. This is true at least for glutamate excitotoxicity, amyotrophic lateral sclerosis, Huntington's disease, and bipolar disorder. Valproate causes birth defects; exposure during pregnancy is associated with about three times as many major anomalies as usual, mainly spina bifida and, more rarely, with several other defects, possibly including a "valproate syndrome". Characteristics of this valproate syndrome include facial features that tend to evolve with age, including trigonocephaly, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth. Women who intend to become pregnant should switch to a different drug if possible. Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although vaproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have even worse consequences.) They should take high-dose folic acid and be offered antenatal screening (alpha-fetoprotein and second-trimester ultrasound scans), although screening and scans do not find all birth defects. Valproate is a folate antagonist, which can cause neural tube defects. Thus, folic acid supplements may alleviate the teratogenic problems. A recent study showed children of mothers taking valproate during pregnancy are at risk for significantly lower IQs. Maternal valproate use during pregnancy has been associated with a significantly higher risk of autism in the offspring. Exposure of the human embryo to valproic acid is associated with risk of autism, and it is possible to duplicate features characteristic of autism by exposing rat embryos to valproic acid at the time of neural tube closure. Valproate exposure on embryonic day 11.5 led to significant local recurrent connectivity in the juvenile rat neocortex, consistent with the underconnectivity theory of autism. A 2009 study found that the 3 year old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed. The foremost and most severe concern for anyone taking valproic acid is its potential for sudden and severe, possibly fatal, fulminating impairments in liver and impairments of hematopoietic or pancreatic function, especially in those just starting the medication. This particular warning is the first one listed on any drug adverse effect listing when one receives the drug at the pharmacy. In rare reports, individuals having used valproic acid for a long time (chronic users) have suffered renal impairment, usually as a result of having been injured or ill or on a drug regimen already and, so, having been overwhelmed. Absolute contraindications are pre-existing severe hepatic (liver) or renal (kidney) damage and certain cases of metastatic cancer, severe hepatitis or pancreatitis, end-stage AIDS HIV infection, marked bone marrow depression, urea cycle disorders, and coagulation hematological disorders that have caused impairment. Some patients with symptomatic but manageable AIDS, cancer, and hepatic or renal disease are kept on the medication (usually at a reduced dose with more frequent blood tests) to avoid having to manipulate the drug regimen for as long as possible. Common side effects are dyspepsia or weight gain. Less common are fatigue, peripheral edema, acne, feelings of feeling cold or chills, blurred vision, burning of the eyes, dizziness, drowsiness, hair loss, headaches, nausea, sedation, and tremors. Valproic acid also causes hyperammonemia, an increase of ammonia levels in the blood, which can lead to vomiting and sluggishness, and ultimately to mental changes and brain damage. Valproate levels within the normal range are capable of causing hyperammonemia and ensuing encephalopathy. Lactulose has been used on a temporary basis to alleviate the hyperammonemia caused by valproic acid. L-Carnitine is used for hyperammonemia caused by valproic acid toxicity. There have been reports of the development of brain encephalopathy without hyperammonemia or elevated valproate levels. In rare circumstances, valproic acid can cause blood dyscrasia, impaired liver function, jaundice, thrombocytopenia, and prolonged coagulation (clotting) times due to a lack of blood cells. In about 5% of pregnant users, valproic acid will cross the placenta and cause congenital anomalies that resemble fetal alcohol syndrome, with a possibility of cognitive impairment. Due to these side effects, most doctors will try to continue the medication, but will ask for blood tests, initially as often as once a week and then once every two months (those taking it for a long period may go six months before being retested; if a pregnant woman and her doctor decide to keep using the drug and to keep the pregnancy, then frequent blood testing, and possibly a higher frequency of diagnostic ultrasounds to identify fetal problems, is a must). Temporary liver enzyme increase has been reported in 20% of cases during the first few months of taking the drug. Inflammation of the liver (hepatitis), the first symptom of which is jaundice, is found in rare cases. According to the information provided with a prescription of this drug, some individuals have become depressed or had a suicidal ideation while on the drug; those taking it should be monitored for this side effect. Excessive amounts of valproic acid can result in tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. Overdosage in children is usually of an accidental nature, whereas with adults it is more likely to be an intentional act. In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/l during controlled therapy, but may reach 150–1500 mg/l following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography. In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body. Supplemental L-carnitine is indicated in patients having an acute overdose and also prophylactically in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly than L-carnitine. Valproic acid may interact with carbamazepine, as valproates inhibit microsomal epoxide hydrolase (mEH), the enzyme responsible for the breakdown of carbamazepine-10,11 epoxide (the main active metabolite of carbamazepine) into inactive metabolites. By inhibiting mEH, valproic acid causes a buildup of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion. Aspirin may decrease the clearance of valproic acid, leading to higher-than-intended serum levels of the anticonvulsant. Also, combining valproic acid with the benzodiazepine clonazepam can lead to profound sedation and increases the risk of absence seizures in patients susceptible to them. Valproic acid and sodium valproate reduce the apparent clearance of lamotrigine (Lamictal). In most patients, the lamotrigine dosage for coadministration with valproate must be reduced to half the monotherapy dosage. Valproic acid is contraindicated in pregnancy, as it decreases the intestinal reabsorption of folate (folic acid), which leads to neural tube defects. Because of a decrease in folate, megaloblastic anemia may also result. Phenytoin also decreases folate absorption, which may lead to the same adverse effects as valproic acid. Valproic acid, 2-propylvaleric acid, is synthesized by the alkylation of ethyl cyanoacetate with two moles of propyl bromide, to give dipropylcyanoacetic ester. Hydrolysis and decarboxylation of the carboethoxy group gives 2-propylpentanenitrile, which is hydrolyzed into valproic acid.

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/index.php/Valproate_semisodium_detailed_information

# Valproate semisodium detailed information Valproate semisodium (INN) or divalproex sodium (USAN) consists of a compound of sodium valproate and valproic acid in a 1:1 molar relationship in an enteric coated form. It is used in the UK and U.S. for the treatment of the manic episodes of bipolar disorder, and increasingly taken long-term for prevention of both manic and depressive phases of bipolar disorder, especially the rapid-cycling variant. It is also used in the US for the treatment of epilepsy, chronic pain associated with neuropathy, and migraine headaches. Its chemical name is sodium hydrogen bis(2-propylpentanoate). The extended release formulation allows for a single daily dose. In the UK semisodium valproate has been sold for a few years as the proprietary drug Depakote and marketed for psychiatric conditions only. It is about five times the price of sodium valproate, which has been marketed for around 30 years as Epilim by the same company for epilepsy and is also available from other manufacturers as a generic product. People who take this drug can experience a variety of side effects, some of which may or may not require immediate medical attention. Especially dangerous side effects include vomiting, loss of appetite, fever, or dark urine. These suggest a possibility of liver damage. People taking this drug should also call their doctor if they experience other serious side effects. Some serious side effects are unusual bleeding (especially in the urine), hallucinations, and extreme drowsiness.

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/index.php/Valproate_sodium_adverse_reactions

# Valproate sodium adverse reactions The adverse reactions that can result from Depacon use include all of those associated with oral forms of valproate. The following describes experience specifically with Depacon. Depacon 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 Depacon 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. In a separate clinical safety trial, 112 patients with epilepsy were given infusions of Depacon (up to 15 mg/kg) over 5 to 10 minutes (1.5-3.0 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 Depacon cannot be provided. Hyperammonemia with encephalopathy has been reported in 2 patients after infusions of Depacon. Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote (divalproex sodium) was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote-treated patients (6%), compared to 1% of placebo-treated patients. Table 2 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs. Although Depacon has not been evaluated for safety and efficacy in the treatment of manic episodes associated with bipolar disorder, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote (Divalproex Sodium) tablets. Although Depacon has not been evaluated for safety and efficacy in the prophylactic treatment of migraine headaches, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote (Divalproex Sodium) tablets. There have been postmarketing reports of reversible and irreversible cerebral and cerebellar atrophy temporally associated with the use of valproate products. In some cases the patients recovered with permanent sequelae [see Warnings and Precautions (5.7)]. Cerebral atrophy has been reported in children exposed to valproate in utero[see Use in Specific Populations (8.1)]. There have been rare reports of Fanconi's syndrome occurring chiefly in children. Decreased carnitine concentrations have been reported although the clinical relevance is undetermined. Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia. Genitourinary: Enuresis and urinary tract infection. Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported.

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/index.php/Valproate_sodium_clinical_pharmacology

# Valproate sodium clinical pharmacology Depacon exists as the valproate ion in the blood. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Equivalent doses of intravenous (IV) valproate and oral valproate products are expected to result in equivalent Cmax, Cmin, and total systemic exposure to the valproate ion when the IV valproate is administered as a 60 minute infusion. However, the rate of valproate ion absorption may vary with the formulation used. These differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. Administration of Depakote (divalproex sodium) tablets and IV valproate (given as a one hour infusion), 250 mg every 6 hours for 4 days to 18 healthy male volunteers resulted in equivalent AUC, Cmax, Cmin at steady state, as well as after the first dose. The Tmax after IV Depacon occurs at the end of the one hour infusion, while the Tmax after oral dosing with Depakote occurs at approximately 4 hours. Because the kinetics of unbound valproate are linear, bioequivalence between Depacon and Depakote up to the maximum recommended dose of 60 mg/kg/day can be assumed. The AUC and Cmax resulting from administration of IV valproate 500 mg as a single one hour infusion and a single 500 mg dose of Depakene syrup to 17 healthy male volunteers were also equivalent. Patients maintained on valproic acid doses of 750 mg to 4250 mg daily (given in divided doses every 6 hours) as oral Depakote (divalproex sodium) alone (n = 24) or with another stabilized antiepileptic drug [carbamazepine (n = 15), phenytoin (n = 11), or phenobarbital (n = 1)], showed comparable plasma levels for valproic acid when switching from oral Depakote to IV valproate (1-hour infusion). Eleven healthy volunteers were given single infusions of 1000 mg IV valproate over 5, 10, 30, and 60 minutes in a 4-period crossover study. Total valproate concentrations were measured; unbound concentrations were not measured. After the 5 minute infusions (mean rate of 2.8 mg/kg/min), mean Cmax was 145 ± 32 mcg/mL, while after the 60 minute infusions, mean Cmax was 115 ± 8 mcg/mL. Ninety to 120 minutes after infusion initiation, total valproate concentrations were similar for all 4 rates of infusion. Because protein binding is nonlinear at higher total valproate concentrations, the corresponding increase in unbound Cmax at faster infusion rates will be greater. The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) (see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs). Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear. Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean terminal half-life for valproate monotherapy after an intravenous infusion of 1,000 mg was 16 ± 3.0 hours. The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.2)]. There are no differences in the body surface area adjusted unbound clearance between males and females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively). Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)].

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# Valproate sodium clinical studies The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. In one, multiclinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate.

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# Valproate sodium contraindications Depacon is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions (5.1)].

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# Valproate sodium description Depacon solution is available in 5 mL single-dose vials for intravenous injection. Each mL contains valproate sodium equivalent to 100 mg valproic acid, edetate disodium 0.40 mg, and water for injection to volume. The pH is adjusted to 7.6 with sodium hydroxide and/or hydrochloric acid. The solution is clear and colorless.

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# Valproate sodium dosage and administration Use of Depacon for periods of more than 14 days has not been studied. Patients should be switched to oral valproate products as soon as it is clinically feasible. Depacon should be administered as a 60 minute infusion (but not more than 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary. In one clinical safety study, approximately 90 patients with epilepsy and with no measurable plasma levels of valproate were given single infusions of Depacon (up to 15 mg/kg and mean dose of 1184 mg) over 5-10 minutes (1.5-3.0 mg/kg/min). Patients generally tolerated the more rapid infusions well [see Adverse Reactions (6.1)]. This study was not designed to assess the effectiveness of these regimens. For pharmacokinetics with rapid infusions, see Clinical Pharmacology (12.3). Depacon has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depacon therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Depacon may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)]. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)]. When switching from oral valproate products, the total daily dose of Depacon should be equivalent to the total daily dose of the oral valproate product [see Clinical Pharmacology (12)], and should be administered as a 60 minute infusion (but not more than 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary. Patients receiving doses near the maximum recommended daily dose of 60 mg/kg/day, particularly those not receiving enzyme-inducing drugs, should be monitored more closely. If the total daily dose exceeds 250 mg, it should be given in a divided regimen. There is no experience with more rapid infusions in patients receiving Depacon as replacement therapy. However, the equivalence shown between Depacon and oral valproate products (Depakote) at steady state was only evaluated in an every 6 hour regimen. Whether, when Depacon is given less frequently (i.e., twice or three times a day), trough levels fall below those that result from an oral dosage form given via the same regimen, is unknown. For this reason, when Depacon is given twice or three times a day, close monitoring of trough plasma levels may be needed. Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these 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. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males)[see Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Rapid infusion of Depacon has been associated with an increase in adverse reactions. There is limited experience with infusion times of less than 60 minutes or rates of infusion > 20 mg/min in patients with epilepsy [see Adverse Reactions (6)]. Depacon should be administered intravenously as a 60 minute infusion, as noted above. It should be diluted with at least 50 mL of a compatible diluent. Any unused portion of the vial contents should be discarded. Depacon was found to be physically compatible and chemically stable in the following parenteral solutions for at least 24 hours when stored in glass or polyvinyl chloride (PVC) bags at controlled room temperature 15-30°C (59-86°F).

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# Valproate sodium dosage forms and strengths Depacon (valproate sodium injection), equivalent to 100 mg of valproic acid per mL, is a clear, colorless solution in 5 mL single-dose vials, available in trays of 10 vials.

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# Valproate sodium drug interactions In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction is not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.13)]. A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronyl transferases. The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n = 6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n = 16) had no effect on the steady-state kinetics of lithium. Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 µg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.9, 5.10)]. Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.9, 5.11)].

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# Valproate sodium how supplied storage and handling Depacon (valproate sodium injection), equivalent to 100 mg of valproic acid per mL, is a clear, colorless solution in 5 mL single-dose vials, available in trays of 10 vials (NDC 0074-1564-10).

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# Valproate sodium indications and usage Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations (8.1), and Patient Counseling Information (17.3)].

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# Valproate sodium nonclinical toxicology Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD dose on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown.

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# Valproate sodium overdosage Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate serum concentrations as high as 2120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepilepsy effects of valproate, it should be used with caution in patients with epilepsy.

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# Valproate sodium patient counseling information Inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to use effective contraception while using valproate. When appropriate, counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death [see Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)]. Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.9, 5.10)]. Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.12)].

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# Valproate sodium use in specific populations To collect information on the effects of in utero exposure to Depacon, physicians should encourage pregnant patients taking Depacon to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)]. Valproate should not be used to treat women with epilepsy who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling. Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully. In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% - 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 - 2000 mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% C.I. 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% C.I. 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. Experience with oral valproate has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning]. The safety of Depacon has not been studied in individuals below the age of 2 years. If a decision is made to use Depacon in this age group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults[see Adverse Reactions (6)]. A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.2)].

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# Valproate sodium warnings and precautions Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months of valproate therapy. However, physicians should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depacon is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Use of Depacon has not been studied in children below the age of 2 years. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Depacon is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depacon should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depacon for the development of acute liver injury with regular clinical assessments and serum liver test monitoring. Women with epilepsy who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416 patients, representing 1044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning]. Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of valproate therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)]. The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depacon be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6, 5.10)]. 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 (5.11)]. 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(5.9)]. 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)]. 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 Depacon in patients with acute head trauma for the prophylaxis of post-traumatic seizures. 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.

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# Valproic acid Valproic acid is a anticonvulsant drug that is FDA approved for the {{{indicationType}}} of absence seizure, Simple and complex, complex partial epileptic seizur, manic, bipolar I disorder, migraine; Prophylaxis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include peripheral edema,alopecia, rash, increased appetite, weight increased, abdominal pain, constipation, diarrhea, indigestion, loss of appetite, nausea, vomiting, ecchymosis, sthenia, backache, amnesia, ataxia, dizziness, headache, insomnia, somnolence, tremor, amblyopia, blurred vision, diplopia, nystagmus, tinnitus, depression, disturbance in thinking, feeling nervous, mood swings, bronchitis, dyspnea, pharyngitis, respiratory tract infection, rhinitis, fever, influenza. Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions . When Depakene is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence . A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. See below, "Patients with Known or Suspected Mitochondrial Disease." Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakene products are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Note - Warnings and Precautions Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal. Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning]. The efficacy of divalproex sodium in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. In one, multiclinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either divalproex sodium or placebo. Randomized patients were to be followed for a total of 16 weeks. The following table presents the findings. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks Add-on TreatmentNumber of PatientsBaseline IncidenceExperimental Incidence* Reduction from baseline statistically significantly greater for divalproex sodium than placebo at p0.05 level.Divalproex sodium7516.08.9*Placebo6914.511.5Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for divalproex sodium than for placebo. For example, 45% of patients treated with divalproex sodium had a50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. There is limited information regarding Valproic acid overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly. Inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to use effective contraception while using valproate. When appropriate, counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death. Advise patients to read the Medication Guide, which appears as the last section of the labeling. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334. Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers. Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately.

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# Valproic acid capsule/solution adverse reactions Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote-treated patients (6%), compared to 1% of placebo-treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-treated patients and for which the incidence was greater than in the placebo group, in a placebo-controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose Depakote group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with Depakote in the controlled trials of complex partial seizures: Although Depakene has not been evaluated for safety and efficacy in the treatment of manic episodes associated with bipolar disorder, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote tablets. Although Depakene has not been evaluated for safety and efficacy in the treatment of prophylaxis of migraine headaches, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote tablets. An additional case of toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7)].

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# Valproic acid capsule/solution clinical pharmacology Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its antiepileptic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours). While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.1)]. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide). (See Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs.) Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg. [See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.

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# Valproic acid capsule/solution clinical studies The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for Depakote than for placebo. For example, 45% of patients treated with Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. The second study assessed the capacity of Depakote to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to Depakote. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose Depakote than for low dose Depakote. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose Depakote.

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# Valproic acid capsule/solution contraindications Depakene is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions (5.1)].

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# Valproic acid capsule/solution description Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic solvents. Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule contains 250 mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5 mL as the sodium salt.

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# Valproic acid capsule/solution dosage and administration Patients should be informed to take Depakene every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions(7.2)]. Depakene has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)]. The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.9)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

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# Valproic acid capsule/solution dosage forms and strengths Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules and as a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of 16 ounces.

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# Valproic acid capsule/solution drug interactions A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction is not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.14)]. Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%.

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# Valproic acid capsule/solution how supplied storage and handling Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC 0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16).

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# Valproic acid capsule/solution indications and usage Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures.

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# Valproic acid capsule/solution overdosage Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however, patients have recovered from valproate levels as high as 2120 mcg/mL.

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# Valproic acid capsule/solution patient counseling information Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations (8.1)]. Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers [see Warnings and Precautions (5.8)]. Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.13)].

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# Valproic acid capsule/solution use in specific populations To collect information on the effects of in utero exposure to Depakene, physicians should encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy. Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Depakene should not be used to treat women with epilepsy who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling. To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.9)]. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully. Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% – 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 – 2000 mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I. 104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning]. When Depakene is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)]. No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.15)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.2)].

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# Valproic acid capsule/solution warnings and precautions Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakene products are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakene should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakene for the development of acute liver injury with regular clinical assessments and serum liver test monitoring. Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. The largest of these studies1 is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]), and phenytoin (108 [95% C.I. 104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of valproate therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.11)]. Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose-related. In a clinical trial of Depakote (divalproex sodium) as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakene (valproic acid) be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. 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 (5.12)]. 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 (5.6, 5.10)]. 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. 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)]. 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.

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# Valproic acid capsule delayed release adverse reactions The incidence of treatment-emergent events has been ascertained based on combined data from 2 placebo-controlled clinical trials of valproate in the treatment of manic episodes associated with bipolar disorder. The adverse events were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, valproate, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, valproate , and lithium carbonate groups, respectively. Table 2 summarizes those adverse events reported for patients in these trials where the incidence rate in the valproate -treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the valproate -treated group was statistically significantly greater than the placebo group. Vomiting was the only event that was reported by significantly (p ≤ 0.05) more patients receiving valproate compared to placebo. The following additional adverse events were reported by greater than 1% but not more than 5% of the 89 valproate-treated patients in controlled clinical trials: Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, valproate was generally well tolerated with most adverse events rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the valproate -treated patients (6%), compared to 1% of placebo-treated patients. Table 3 lists treatment-emergent adverse events which were reported by ≥ 5% of valproate -treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse events can be ascribed to valproate alone, or the combination of valproate and other antiepilepsy drugs. Table 4 lists treatment-emergent adverse events which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of valproate monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse events can be ascribed to valproate alone, or the combination of valproate and other antiepilepsy drugs. The following additional adverse events were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: Based on 2 placebo-controlled clinical trials and their long-term extension, valproate was generally well tolerated with most adverse events rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long-term extension study, the adverse events reported as the primary reason for discontinuation by ≥ 1% of 248 valproate -treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). Table 5 includes those adverse events reported for patients in the placebo-controlled trials where the incidence rate in the valproate -treated group was greater than 5% and was greater than that for placebo patients. Adverse events that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system. The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. The administration of delayed-release valproic acid capsules may result in reduction of gastrointestinal side effects in some patients. Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose- related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances, encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders [see Warnings and Precautions (5.5)]. Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month-old infant taking valproate and several other concomitant medications. An additional case of toxic epidermal necrosis resulting in death was reported in a 35 year-old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7)]. Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage [see Warnings and Precautions (5.7) and Drug Interactions (7)]. Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. Minor elevations of transaminases (eg, SGOT and SGPT) and LDH are frequent and appear to be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and Precautions (5.1)].

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# Valproic acid capsule delayed release clinical pharmacology Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). A single-dose randomized crossover study compared Stavzor 500-mg strength capsules to 500-mg Depakote delayed-release tablets. These studies demonstrated that the 2 products had similar plasma concentration-time profiles under fasted conditions in terms of valproic acid, although the median Tmax occurred earlier with STAVZOR (2.0 hrs versus 3.5 hrs). Co-administration with food increased the Tmax of Stavzor (2.0 hrs without food and approximately 4.8 hours with food), and resulted in a 23% decrease in Cmax of valproic acid, although there was no change in systemic exposure (AUC). Although the rate of valproate ion absorption may vary with the conditions of use (eg. fasting or postprandial), these differences should be of minor clinical importance under the steady-state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had an influence on the rate of absorption of the capsule (increase in Tmax from 2.3 to 6.1 hours). While the absorption rate from the GI tract and fluctuation in valproate plasma concentrations vary with dosing regimen, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to 4-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicates that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. Co-administration of oral valproate products with food should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2)] . An in vitro study evaluating dissolution of valproic acid showed earlier dissolution in the presence of ethanol than in the absence of ethanol. This has not been studied in humans. However, there is a potential for an earlier Tmax and therefore a higher Cmax when valproic acid is given with alcohol. Any changes in dosage administration, or the addition or discontinuance of concomitant drugs, should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (eg. aspirin). Conversely, valproate may displace certain protein-bound drugs (eg. phenytoin, carbamazepine, warfarin, and tolbutamide). [See Drug Interactions (7) for more detailed information on the pharmacokinetic interactions of valproate with other drugs]. Children within the first 2 months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.4)] . Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2- to 2.6-fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [See Boxed Warning, Contraindications (4), Warnings and Precautions (5.1)] . A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration (2.1)] .

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# Valproic acid capsule delayed release clinical studies (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Valproate was initiated at a dose of 250 mg TID and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean valproate doses for completers in this study were 1118, 1525, and 2402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carried-forward[LOCF]) analysis were as follows: (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Valproate was initiated at a dose of 250 mg TID and adjusted within a dose range of 750-2500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean valproate doses for completers in this study were 1116, 1683, and 2006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1312, 1869, and 1984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for 2 subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (LOCF) analysis were as follows: Valproate was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in 2 controlled trials. In one, multiclinic, placebo-controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer 8 or more CPS per 8 weeks during an 8-week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either valproate or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high- or low-dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8- to 12- week-long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a 2-week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to valproate monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low-dose and high-dose groups, respectively. Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high-dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high-dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low-dose valproate. Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception. In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Valproate or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase. In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, valproate to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250-mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on valproate doses ranged from 500 to 2500 mg a day. Doses over 500 mg were given in 3 divided doses (TID). The mean dose during the treatment phase was 1087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL. The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the valproate group (see Figure 2). These rates were significantly different. In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three valproate dose groups (500, 1000, or 1500 mg/day) or placebo. The treatments were given in 2 divided doses (BID). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1000/1500 mg/day group and placebo group. The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the valproate 500, 1000, and 1500 mg/day groups, respectively. The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the valproate 500, 1000, and 1500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined valproate 1000/1500 mg group were significantly lower than in the placebo group.

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# Valproic acid capsule delayed release contraindications Stavzor should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)]. is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder[see Warnings and Precautions (5.1)].

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# Valproic acid capsule delayed release description Valproic acid is a carboxylic acid designated as 2–propylpentanoic acid. It is also known as dipropylacetic acid. Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a characteristic odor. It is slightly soluble in water (1.3 mg/ml) and very soluble in organic solvents. Valproic acid has the following structure Stavzor (valproic acid) delayed release capsules are for oral administration and are provided as orange-colored, oval-shaped capsules in 3 dosage strengths: 125 mg, 250 mg, 500 mg of valproic acid. Stavzor (valproic acid) delayed release capsules also contain ammonia hydroxide, gelatin, glycerin, methacrylic acid copolymer, triethyl citrate, water and FD&C Yellow No. 6 as the colorant. Each capsule is printed with a Opacode WB as the black printing ink.

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# Valproic acid capsule delayed release dosage and administration Stavzor (valproic acid) delayed release capsules are administered orally, and must be swallowed whole. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during Stavzor treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the benefits of Stavzor in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Stavzor, the safety of Stavzor in long-term use is supported by data from record reviews involving approximately 360 patients treated with valproate for greater than 3 months. Stavzor (valproic acid) delayed release capsules are administered orally, and must be swallowed whole. As Stavzor dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)] . Valproate has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 - 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Stavzor therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Stavzor may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in 2 to 3 doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical studies Studies (14.3)] . However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)]. The recommended initial dose is 15 mg/kg/day, increasing at 1-week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in 2 to 3 doses. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures are considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)]. In epileptic patients previously receiving Depakene (valproic acid) therapy, Stavzor should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Stavzor, a dosing schedule of 2 or 3 times a day may be elected in selected patients. Stavzor (valproic acid) delayed release capsules are administered orally, and must be swallowed whole. The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1000 mg/day. In clinical trials, there was no evidence that higher doses led to greater efficacy. Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these 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. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.13)]. The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose- related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males)[see Warnings and Precautions (5.7)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

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# Valproic acid capsule delayed release drug interactions In contrast, drugs that are inhibitors of cytochrome P450 isozymes, eg. antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate-free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (ertapenem, imipenem, meropenem) and may result in loss of seizure control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.12)]. A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. An in vitro study evaluating dissolution of valproic acid showed earlier dissolution in the presence of ethanol than in the absence of ethanol. This has not been studied in humans. However, there is a potential for an earlier Tmax and therefore a higher Cmax when valproic acid is given with alcohol. Caution is advised if valproic acid is taken with alcohol. Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproic acid therapy is instituted in patients taking anticoagulants. In 6 patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy[see Warnings and Precautions (5.5), (5.8) and (5.9)]. Concomitant administration of topiramate with valproic acid has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.8, 5.10)].

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# Valproic acid capsule delayed release indications and usage Stavzor® is indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. The efficacy of valproate was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1)]. The safety and effectiveness of valproate for long-term use in mania, i.e., more than 3 weeks, has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use Stavzor for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient. Stavzor is indicated as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures. Stavzor is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations (8.1), and Patient Counseling Information (17.3)].

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# Valproic acid capsule delayed release nonclinical toxicology Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum human dose on a mg/m2 basis) for 2 years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days.The effect of valproate on testicular development and on sperm production and fertility in humans is unknown.

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# Valproic acid capsule delayed release overdosage Over dosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2120 mcg/mL. Naloxone has been reported to reverse the CNS depressant effects of valproate over dosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.

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# Valproic acid capsule delayed release patient counseling information Patients and guardians should be warned that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly[see Warnings and Precautions (5.4)] Prescribers should inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Prescribers should advise women to use effective contraception while using valproate. Prescribers should counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Patients should read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [See Use in Specific Populations (8.1)] Patients, their caregivers, and families should be counseled that AEDs, including Stavzor, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur. [see Warnings and Precautions (5.8, 5.9)] . Since valproate products may produce CNS depression, especially when combined with another CNS depressant (eg, alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug. Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions (5.11)]. Read this Medication Guide before you start taking STAVZOR and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. 1. Serious liver damage that can cause death, especially in children younger than 2 years old. The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment. If you take STAVZOR during pregnancy for any medical condition, your baby is at risk for serious birth defects. The most common birth defects with STAVZOR affect the brain and spinal cord and are called spina bifida or neural tube defects. They may occur in up to 5 out of every 100 babies born to mothers who use this medicine at high doses during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects can happen. All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of STAVZOR. If the decision is made to use Stavzor, you should use effective birth control (contraception). Tell your healthcare provider right away if you become pregnant while taking STAVZOR. You and your healthcare provider should decide if you will continue to take STAVZOR while you are pregnant. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. Do not stop Stavzor without first talking to a healthcare provider. Stopping Stavzor suddenly can cause serious problems.Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that do not stop (status epilepticus). Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, herbal supplements, and medicines that you take for a short period of time. Taking STAVZOR with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine. Take STAVZOR exactly as your healthcare provider tells you. Your healthcare provider will tell you how much STAVZOR to take and when to take it. Swallow STAVZOR whole. Do not crush, chew, or break STAVZOR. Tell your healthcare provider if you can not swallow STAVZOR whole.You may need a different medicine. If you take too much STAVZOR, call your healthcare provider or local Poison Control Center right away. STAVZOR can make you sleepy or dizzy. Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking STAVZOR, until you talk to your doctor. Taking STAVZOR with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. Do not drive, operate heavy machinery, or do other dangerous activities until you know how STAVZOR affects you. STAVZOR can slow your thinking and motor skills. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use STAVZOR for a condition for which it was not prescribed. Do not give STAVZOR to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about STAVZOR. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about STAVZOR that is written for health professionals

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# Valproic acid capsule delayed release use in specific populations To collect information on the effects of in utero exposure to Stavzor, physicians should encourage pregnant patients taking Stavzor to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies. Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. [see Warnings and Precautions (5.3)] Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.7)] . A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully. Patients taking valproate may develop hepatic failure [see Warnings and Boxed Warnings]. Fatal hepatic failures, in a newborn and in an infant, have been reported following the maternal use of valproate during pregnancy. Published epidemiological studies have indicated that children exposed to valproate in utero have IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I. 104–112 It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Valproate is excreted in breast milk. Concentrations in breast milk have been reported to be 1-10% of serum concentrations. Because of the potential for adverse reactions in a nursing infant, a decision should be made whether to discontinue nursing or drug taking into account the importance of the drug to the mother. Experience has indicated that pediatric patients under the age of 2 years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning, Warning and Precautions (5.1)]. When valproic acid is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Valproate was studied in seven pediatric clinical trials. A double-blind placebo-controlled trial evaluated the efficacy of valproate for the treatment of mania in 150 patients aged 10 to 17 years, 76 of whom were on valproate. Efficacy was not established. A double-blind placebo-controlled trial evaluated the efficacy of valproate for the treatment of migraine in 304 patients aged 12 to 17 years, 231 of whom were on valproate. Efficacy was not established. Based on the results of this study, it is not expected that valproate would be effective in patients with migraine below the age of 12. The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of valproate for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of valproate for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of valproate in the indication of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)]. Discontinuation of valproate was occasionally associated with the latter two 2 events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.13)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.4)]. There is insufficient information available to discern the safety and effectiveness of valproic acid for the prophylaxis of migraines in patients over 65. The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26) [see Clinical Pharmacology (12.3)].

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# Valproic acid capsule delayed release warnings and precautions Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first sixmonths. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. See below, "Patients with known or suspected mitochondrial disease." Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Stavzor is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate then those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents. POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testingshould be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations, are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders. Stavzor is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Stavzor should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Stavzor for the development of acute liver injury with regular clinical assessments and serum liver test monitoring Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (N=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero causes decreased IQ in children. In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits. [see Use in Specific Populations (8.1)] Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients. [see Boxed Warning and Use in Specific Populations (8.1)]. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients receiving valproate. Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416 patients, representing 1044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Stavzor should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated. [see Boxed Warning]. Stavzor is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with UCD, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of Stavzor therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low blood urea nitrogen (BUN), or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying UCD. [see Contraindications (4)and Warnings and Precautions (5.8,5.9)]. Antiepileptic drugs (AEDs), including Stavzor, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose- related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤75 x 109%L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg%mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (eg, low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Stavzor be monitored for platelet count and coagulation parameters prior to planned surgery. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥110 mcg/mL (females) or ≥135 mcg/mL (males). Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.10)] If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders andsee Contraindications and Warnings and Precautions (4,5.5)] Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered . Concomitant administration of topiramate and valproic acid 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 event 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 valproic acid 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)]. 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. Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (eg. eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. Carbapenem antibiotics (ertapenem, imipenem, meropenem) may reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)] . Since valproic acid 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)] . 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.

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/index.php/Valpromide

# Valpromide Valpromide (marketed as Depamide by Sanofi-Aventis) is a carboxamide derivative of valproic acid used in the treatment of epilepsy and some affective disorders. It is rapidly metabolised (80%) to valproic acid (another anticonvulsant) but has anticonvulsant properties itself. It may produce more stable plasma levels than valproic acid or sodium valproate and may be more effective at preventing febrile seizures. However, it is over one hundred times more potent as an inhibitor of liver microsomal epoxide hydrolase. This makes it incompatible with carbamazepine and can affect the ability of the body to remove other toxins. Valpromide is no safer during pregnancy than valproic acid. In pure form, valpromide is a white crystalline powder and has melting point 125–126 °C. It is practically insoluble in water but soluble in hot water. It is available on the market in some European countries.

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/index.php/Valrubicin

# Valrubicin Valrubicin is an anti neoplastic that is FDA approved for the treatment of BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.. Common adverse reactions include abdominal pain, nausea, myalgia, asthenia, headache, bladder pain, cystitis, dysuria, hematuria, incontinence, increased frequency of urination, pain in urethra, burning sensation, malaise.

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/index.php/Valsalva

# Valsalva maneuver In medicine, the Valsalva maneuver is performed by forcibly exhaling against closed lips and pinched nose, forcing air into the middle ear if the Eustachian tube is open. This maneuver with slight modifications can be used as a test of cardiac function and autonomic nervous control of the heart or to 'clear' the ears (equalize pressure) when ambient pressure changes, as in diving or aviation. The technique is named for Antonio Maria Valsalva, the 17th Century physician and anatomist from Bologna, whose principal scientific interest was the human ear. He described the Eustachian tube and the maneuver to test its patency. When rapid ambient pressure increase occurs as in diving or aircraft descent, this pressure tends to hold the Eustachian tubes closed, preventing pressure equalization across the ear drum, with painful results. To avoid this painful situation, divers, caisson workers and aircrew attempt to open the Eustachian tubes by swallowing, which tends to open the tubes, allowing the ear to equalize itself. If this fails, then the Valsalva maneuver may be used. It should be noted this maneuver, when used as a tool to equalize middle ear pressure, carries with it the risk of auditory damage from over pressurization of the middle ear. It is safer, if time permits, to attempt to open the Eustachian tubes by swallowing a few times, or yawning. The effectiveness of the "yawning" method can be improved with practise; some people are able to achieve release or opening by moving their jaws forward or forward and down, rather than straight down as in a classical yawn. Opening can often be clearly heard by the practitioner, thus providing feedback that the maneuver was successful. Note that in a clinical setting the Valsalva maneuver will be done either against a closed glottis, or against an external pressure measuring device, in each case either eliminating or minimizing the pressure on the Eustachian tubes. Straining, blowing against resistance as in blowing up balloons has a Valsalva effect and the fall in blood pressure can result in dizziness and even fainting. The maneuver can sometimes be used to diagnose heart abnormalities, especially when used in conjunction with echocardiogram. For example, the Valsalva maneuver classically increases the intensity of hypertrophic cardiomyopathy murmurs, viz. those of dynamic subvalvular left ventricular outflow obstruction; whereas it decreases the intensity all other murmurs, including aortic stenosis and atrial septal defect. The Valsalva maneuver is used to aid in the clinical diagnosis of problems or injury in the nerves of the cervical spine. Upon the exertion of pressure, neuropathies or radicular pain may be felt, and may indicate impingement on a nerve by an intervertebral disc or other part of the anatomy. A pathologic syndrome associated with the Valsalva maneuver is Valsalva retinopathy. It presents as preretinal hemorrhage (bleeding in front of the retina) in people with a history of transient increase in the intrathoracic pressure. The bleeding may be associated with a history of heavy lifting, forceful coughing, straining on the toilet, or vomiting. The bleeding may cause a reduction of vision if it obstructs the visual axis. Patients may also note floaters in their vision. Usually a full recovery of vision is made.

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/index.php/Valsartan

# Valsartan {{DrugProjectFormSinglePage |authorTag=Sheng Shi, M.D. , Rabin Bista, M.B.B.S. |genericName=Valsartan |aOrAn=an |drugClass=Angiotensin 2 Receptor Blocker |indicationType=treatment |indication=hypertension, heart failure |hasBlackBoxWarning=Yes |adverseReactions=hypotension, dizziness, headache, raised serum blood urea nitrogen , raised serum creatinine , cough |blackBoxWarningTitle=WARNING: FETAL TOXICITY |blackBoxWarningBody= |offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Valsartan in pediatric patients. |offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Valsartan in pediatric patients. |contraindications=* Do not use in patients with known hypersensitivity to any component. |drugInteractions=* No clinically significant pharmacokinetic interactions were observed when Diovan (valsartan) was coadministered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone. CYP 450 Interactions: In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of inhibitors of the uptake transporter (rifampin,cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan. Potassium: Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium sparing diuretics(e.g. spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co-medication is considered necessary, monitoring of serum potassium is advisable. Creatinine: Minor elevations in creatinine occurred in 0.8% of patients taking Diovan and 0.6% given placebo in controlled clinical trials of hypertensive patients. In heart failure trials, greater than 50% increases in creatinine were observed in 3.9% of Diovan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients. Hemoglobin and Hematocrit: Greater than 20% decreases in hemoglobin and hematocrit were observed in 0.4% and 0.8%, respectively, of Diovan patients, compared with 0.1% and 0.1% in placebo-treated patients. One valsartan patient discontinued treatment for microcytic anemia. Liver Function Tests: Occasional elevations (greater than 150%) of liver chemistries occurred in Diovan-treated patients. Three patients (< 0.1%) treated with valsartan discontinued treatment for elevated liver chemistries. Serum Potassium: In hypertensive patients, greater than 20% increases in serum potassium were observed in 4.4% of Diovan-treated patients compared to 2.9% of placebo-treated patients. In heart failure patients, greater than 20% increases in serum potassium were observed in 10.0% of Diovan-treated patients compared to 5.1% of placebo-treated patients. Blood Urea Nitrogen (BUN): In heart failure trials, greater than 50% increases in BUN were observed in 16.6% of Diovan-treated patients compared to 6.3% of placebo-treated patients. |FDAPregCat=D |useInPregnancyFDA=* Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnioscan be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Diovan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. |useInNursing=* It is not known whether Diovan is excreted in human milk. Diovan was excreted in the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because many drugs are excreted into human milk and because of the potential for adverse reactions in nursing infants from Diovan, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. |useInPed=* The antihypertensive effects of Diovan have been evaluated in two randomized, double-blind clinical studies in pediatric patients from 1-5 and 6-16 years of age. The pharmacokinetics of Diovan have been evaluated in pediatric patients 1 to 16 years of age. Diovan was generally well tolerated in children 6-16 years and the adverse experience profile was similar to that described for adults. |useInGeri=* In the controlled clinical trials of valsartan, 1,214 (36.2%) hypertensive patients treated with valsartan were ≥65 years and 265 (7.9%) were ≥75 years. No overall difference in the efficacy or safety of valsartan was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out. |useInRenalImpair=* Safety and effectiveness of Diovan in patients with severe renal impairment (CrCl ≤ 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCl 60-90 mL/min) or moderate (CrCl 30-60) renal impairment. |useInHepaticImpair=* No dose adjustment is necessary for patients with mild-to-moderate liver disease. No dosing recommendations can be provided for patients with severe liver disease. |administration=* Oral |IVCompat=Oral |overdose=FDA Package Insert for Valsartan contains no information regarding drug overdose. |drugBox={{Drugbox2 | verifiedrevid = 470628341 | IUPAC_name = (S)-3-methyl-2-(N-{[2'-(2H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butanoic acid | image = Valsartan.png | image2 = Valsartan ball-and-stick.png | tradename = Diovan | Drugs.com = Monograph | MedlinePlus = a697015 | licence_US = Valsartan | pregnancy_US = D | pregnancy_category = | legal_US = Rx-only | legal_status = | routes_of_administration = oral | CASNo_Ref =  Y | CAS_number_Ref =  Y | CAS_number = 137862-53-4 | ATC_prefix = C09 | ATC_suffix = CA03 | ATC_supplemental = | PubChem = 60846 | IUPHAR_ligand =3937 | DrugBank_Ref =  Y | ChemSpiderID_Ref =  Y | ChemSpiderID = 54833 | UNII_Ref =  Y | UNII = 80M03YXJ7I | KEGG_Ref =  Y | KEGG = D00400 | ChEBI_Ref =  Y | ChEBI = 9927 | ChEMBL_Ref =  Y | ChEMBL = 1069 | C=24 | H=29 | N=5 | O=3 | molecular_weight = 435.519 g/mol | smiles = O=C(O)[C@@H](N(C(=O)CCCC)Cc3ccc(c1ccccc1c2nnnn2)cc3)C(C)C | InChI = 1/C24H29N5O3/c1-4-5-10-21(30)29(22(16(2)3)24(31)32)15-17-11-13-18(14-12-17)19-8-6-7-9-20(19)23-25-27-28-26-23/h6-9,11-14,16,22H,4-5,10,15H2,1-3H3,(H,31,32)(H,25,26,27,28)/t22-/m0/s1 | InChIKey = ACWBQPMHZXGDFX-QFIPXVFZBU | StdInChI_Ref =  Y | StdInChI = 1S/C24H29N5O3/c1-4-5-10-21(30)29(22(16(2)3)24(31)32)15-17-11-13-18(14-12-17)19-8-6-7-9-20(19)23-25-27-28-26-23/h6-9,11-14,16,22H,4-5,10,15H2,1-3H3,(H,31,32)(H,25,26,27,28)/t22-/m0/s1 | StdInChIKey_Ref =  Y | StdInChIKey = ACWBQPMHZXGDFX-QFIPXVFZSA-N }} |mechAction=* Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). angiotensinII is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Diovan (valsartan) blocks the vasoconstrictor and aldosterone-secreting effects of angiotensinII by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. |PD=Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is available. |PK=* Valsartan peak plasma concentration is reached 2 to 4 hours after dosing. Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours. Absolute bioavailability for Diovan is about 25% (range 10%-35%). The bioavailability of the suspension is 1.6 times greater than with the tablet. With the tablet, food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%. AUC and Cmax values of valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration. Metabolism and Elimination: Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. Distribution: The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin. Pediatric: In a study of pediatric hypertensive patients (n=26, 1-16 years of age) given single doses of a suspension of Diovan (mean: 0.9 to 2 mg/kg), the clearance (L/h/kg) of valsartan for children was similar to that of adults receiving the same formulation. Geriatric: Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary. Heart Failure: The average time to peak concentration and elimination half-life of valsartan in heart failure patients are similar to those observed in healthy volunteers. AUC and Cmax values of valsartan increase linearly and are almost proportional with increasing dose over the clinical dosing range (40 to 160 mg twice a day). The average accumulation factor is about 1.7. The apparent clearance of valsartan following oral administration is approximately 4.5 L/h. Age does not affect the apparent clearance in heart failure patients. Renal Insufficiency: There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of valsartan. Hepatic Insufficiency: On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease |nonClinToxic====Carcinogenesis, Mutagenesis, Impairment of Fertility=== |howSupplied=* Valsartan is available as tablets containing valsartan, USP 40 mg, 80 mg, 160 mg, or 320 mg. All strengths are packaged in bottles as described below. 40 mg tablets are yellow colored, film-coated, oval-shaped tablets debossed with ' RX121' on one side and break line on the other side NDC 51660-140-03 Bottles of 10 NDC 51660-140-30 Bottles of 30 NDC 51660-140-05 Bottles of 500 80 mg tablets are yellowish brown colored, film-coated, oval-shaped tablets debossed with ' RX124' on one side and plain on the other side NDC 51660-141-03 Bottles of 10 NDC 51660-141-90 Bottles of 90 NDC 51660-141-05 Bottles of 500 160 mg tablets are pink colored, film-coated, oval-shaped tablets debossed with ' RX125' on one side and plain on the other side NDC 51660-142-03 Bottles of 10 NDC 51660-142-90 Bottles of 90 NDC 51660-142-05 Bottles of 500 320 mg tablets are brown colored, film-coated, oval-shaped tablets debossed with ' RX126' on one side and plain on the other side NDC 51660-143-03 Bottles of 10 NDC 51660-143-90 Bottles of 90 NDC 51660-143-05 Bottles of 500 |storage=* Store at 20 o - 25o C (68o - 77o F) [See USP Controlled Room Temperature]. Protect from moisture. Dispense in tight container (USP). |fdaPatientInfo=Information for Patients Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to valsartan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. Distributed by: Ohm Laboratories Inc. North Brunswick, NJ 08902 USA March 2014 FDA-02 |alcohol=Alcohol-Valsartan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. |brandNames=* Diovan |lookAlike=There is limited information about the Look-Alike Drug Names. }} {{#subobject:

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/index.php/Valve_of_the_coronary_sinus

# Valve of the coronary sinus The valve of the coronary sinus (Thebesian valve) is a semicircular fold of the lining membrane of the atrium, at the orifice of the coronary sinus.

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/index.php/Valve_of_the_inferior_vena_cava

# Valve of the inferior vena cava The valve of the inferior vena cava (eustachian valve, valvulae venae cavae inferioris) is the valve at the distal end of the inferior vena cava. It passes blood from the lower extremities into the right atrium.

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/index.php/Valvular_abnormalities

# Valvular heart disease Valvular heart disease (VHD) is the pathological defect affecting one of the four valves of the heart: aortic valve, mitral valve, pulmonic valve, or tricuspid valve. VHD may be congenital or acquired. Congenital causes of VHD include tetralogy of Fallot, Ebstein's anomaly, Noonan syndrome, congenital rubella syndrome, and bicuspid valve among others. Acquired causes of VHD include rheumatic heart disease, infective endocarditis, senile calcification of valves, or valve deformities secondary to structural changes of the myocardium (e.g. dilated cardiomyopathy). Regardless of the underlying cause, VHD may result in valve stenosis, valve regurgitation or , in some cases, valve prolapse. Valvular heart disease can often be asymptomatic and may go undiagnosed. In patients who develop symptoms suggestive of valvular heart disease, cardiac auscultation for heart murmurs is often the first step of a focused physical examination to rule out valvular heart disease. Echocardiography is the gold standard diagnostic modality for valvular heart disease. In addition to a thorough and focused physical examination, a well-performed echocardiogram aids the clinician in determining the severity of the disease, the prognosis, and the need for surgical intervention. Clinicians may differentiate among different valvular heart diseases on the basis of the characteristics of the murmur and collecting a thorough patient history, as shown in the following table:

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/index.php/Van_Gieson%27s_stain

# Van Gieson's stain Van Gieson's Stain is a mixture of Picric Acid and Acid Fuchsin. It is the simplest method of differential staining of Collagen and other Connective Tissue.

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/index.php/Van_der_Waals_strain

# Van der Waals strain In chemistry van der Waals strain is strain resulting from van der Waals repulsion when two substituents in a molecule approach each other with a distance less than the sum of their van der Waals radii. Van der Waals strain is also called van der Waals repulsion and related to steric hindrance. One of the most common forms of this strain is eclipsing hydrogen, in Alkanes.

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/index.php/Van_der_Woude_syndrome_(patient_information)

# Van der Woude syndrome (patient information) Van der Woude syndrome is a condition that affects the development of the face. Many people with this disorder are born with a cleft lip, a cleft palate (an opening in the roof of the mouth), or both. Affected individuals usually have depressions (pits) near the center of the lower lip, which may appear moist due to the presence of salivary and mucous glands in the pits. Small mounds of tissue on the lower lip may also occur. In some cases, people with van der Woude syndrome have missing teeth. People with van der Woude syndrome who have cleft lip and/or palate, like other individuals with these facial conditions, have an increased risk of delayed language development, learning disabilities, or other mild cognitive problems. The average IQ of individuals with van der Woude syndrome is not significantly different from that of the general population. Mutations in the IRF6 gene cause van der Woude syndrome. The IRF6 gene provides instructions for making a protein that plays an important role in early development. This protein is a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity of particular genes. The IRF6 protein is active in cells that give rise to tissues in the head and face. It is also involved in the development of other parts of the body, including the skin and genitals. Mutations in the IRF6 gene that cause van der Woude syndrome prevent one copy of the gene in each cell from making any functional protein. A shortage of the IRF6 protein affects the development and maturation of tissues in the face, resulting in the signs and symptoms of van der Woude syndrome. Individuals with parents that carry a mutation in IRF6 gene are at risk. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition. Occasionally, an individual who has a copy of the altered gene does not show any signs or symptoms of the disorder.

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/index.php/Vanadium

# Vanadium Vanadium (Template:IPAEng) is a chemical element that has the symbol V and atomic number 23. A soft and ductile element, vanadium naturally occurs in certain minerals and is used mainly to produce certain alloys. It is one of the 26 elements found in most living organisms. Vanadium is a soft and ductile, silver-grey metal. It has good resistance to corrosion by alkalis, sulfuric and hydrochloric acid. It oxidizes readily at about 933 K (660 C). Vanadium has good structural strength and a low fission neutron cross section, making it useful in nuclear applications. Although a metal, it shares with chromium and manganese the property of having valency oxides with acid properties. Common oxidation states of vanadium include +2, +3, +4 and +5. A popular experiment with ammonium vanadate NH4VO3, reducing the compound with zinc metal, can demonstrate colorimetrically all four of these vanadium oxidation states. A +1 oxidation state is rarely seen. Vanadium was originally discovered by Andrés Manuel del Río (a Spanish-born Mexican mineralogist) in Mexico City, in 1801. He called it "brown lead" (now named vanadinite). Through experimentation, its colors reminded him of chromium, so he named the element panchromium. He later renamed this compound erythronium, since most of the salts turned red when heated. The French chemist Hippolyte Victor Collet-Descotils incorrectly declared that del Río's new element was only impure chromium. Del Río thought himself to be mistaken and accepted the statement of the French chemist that was also backed by del Río's friend Baron Alexander von Humboldt. In 1831, Sefström of Sweden rediscovered vanadium in a new oxide he found while working with some iron ores and later that same year Friedrich Wöhler confirmed del Río's earlier work. Later, George William Featherstonhaugh, one of the first US geologists, suggested that the element should be named "rionium" after del Río, but this never happened. Metallic vanadium was isolated by Henry Enfield Roscoe in 1867, who reduced vanadium(III) chloride VCl3 with hydrogen. The name vanadium comes from Vanadis, a goddess in Scandinavian mythology, because the element has beautiful multicolored chemical compounds. In biology, a vanadium atom is an essential component of some enzymes, particularly the vanadium nitrogenase used by some nitrogen-fixing micro-organisms. Vanadium is essential to ascidians or sea squirts in vanadium chromagen proteins. The concentration of vanadium in their blood is more than 100 times higher than the concentration of vanadium in the seawater around them. Rats and chickens are also known to require vanadium in very small amounts and deficiencies result in reduced growth and impaired reproduction. Ten percent of the blood cell pigment of the sea cucumber is vanadium. Just as the horseshoe crab has blue blood rather than red blood (colored by iron in hemoglobin) because of copper in the hemocyanin pigment, the blood of the sea cucumber is yellow because of the vanadium in the vanabin pigment . Nonetheless, there is no evidence that vanabins carry oxygen, in contrast to hemoglobin and hemocyanin. Most continental waters show a vanadium concentration of less than 3 ppb. However, the groundwater of Mt. Fuji contains a very high concentration of vanadium—up to 150 ppb. This vanadium is solubilized from the basalt by the groundwater. The vanadium content in Mt. Fuji becomes higher at places nearer the summit and deeper in the ground. Recently this high-vanadium water of Mt. Fuji has been sold by many companies as an agent to cope with diabetes. However, there is no concrete evidence for its efficacy. The rainbow trout living in the Mt. Fuji water showed much higher accumulation of vanadium in kidneys and bone. Vanadium is never found unbound in nature but it does occur in about 65 different minerals among which are patronite VS4, vanadinite Pb5(VO4)3Cl, and carnotite K2(UO2)2(VO4)2.3H2O. Vanadium is also present in bauxite, and in carbon containing deposits such as crude oil, coal, oil shale and tar sands. Vanadium has also been detected spectroscopically in light from the Sun and some other stars. Much of the vanadium metal being produced is now made by calcium reduction of V2O5 in a pressure vessel. Vanadium is usually recovered as a by-product or co-product, and so world resources of the element are not really indicative of available supply. Vanadium is available commercially and production of a sample in the laboratory is not normally required. Commercially, routes leading to metallic vanadium as main product are not usually required as enough is produced as byproduct in other processes. In industry, heating of vanadium ore or residues from other processes with salt NaCl or sodium carbonate Na2CO3 at about 850°C gives sodium vanadate NaVO3. This is dissolved in water and acidified to give a red solid which in turn is melted to form a crude form of vanadium pentoxide V2O5. Reduction of vanadium pentoxide with calcium gives pure vanadium. An alternative suitable for small scales is the reduction of vanadium pentachloride VCl5 with hydrogen or magnesium. Many other methods are also in use. Industrially, most vanadium is used as an additive to improve steels. Rather than proceed via pure vanadium metal it is often sufficient to react the crude of vanadium pentoxide V2O5 with crude iron. This produces ferrovanadium suitable for further work. Vanadium pentoxide V2O5 is used as a catalyst principally in the production of sulfuric acid. It is the source of vanadium used in the manufacture of ferrovanadium. It can be used as a dye and color-fixer. Vanadyl sulfate VOSO4, also called vanadium(IV) sulfate oxide hydrate, is used as a relatively controversial dietary supplement, primarily for increasing insulin sensitivity and body-building. Whether it works for the latter purpose has not been proven, and there is some evidence that athletes who take it are merely experiencing a placebo effect. Vanadium(IV) chloride VCl4 is a soluble form of vanadium that is commonly used in the laboratory. V(IV) is the reduced form of V(V), and commonly occurs after anaerobic respiration by dissimilatory metal reducing bacteria. VCl4 reacts violently with water. The toxicity of vanadium depends on its physico-chemical state; particularly on its valence state and solubility. Tetravalent VOSO4 has been reported to be more than 5 times as toxic as trivalent V2O3 (Roschin, 1967). Vanadium compounds are poorly absorbed through the gastrointestinal system. Inhalation exposures to vanadium and vanadium compounds result primarily in adverse effects to the respiratory system (Sax, 1984; ATSDR, 1990; Ress et al., 2003; Worle-Knirsch et al., 2007). Quantitative data are, however, insufficient to derive a subchronic or chronic inhalation reference dose. Other effects have been reported on blood parameters after oral or inhalation exposures (Scibior et al., 2006; Gonzalez-Villalva et al., 2006), on liver (Kobayashi et al., 2006), neurological development in rats (Soaso and Garcia, 2007), and other organs. There is little evidence that vanadium or vanadium compounds are reproductive toxins or teratogens. Vanadium pentoxide was reported to be carcinogenic in male rats and male and female mice by inhalation in an NTP study (Ress et al., 2003), although the interpretation of the results has recently been disputed (Duffus, 2007). Vanadium has not been classified as to carcinogenicity by the U.S. EPA (1991a). It is known that vanadium gets the oxidation states +2, +3, +4, +5. To observe the colours of these states, ammonium metavanadate (NH4VO3) can be used as a starting agent. It must be acidified beforehand so dioxovanadium(V) ion, VO2+ (yellow +5 oxidation number) is produced. In alkaline medium, the stable form of vanadium(V) state is VO3-. It can be seen that during the reaction, the mixture is green in colour as the original yellow of the +5 state and the blue of the +4 are present. Continuously adding Zn powder and concentrated HCl, blue VO2+ is reduced to green V3+. V3+ is then reduced to violet V2+ by Zn powder and concentrated HCl again. Naturally occurring vanadium is composed of one stable isotope 51V and one radioactive isotope 50V with a half-life of 1.5×1017 years. 24 artificial radioisotopes have been characterized (in the range of mass number between 40 and 65) with the most stable being 49V with a half-life of 330 days, and 48V with a half-life of 15.9735 days. All of the remaining radioactive isotopes have half-lives shorter than an hour, the majority of them below 10 seconds. In 4 isotopes, metastable excited states were found (including 2 metastable states for 60V). The primary decay mode before the most abundant stable isotope 51V is electron capture. The next most common mode is beta decay. The primary decay products before 51V are element 22 (titanium) isotopes and the primary products after are element 24 (chromium) isotopes. Powdered metallic vanadium is a fire hazard, and unless known otherwise, all vanadium compounds should be considered highly toxic. Generally, the higher the oxidation state of vanadium, the more toxic the compound is. The most dangerous compound is vanadium pentoxide. The Occupational Safety and Health Administration (OSHA) has set an exposure limit of 0.05 mg/m3 for vanadium pentoxide dust and 0.1 mg/m3 for vanadium pentoxide fumes in workplace air for an 8-hour workday, 40-hour work week. The National Institute for Occupational Safety and Health (NIOSH) has recommended that 35 mg/m3 of vanadium be considered immediately dangerous to life and health. This is the exposure level of a chemical that is likely to cause permanent health problems or death.

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/index.php/Vancomycin-resistant_Staphylococcus_aureus_causes

# Vancomycin-resistant Staphylococcus aureus causes VISA and VRSA are specific types of antimicrobial-resistant Staphylococcus aureus. Staphylococcus aureus, often simply referred to as "staph", are bacteria commonly found on the skin and in the nose of healthy people. Occasionally, they can cause infection and they are one of the most common causes of skin infections in the United States.

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/index.php/Vancomycin-resistant_Staphylococcus_aureus_epidemiology_and_demographics

# Vancomycin-resistant Staphylococcus aureus epidemiology and demographics VISA and VRSA infections are rare. Only sixteen cases of infection caused by VISA (Michigan 1997, New Jersey 1997, New York 1998, Illinois 1999, Minnesota 2000, Nevada 2000, Maryland 2000, and Ohio 2001) and six cases of infection caused by VRSA (Michigan 2002 , Pennsylvania 2002, New York 2004, and 3 from Michigan in 2005) have been reported in the United States.

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/index.php/Vancomycin-resistant_Staphylococcus_aureus_historical_perspective

# Vancomycin-resistant Staphylococcus aureus historical perspective VISA (vancomycin-intermediate Staphylococcus aureus) was first identified in Japan in 1996 and has since been found in hospitals in England, France, the U.S., Asia and Brazil. It is also termed GISA (glycopeptide-intermediate Staphylococcus aureus) indicating resistance to all glycopeptide antibiotics. These bacterial strains present a thickening of the cell wall which is believed to deplete the vancomycin available to kill the bacteria.

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/index.php/Vancomycin-resistant_Staphylococcus_aureus_laboratory_findings

# Vancomycin-resistant Staphylococcus aureus laboratory findings Staph bacteria are classified as VISA or VRSA based on laboratory tests. Laboratories perform tests to determine if staph bacteria are resistant to antimicrobial agents that might be used for treatment of infections. For vancomycin and other antimicrobial agents, laboratories determine how much of the agent it requires to inhibit the growth of the organism in a test tube. The result of the test is usually expressed as a minimum inhibitory concentration (MIC) or the minimum amount of antimicrobial agent that inhibits bacterial growth in the test tube. Therefore, staph bacteria are classified as VISA if the MIC for vancomycin is 4-8µg/ml, and classified as VRSA if the vancomycin MIC is >16µg/ml. All laboratories should develop a step-by-step problem-solving procedure or algorithm for detecting VISA/VRSA that is specific for their laboratory. A sample algorithm is available here and highlights the recommended testing methodologies for detecting VISA/VRSA and actions based on results. Not all susceptibility testing methods detect VISA and VRSA isolates. Three out of six confirmed VRSA isolates were not reliably detected by automated testing systems in a recent report. Subsequently, some manufacturers have optimized their systems for VRSA detection, so laboratories should check with manufacturers to determine if their system has FDA clearance for VRSA detection. VRSA are detected by reference broth microdilution, agar dilution, Etest®, MicroScan® overnight and Synergies plus™; BD Phoenix™ system, disk diffusion, and the vancomycin screen agar plate (brain heart infusion (BHI) agar containing 6 µg/ml of vancomycin). VISA isolates are not detected by disk diffusion. Methods that typically detect VISA are non-automated MIC methods including reference broth microdilution, agar dilution, and Etest® using a 0.5 McFarland standard to prepare inoculum. Automated methods and vancomycin screen agar plates usually detect VISA for which the vancomycin MICs are 8 µg/ml, but further studies are need to define the level of sensitivity of these methods for S. aureus for which the vancomycin MICs are 4 µg/ml.

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/index.php/Vancomycin-resistant_Staphylococcus_aureus_medical_therapy

# Vancomycin-resistant Staphylococcus aureus medical therapy VISA and VRSA cannot be successfully treated with vancomycin because these organisms are no longer susceptibile to vancomycin. However, to date, all VISA and VRSA isolates have been susceptible to other Food and Drug Administration (FDA) approved drugs like trimethoprim/sulfamethoxazole, clindamycin, or ceftaroline.

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/index.php/Vancomycin-resistant_Staphylococcus_aureus_overview

# Vancomycin-resistant Staphylococcus aureus overview Vancomycin-resistant Staphylococcus aureus (VRSA) is a strain of Staphylococcus aureus that has become resistant to the glycopeptide antibiotic vancomycin. With the increase of staphylococcal resistance to methicillin, vancomycin (or teicoplanin) is often a treatment of choice in infections with methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin resistance is still a rare occurrence. Unfortunately, VRSA may also be resistant to meropenem and imipenem, two other antibiotics that can be used in sensitive staphylococcus strains. Even with the absence of high-level resistance to vancomycin, another concern posed by the presence of VISA (vancomycin-intermediate Staphylococcus aureus) is the increased difficulty in prescribing treatments, especially in situations where an effective treatment for an infection is needed urgently, before detailed resistance profiles can be obtained. In hospitals already endemic with multiresistant MRSA, the appearance of VRSA would make the treatment of infected patients much more difficult. At present, high-level resistances to both glycopeptide and β-lactam antibiotics in Staphylococcus aureus seem to be mutually exclusive, in that both resistances are not seen at once in the same strain of bacterium. However, this is not due to a fundamental biochemical incompatibility. Theoretically, a superbug displaying high-level resistances to both classes of antibiotics could evolve given the current selective environment. VISA and VRSA are specific types of antimicrobial-resistant staph bacteria. While most staph bacteria are susceptible to the antimicrobial agent vancomycin, some have developed resistance. Persons with underlying health conditions (such as diabetes and kidney disease), previous infections with methicillin-resistant Staphylococcus aureus (MRSA), tubes going into their bodies (such as intravenous catheters), recent hospitalizations, and recent exposure to vancomycin and other antimicrobial agents are at increased risk of developing VISA and VRSA infections. Use of appropriate infection control practices (such as wearing gloves before and after contact with infectious body substances and adherence to hand hygiene) by healthcare personnel can reduce the spread of VISA and VRSA.

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/index.php/Vancomycin-resistant_Staphylococcus_aureus_primary_prevention

# Vancomycin-resistant Staphylococcus aureus primary prevention Because VISA and VRSA are only part of the larger problem of antimicrobial resistance in healthcare settings, CDC has started a campaign to prevent antimicrobial resistance. The campaign centers around four strategies that clinicians can use to prevent antimicrobial resistance:

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/index.php/Vancomycin-resistant_Staphylococcus_aureus_screening

# Vancomycin-resistant Staphylococcus aureus screening Laboratories that use automated methods that are not validated for VRSA detection should also include a vancomycin screen agar plate for enhanced detection of VRSA. If possible, laboratories should incorporate the vancomycin agar screen plate for testing all S. aureus. Alternatively, the screening may be limited to MRSA isolates, since nearly all VISA and all VRSA reported to date (i.e., April 2006) were also MRSA. Laboratories using disk diffusion to determine vancomycin susceptibility should consider adding a second method for VISA detection. The vancomycin screen plate is useful for detecting VISA (MIC = 8 µg/ml). Reliable detection of VISA (MIC = 4 µg/ml) may require a non-automated MIC method. The vancomycin agar screen test uses commercially prepared agar plates to screen pure cultures of bacteria for vancomycin. These plates contain BHI agar and 6 µg/ml of vancomycin. A 10µl inoculum of a 0.5 McFarland suspension should be spotted on the agar using a micropipette (final concentration=106 CFU/ml). Alternatively, a swab may be dipped in the McFarland suspension, the excess liquid expressed, and used to inoculate the vancomycin agar screen plate. For quality control, laboratories should use Entercococcus faecalis ATCC 29212 as the susceptible control and E. faecalis ATCC 51299 as the resistant control. Up to eight isolates can be tested per plate; quality control should be performed each day of testing. Growth of more than one colony is considered a positive result. All staphylococci that grow on these plates should be inspected for purity, and the original clinical isolates should be tested using an FDA-cleared MIC method for confirmation. Plates prepared in-house using various lots of media performed inconsistently and were inferior to those obtained commercially (CDC unpublished data). Performance of commercially prepared plates varies by individual manufacturer.

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/index.php/Vancomycin-resistant_enterococcus

# Vancomycin-resistant enterococcus Vancomycin-resistant enterococcus (VRE) is the name given to a group of bacterial species of the genus Enterococcus that is resistant to the antibiotic vancomycin. Enterococci are enteric and can be found in the digestive and urinary tracts of some humans. VRE was discovered in 1985 and are particularly dangerous to immunocompromised individuals. VRE spp. have an enhanced ability to pass resistant genes to other bacteria. While infection of healthy individuals is uncommon, it is possible that they could be colonized with newly-resistant bacteria. There are six different types of vancomycin resistance shown by enterococci: Van-A, Van-B, Van-C, Van-D, Van-E and Van-F. Of these, only Van-A, Van-B and Van-C have been seen in general clinical practice so far. The significance is that Van-A VRE is resistant to both vancomycin and teicoplanin, Van-B VRE is resistant to vancomycin but sensitive to teicoplanin, and Van-C is only partly resistant to vancomycin, and sensitive to teicoplanin. VRE can be carried by healthy people who have come into contact with the bacteria. The most likely place where such contact can occur is in a hospital (nosocomial infections), although it is thought that a significant percentage of intensively-farmed chicken also carries VRE. , In 2005, Lactobacillus rhamnosus GG (LGG), a strain of L. rhamnosus, was used successfully for the first time to treat gastrointestinal carriage of VRE in renal patients.

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/index.php/Vancomycin_(injection)

# Vancomycin (injection) Vancomycin (injection) is an antibiotic that is FDA approved for the treatment of serious or severe infections caused by susceptible strains of methicillin-resistant (beta-lactam-resistant) Staphylococci. It is indicated for penicillin-allergic patients, for patients who cannot receive or who have failed to respond to other drugs, including the penicillins or cephalosporins, and for infections caused by vancomycin-susceptible organisms that are resistant to other antimicrobial drugs. Common adverse reactions include local pain.

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/index.php/Vanderbilt_University_Medical_Center

# Vanderbilt University Medical Center VUMC also has numerous satellite facilities in and around middle Tennessee, serving a large community. VUMC is known for its highly-acclaimed teaching hospital and its groundbreaking efforts in electronic medical records. Vanderbilt staffs some of the world's most accomplished physicians and employs over 10,000 middle Tennesseans.

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/index.php/Vandetanib

# Vandetanib Vandetanib is an tyrosine kinase inhibitor that is FDA approved for the treatment of symptomatic or progressive medullary thyroid cancer. Common adverse reactions include diarrhea, nausea, fatigue, rash, headache, abdominal pain, dyspepsia, hypocalcemia, cough, depression. Vandetanib has a molecular weight of 475.36. Vandetanib exhibits pH-dependent solubility, with increased solubility at lower pH. Vandetanib is practically insoluble in water with a value of 0.008 mg/mL at 25°C (77°F ).

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/index.php/Vanillin

# Vanillin Vanillin, methyl vanillin, or 4-hydroxy-3-methoxybenzaldehyde, is an organic compound with the molecular formula C8H8O3. Its functional groups include aldehyde, ether, and phenol. It is the primary component of the extract of the vanilla bean. Synthetic vanillin is used as a flavoring agent in foods, beverages, and pharmaceuticals. Methyl vanillin is used by the food industry as well as ethyl vanillin. The ethyl is more expensive but has a stronger note, and differs by having an ethoxy group (-O-CH2CH3) instead of a methoxy group (-O-CH3). Natural vanilla extract is a mixture of several hundred different compounds in addition to vanillin. Artificial vanilla flavoring is a solution of pure vanillin, usually of synthetic origin. Because of the scarcity and expense of natural vanilla extract, there has long been interest in the synthetic preparation of its predominant component. The first commercial synthesis of vanillin began with the more readily available natural compound eugenol. Today, artificial vanillin is made from either the petrochemical guaiacol, or from lignin, a natural constituent of wood which is a byproduct of the paper industry. Lignin-based artificial vanilla flavoring is alleged to have a richer flavor profile than oil-based flavoring; the difference is due to the presence of acetovanillone in the lignin-derived product, an impurity not found in vanillin synthesized from guaiacol. Vanilla was cultivated as a flavoring by pre-Columbian Mesoamerican peoples; at the time of their conquest by Hernándo Cortés, the Aztecs used it as a flavoring for chocolate. Europeans became aware of both chocolate and vanilla around the year 1520. Vanillin was first isolated as a relatively pure substance in 1858 by Nicolas-Theodore Gobley, who obtained it by evaporating a vanilla extract to dryness, and recrystallizing the resulting solids from hot water. In 1874, the German scientists Ferdinand Tiemann and Wilhelm Haarmann deduced its chemical structure, at the same time finding a synthesis for vanillin from coniferin, a glycoside of isoeugenol found in pine bark, and in 1876, Karl Reimer synthesized vanillin from guaiacol. By the late 19th century, semisynthetic vanillin derived from the eugenol found in clove oil was commercially available. Synthetic vanillin became significantly more available in the 1930s, when production from clove oil was supplanted by production from the lignin-containing waste produced by the Kraft process for preparing wood pulp for the paper industry. By 1981, a single pulp and paper mill in Ontario supplied 60% of the world market for synthetic vanillin. However, subsequent developments in the wood pulp industry have made its lignin wastes less attractive as a raw material for vanillin synthesis. While some vanillin is still made from lignin wastes, most synthetic vanillin is today synthesized in a two-step process from the petrochemical precursors guaiacol and glyoxylic acid. Beginning in 2000, Rhodia began marketing biosynthetic vanillin prepared by the action of microorganisms on ferulic acid extracted from rice bran. At $700/kg, this product, sold under the trademarked name Rhovanil Natural, is not cost-competitive with petrochemical vanillin, which sells for around $15/kg. However, unlike vanillin synthesized from lignin or guaiacol, it can be labeled as a natural flavoring. Vanillin is most prominent as the principal flavor and aroma compound in vanilla. Cured vanilla pods contain approximately 2% by dry weight vanillin; on cured pods of high quality, relatively pure vanillin may be visible as a white dust or "frost" on the exterior of the pod. At smaller concentrations, vanillin contributes to the flavor and aroma profiles of foodstuffs as diverse as olive oil, butter, and raspberry and lychee fruits. Aging in oak barrels imparts vanillin to some wines and spirits. In other foods, heat treatment evolves vanillin from other chemicals. In this way, vanillin contributes to the flavor and aroma of coffee, maple syrup, and whole grain products including corn tortillas and oatmeal. Natural vanillin is extracted from the seed pods of Vanilla planifola, a vining orchid native to Mexico, but now grown in tropical areas around the globe. Madagascar is presently the largest producer of natural vanillin. As harvested, the green seed pods contain vanillin in the form of its β-D-glycoside; the green pods do not have the flavor or odor of vanilla. After being harvested, their flavor is developed by a months-long curing process, the details of which vary among vanilla-producing regions, but in broad terms it proceeds as follows: First, the seed pods are blanched in hot water, to arrest the processes of the living plant tissues. Then, for 1–2 weeks, the pods are alternately sunned and sweated: during the day, they are laid out in the sun, and each night, wrapped in cloth and packed in airtight boxes to sweat. During this process, the pods become a dark brown, and enzymes in the pod release vanillin as the free molecule. Finally, the pods are dried and further aged for several months, during which time their flavors further develop. Several methods have been described for curing vanilla in days rather than months, although they have not been widely developed in the natural vanilla industry, with its focus on producing a premium product by established methods, rather than on innovations that might alter the product's flavor profile. Vanillin accounts for about 2% of the dry weight of cured vanilla beans, and is the chief among about 200 other flavor compounds found in vanilla. The demand for vanilla flavoring has long exceeded the supply of vanilla beans. As of 2001, the annual demand for vanillin was 12,000 tons, but only 1800 tons of natural vanillin were produced. The remainder was produced by chemical synthesis. Vanillin was first synthesized from eugenol (found in oil of clove) in 1874–75, less than 20 years after it was first identified and isolated. Vanillin was commercially produced from eugenol until the 1920s. Later it was synthesized from lignin-containing sulfite liquor, a byproduct of wood pulp processing in paper manufacture. Counter-intuitively, even though it uses waste materials, the lignin process is no longer popular because of environmental concerns, and today most vanillin is produced from the petrochemical raw material guaiacol. Several routes exist for synthesizing vanillin from guaiacol. At present, the most significant of these is the two-step process practiced by Rhodia since the 1970s, in which guaiacol reacts with glyoxylic acid by electrophilic aromatic substitution. The resulting vanilmandelic acid is then converted to vanillin by oxidative decarboxylation. The largest single use of vanillin is as a flavoring, usually in sweet foods. The ice cream and chocolate industries together comprise 75% of the market for vanillin as a flavoring, with smaller amounts being used in confections and baked goods. Vanillin has been used as a chemical intermediate in the production of pharmaceuticals and other fine chemicals. In 1970, more than half the world's vanillin production was used in the synthesis of other chemicals, but as of 2004 this use accounts for only 13% of the market for vanillin.

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/index.php/Vanillyl_mandelic_acid

# Vanillyl mandelic acid VMA is found in the urine, along with other catecholamine metabolites, including homovanillic acid (HVA). In timed urine tests the quantity (concentration μg /24 h) is assessed, along with creatinine clearance, and the concentration of cortisols, catecholamines, and metanephrines. These urinalysis tests are used to diagnose an adrenal gland tumor called pheochromocytoma, a tumor of catecholamine-secreting chromaffin cells. These tests may also be used to diagnose neuroblastomas, and to monitor treatment of these conditions. Norepinephrine breaks down into normetanephrine and VMA. Norepinephrine is one of the hormones produced by the adrenal glands, which are found on top of the kidneys. They are released into the blood during times of physical or emotional stress, which are factors that may skew the results of the test.

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/index.php/Vanishing_mediator

# Vanishing mediator A vanishing mediator is a concept that exists to mediate between two opposing ideas, as a transition occurs between them. At the point where one idea has been replaced by the other, and the concept is no longer required, the mediator vanishes. In terms of Hegelian dialectics, the conflict between thesis and antithesis is resolved by a synthesis of the two ideas, although the synthesis represents the final solution, whereupon the mediator vanishes. In terms of Psychoanalytic theory, when someone is caught in a dilemma they experience Hysteria. The conceptual deadlock, exists until the resulting Hysteric breakdown precipitates some kind of resolution, therefore the Hysteria is a vanishing mediator in this case. In terms of Political history, it refers to social movements, which operate in a particular way to influence politics, until they either are forgotten or change their purpose. It is a concept that was originally described by Fredric Jameson:- In The Ideologies of Theory , a two volume compilation of his essays, Jameson first defines the instance of textual unconscious outlined by Jacques Lacan, before the general idea of a vanishing mediator. Since, this concept has been adopted by Zizek in "For They Know Not What They Do: Enjoyment as a Political factor", where he uses it in a political sense, similar to Marx's Analysis of Revolution .

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/index.php/Vanishing_twin

# Vanishing twin A vanishing twin is a fetus in a multi-gestation pregnancy which dies in utero and is then partially or completely reabsorbed by the mother Template:Harv. The occurrence of this phenomenon is sometimes referred to as twin embolisation syndrome or vanishing twin syndrome (VTS), since the 1980s when twin pregnancies were made visible early on by means of ultrasound. The term wombtwin has been used since 2003 to describe the deceased embryo or fetus. Occasionally, rather than being completely resorbed, the dead fetus will undergo mechanical compression by its wombmate(s), resulting in a flattened, parchment-like state known as fetus papyraceus Template:Harv. If the fetus is absorbed completely, there are usually no further complications to the pregnancy, other than first trimester vaginal bleeding Template:Harv. However, if the event occurs in the second or third trimester, serious complications may include premature labor, infection due to the demise of the fetus, and hemorrhage. Even at the end of the pregnancy, a low-lying fetus papyraceus may block the cervix and require a cesarean to deliver the living twin. The wombtwin can die owing to a poorly implanted placenta, a developmental anomaly that may cause major organs to fail or be missing completely, or there may be a chromosome abnormality incompatible with life. Frequently the twin is a blighted ovum, one that never developed beyond the very earliest stages of embryogenesis. According to Charles Template:Harvcoltxt, who is a professor in the Department of Pediatrics in the Brody School of Medicine and adjunct professor of biology at East Carolina University, vanishing twins occur in up to one out of every eight pregnancies and may not even be known in most cases. However, Patricia J. Sulak, M.D. has reported otherwise. "In reporting 300 early pregnancies evaluated by means of ultrasound noted 21 twins, one triplet, and one quadruplet. Only three pairs of twins survived to term (85.6% loss of the second twin), whereas the triplet pregnancy evolved into a normal twin gestation, and the quadruplet pregnancy reported here also evolved into a singleton gestation. Additonally, the triplet pregnancy reported here also evolved into a pregnancy diagnosed by means of ultrasound that evolved into a twin gestation. These very high resorption rates, which cannot be explained on the basis of the expected abortion rate, again suggest intense fetal competition for space, nutrition, or other factors during early gestation, with frequent loss or resorption of the other twin(s)." Multiple gestation occurs at 7.6% in this particular study, and vanishing syndrome effect occurs within 85.6%. Therefore 6.88% of the 300 pregnancies experienced vanishing twin syndrome. Thus it seems more likely that VTS occurs 19.68 pregnancies out of 300, or about six out of every hundred pregnancies. † Article 7: The Vanishing Twin: pathologic Confirmation of an Ultrasonographic Phenomenon Sulak, M.D., L., Dodson, M.D., M. Since it is hypothesized that in some instances vanishing twins leave no detectable trace at birth or before, it is impossible to say for certain how frequent the phenomenon is. It was hypothesized for a long time that non-righthanded and left-handed individuals may be the survivors of "mirror image" identical twinning Template:Harv but recent research does not seem to support that view Template:Harv. "Vanishing" twins are frequently encountered in pregnancies created as a result of IVF. Ultrasound scans are taken very early in these pregnancies (5-8 weeks), so that, where a multiple conception has occurred, it frequently happens that more than one amniotic sac can be seen in early pregnancy, whereas a few weeks later there is only one to be seen and the other has "vanished" Template:Harv. It has been speculated that the children born of such a pregnancy may have some memories of their vanished twins, and may feel lonely because of this Template:Harv. There is no scientific evidence to support this claim. Talk shows, such as Coast to Coast AM, have discussed the alleged phenomenon. The vanishing twin syndrome has been cited by biotech company Acu-Gen as an ad hoc hypothesis to explain false results of the company's Baby Gender Mentor test. According to the company, on occasions where their pregnancy gender test has apparently given the incorrect gender of the fetus, the apparent mistake can be explained by a fetus having been present at the time of testing, but later being reabsorbed as a vanished twin. According to the company's critics, this excuse does not seem plausible.

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/index.php/Vapor-liquid_separator

# Vapor-liquid separator A Vapor-liquid separator is a vertical vessel into which a liquid and vapor mixture is fed and, in which, the liquid is separated by gravity, falls to the bottom of the vessel, and is withdrawn. The vapor travels upward at a design velocity which minimizes the entrainment of any liquid droplets in the vapor as it exits the top of the vessel. The feed to a vapor-liquid separator may also be a liquid that is being partially or totally flashed into a vapor and liquid as it enters the separator.

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/index.php/Vapreotide

# Vapreotide Vapreotide (Sanvar) is a synthetic somatostatin analog. It is used in the treatment of esophageal variceal bleeding in patients with cirrhotic liver disease and AIDS-related diarrhea.

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/index.php/Vardenafil

# Vardenafil Vardenafil is a Phosphodiesterase 5 Inhibitor that is FDA approved for the treatment of treatment of erectile dysfunction. Common adverse reactions include flushing, dizziness, headache, rhinitis. In placebo-controlled clinical trials, the discontinuation rate due to adverse events was 3.4% for Vardenafil compared to 1.1% for placebo. When Vardenafil was taken as recommended in placebo-controlled clinical trials, the following adverse reactions were reported (see Table 1). Placebo-controlled trials suggested a dose effect in the incidence of some adverse reactions (headache, flushing, dyspepsia, nausea, and rhinitis) over the 5 mg, 10 mg, and 20 mg doses of Vardenafil. All Vardenafil Studies: Vardenafil film-coated tablets and vardenafil orally disintegrating tablets have been administered to over 17,000 men (mean age 54.5, range 18–89 years; 70% White, 5% Black, 13% Asian, 4% Hispanic and 8% Other) during controlled and uncontrolled clinical trials worldwide. The number of patients treated for 6 months or longer was 3357, and 1350 patients were treated for at least 1 year. In the placebo-controlled clinical trials for Vardenafil film-coated tablets and vardenafil orally disintegrating tablets, the discontinuation rate due to adverse events was 1.9% for vardenafil compared to 0.8% for placebo. Body as a whole: allergic edema and angioedema, feeling unwell, allergic reactions, chest pain Auditory: tinnitus, vertigo Cardiovascular: palpitation, tachycardia, angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension Digestive: nausea, gastrointestinal and abdominal pain, dry mouth, diarrhea, gastroesophagea reflux disease, gastritis, vomiting, increase in transaminases Musculoskeletal: increase in creatine phosphokinase (CPK), increased muscle tone and cramping, myalgia Nervous: paresthesia and dysesthesia, somnolence, sleep disorder, syncope, amnesia, seizure Respiratory: dyspnea, sinus congestion Skin and appendages: erythema, rash Ophthalmologic: visual disturbance, ocular hyperemia, visual color distortions, eye pain and eye discomfort, photophobia, increase in intraocular pressure, conjunctivitis Urogenital: increase in erection, priapism The following adverse reactions have been identified during post approval use of Vardenafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Ophthalmologic: Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors. Visual disturbances including vision loss (temporary or permanent), such as visual field defect, retinal vein occlusion, and reduced visual acuity, have also been reported rarely in postmarketing experience. It is not possible to determine whether these events are related directly to the use of vardenafil. Neurologic: Seizure, seizure recurrence and transient global amnesia have been reported postmarketing in temporal association with vardenafil. Otologic: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. In some cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of vardenafil, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors Nitrates: Concomitant use of Vardenafil and nitrates and nitric oxide donors is contraindicated. The blood pressure lowering effects of sublingual nitrates (0.4 mg) taken 1 and 4 hours after vardenafil and increases in heart rate when taken at 1, 4 and 8 hours after vardenafil were potentiated by a 20 mg dose of Vardenafil in healthy middle-aged subjects. These effects were not observed when Vardenafil 20 mg was taken 24 hours before the nitroglycerin (NTG). Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of Vardenafil and nitrates is contraindicated. Alpha-Blockers: Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including Vardenafil and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with co-administration of vardenafil with alfuzosin, terazosin or tamsulosin. Antihypertensives: Vardenafil may add to the blood pressure lowering effects of antihypertensive agents. In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1. Alcohol: Vardenafil (20 mg) did not potentiate the hypotensive effects of alcohol during the 4-hour observation period in healthy volunteers when administered with alcohol (0.5 g/kg body weight, approximately 40 mL of absolute alcohol in a 70 kg person). Alcohol and vardenafil plasma levels were not altered when dosed simultaneously. Cimetidine (400 mg b.i.d.) had no effect on vardenafil bioavailability (AUC) and maximum concentration (Cmax) of vardenafil when co-administered with 20 mg Vardenafil in healthy volunteers. Nifedipine:Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the AUC or Cmax of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of Vardenafil when taken in combination. In these patients whose hypertension was controlled with nifedipine, Vardenafil 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mmHg compared to placebo. Ritonavir and Indinavir: Upon concomitant administration of 5 mg of Vardenafil with 600 mg BID ritonavir, the Cmax and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of Vardenafil with 800 mg TID indinavir, the Cmax and AUC of indinavir were reduced by 40% and 30%, respectively. Aspirin: Vardenafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets). Other interactions: Vardenafil had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters). Vardenafil was secreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma. Following a single oral dose of 3 mg/kg, 3.3% of the administered dose was excreted into the milk within 24 hours. No dosage adjustment is necessary in patients with creatinine clearance (CLcr) of 30–80 mL/min. In male volunteers with CLcr = 50-80 ml/min, the pharmacokinetics of vardenafil were similar to those observed in a control group with CLcr >80 mL/min. In male volunteers with CLcr = 30-50 mL/min or CLcr less than 30 mL/min, the AUC of vardenafil was 20–30% higher compared to that observed in a control group with CLcr greater than 80 mL/min. Dosage adjustment is necessary in patients with moderate hepatic impairment. Do not use Vardenafil in patients with severe hepatic impairment (Child-Pugh C). Vardenafil has not been evaluated in this patient population. A starting dose of 5 mg is recommended in patients with moderate hepatic impairment (Child-Pugh B) and the maximum dose should not exceed 10 mg. In volunteers with moderate hepatic impairment, the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects. When 40 mg of vardenafil was administered twice daily, cases of severe back pain were observed. No muscle or neurological toxicity was identified. In cases of overdose, standard supportive measures should be taken as required. Renal dialysis is not expected to accelerate clearance as vardenafil is highly bound to plasma proteins and is not significantly eliminated in the urine. In vitro studies have shown that vardenafil is a selective inhibitor of PDE5. The inhibitory effect of vardenafil is more selective on PDE5 than for other known phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative to PDE11, and >1,000-fold relative to PDE2, 3, 4, 7, 8, 9, and 10). Vardenafil is formulated as orange, round, film-coated tablets with "BAYER" cross debossed on one side and "2.5", "5", "10", and "20" on the other side corresponding to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively. In addition to the active ingredient, vardenafil HCl, each tablet contains microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, yellow ferric oxide, and red ferric oxide. Study 1: This study was designed to evaluate the effect of 5 mg vardenafil compared to placebo when administered to BPH patients on chronic alpha-blocker therapy in two separate cohorts: tamsulosin 0.4 mg daily (cohort 1, n=21) and terazosin 5 or 10 mg daily (cohort 2, n=21). The design was a randomized, double blind, cross-over study with four treatments: vardenafil 5 mg or placebo administered simultaneously with the alpha-blocker and vardenafil 5 mg or placebo administered 6 hours after the alpha-blocker. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil dosing. For blood pressure (BP) results see Table 2. One patient after simultaneous treatment with 5 mg vardenafil and 10 mg terazosin exhibited symptomatic hypotension with standing blood pressure of 80/60 mmHg occurring one hour after administration and subsequent mild dizziness and moderate lightheadedness lasting for 6 hours. For vardenafil and placebo, five and two patients, respectively, experienced a decrease in standing systolic blood pressure (SBP) of >30 mmHg following simultaneous administration of terazosin. Hypotension was not observed when vardenafil 5 mg and terazosin were administered 6 hours apart. Following simultaneous administration of vardenafil 5 mg and tamsulosin, two patients had a standing SBP of less than 85 mmHg. A decrease in standing SBP of greater than 30 mmHg was observed in two patients on tamsulosin receiving simultaneous vardenafil and in one patient receiving simultaneous placebo treatment. When tamsulosin and vardenafil 5 mg were separated by 6 hours, two patients had a standing SBP less than 85 mmHg and one patient had a decrease in SBP of greater than 30 mmHg. There were no severe adverse events related to hypotension reported during the study. There were no cases of syncope. Study 3: This study was designed to evaluate the effect of single doses of 5 mg vardenafil (stage 1) and 10 mg vardenafil (stage 2) compared to placebo, when administered to a single cohort of BPH patients (n=24) on stable therapy with alfuzosin 10 mg daily for at least four weeks. The design was a randomized, double blind, 3-period cross-over study. Vardenafil or placebo was administered 4 hours after the administration of alfuzosin. Blood pressure and pulse were evaluated over a 10-hour interval after dosing of vardenafil or placebo. For BP results see Table 4. Vardenafil can cause your blood pressure to drop suddenly to an unsafe level if it is taken with certain other medicines. With a sudden drop in blood pressure, you could get dizzy, faint, or have a heart attack or stroke. 1.Have heart problems such as angina, heart failure, irregular heartbeats, or have had a heart attack. Ask your doctor if it is safe for you to have sexual activity. 2.Have low blood pressure or have high blood pressure that is not controlled. 3.Have had a stroke. 4.Have had a seizure. 5.Or any family members have a rare heart condition known as prolongation of the QT interval (long QT syndrome). 6.Have liver problems. 7.Have kidney problems and require dialysis. 8.Have retinitis pigmentosa, a rare genetic (runs in families) eye disease 9.Have ever had severe vision loss, or if you have an eye condition called non-arteritic anterior ischemic optic neuropathy (NAION). 10.Have stomach ulcers. 11.Have a bleeding problem. 12.Have a deformed penis shape or Peyronie's disease. 13.Have had an erection that lasted more than 4 hours. 14.Have blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia. 15.Have hearing problems. Take Vardenafil exactly as your doctor prescribes. Do not take more than one Vardenafil a day. Doses should be taken at least 24 hours apart. Some men can only take a low dose of Vardenafil because of medical conditions or medicines they take. Your doctor will prescribe the dose that is right for you. Take 1 Vardenafil tablet about 1 hour (60 minutes) before sexual activity. Some form of sexual stimulation is needed for an erection to happen with Vardenafil. Vardenafil may be taken with or without meals. Do not change your dose of Vardenafil without talking to your doctor. Your doctor may lower your dose or raise your dose, depending on how your body reacts to Vardenafil. The most common side effects with Vardenafil are headache, flushing, stuffy or runny nose, indigestion, upset stomach, dizziness or back pain. These side effects usually go away after a few hours. Call your doctor if you get a side effect that bothers you or one that will not go away. In rare instances, men taking PDE5 inhibitors (oral erectile dysfunction medicines, including Vardenafil) reported a sudden decrease or loss of vision in one or both eyes. It is not possible to determine whether these events are related directly to these medicines, to other factors such as high blood pressure or diabetes, or to a combination of these. If you experience sudden decrease or loss of vision, stop taking PDE5 inhibitors, including Vardenafil, and call a doctor right away. Sudden loss or decrease in hearing, sometimes with ringing in the ears and dizziness, has been rarely reported in people taking PDE5 inhibitors, including Vardenafil. It is not possible to determine whether these events are related directly to the PDE5 inhibitors, to other diseases or medications, to other factors, or to a combination of factors. If you experience these symptoms, stop taking Vardenafil and contact a doctor right away. Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use Vardenafil for a condition for which it was not prescribed. Do not give Vardenafil to other people, even if they have the same symptoms that you have. It may harm them. This leaflet summarizes the most important information about Vardenafil. If you would like more information, talk with your healthcare provider. You can ask your doctor or pharmacist for information about Vardenafil that is written for health professionals. Norvir (ritonavir) is a trademark of Abbott Laboratories Crixivan (indinavir sulfate) is a trademark of Merck & Co., Inc. Invirase or Fortavase (saquinavir mesylate) is a trademark of Roche Laboratories Inc. Reyataz (atazanavir sulfate) is a trademark of Bristol-Myers Squibb Company Nizoral (ketoconazole) is a trademark of Johnson & Johnson Sporanox (itraconazole) is a trademark of Johnson & Johnson Hytrin (terazosin HCl) is a trademark of Abbott Laboratories Flomax (tamsulosin HCl) is a trademark of Yamanouchi Pharmaceutical Co., Ltd. Cardura (doxazosin mesylate) is a trademark of Pfizer Inc. Minipress (prazosin HCl) is a trademark of Pfizer Inc. Rapaflo (silodosin) is a trademark of Watson Pharma Inc. Uroxatral (alfuzosin HCl) is a trademark of Sanofi-Synthelabo

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/index.php/Variable_number_tandem_repeat

# Variable number tandem repeat A variable number tandem repeats (VNTR) is a short nucleotide sequence ranging from 14 to 100 nucleotides long that is organized into clusters of tandem repeats, usually repeated in the range of between 4 and 40 times per occurrence. Clusters of such repeats are scattered on many chromosomes. Each variant is an allele and they are inherited codominantly. Coupled with Polymerase chain reactions, VNTRs have been very effective in forensic crime investigations. When VNTRs are cut out, on either side of the sequence, by restriction enzymes and the results are visualized with a gel electrophoresis, a pattern of bands unique to each individual is produced. The number of times that a sequence is repeated varies between different individuals and between maternal and paternal loci of an individual. The likelihood of two individuals having the same band pattern is extremely improbable. Southern blotting is also used to visualize the repeat numbers on the chromosomes. Once the tandem repeat has been found, identification of possible restriction sites on either side of the repeats are carried out. Using restriction enzymes will break the DNA into the repeat sequences plus a little on each end. The number of repeats will determine the length of the fragment of DNA. The repeat sequence itself can be used as a probe, or if the repeat is not long enough, a sequence from the upstream or downstream side can be used. The probe can either be radioactive or have a biotinylated linker for a fluorescent molecule. VNTR evidence is considered to be exclusionary, which means that a mismatch (or no match at all) sample can be excluded from the genetic relationship of the original sample trying to be matched. There are two principal families of VNTR: minisatellites and microsatelites. The former are sequences of 11-16 bp repeated 1000 times. They are important because they are highly repetitive and dispersed into the genome. In humans, they are present in 60 autosomic loci and can be examined by digesting the DNA and hybriding with a monolocus probe or with another probe derived from a sequence that is common to each locus. The other members of the VNTR family are the microsatellites or STR (short tandem repeats).They are represented by short sequences of 100-200 bp given by the repetition of 1-6 bp sequences. They cannot be digested, so they are amplified by a multiplex PCR. Parental investigation with these kind of markers are non suitable between consanguineous, because electrophoresis profiles will be very similar. So it is possible to examine only one locus. In this way the system is perfect: one allele derives from the mother and the other one from the father. Microsatellites have many uses: they can be used in forensics, genetic variability and parentage studies.

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/index.php/Varices_and_variceal_bleed_resident_survival_guide

# Varices and variceal bleed resident survival guide Gastroesophageal varices are portosystemic collaterals resulting from portal hypertension which is a complication of cirrhosis. Gastroesophageal varices are prone to rupture leading to life threatening hemorrhage. Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. Variceal bleed is a life-threatening condition and must be treated as such irrespective of the causes. Shown below is an algorithm depicting the screening and prophylaxis management of non bleeding varices in cirrhosis based on the practice guidelines approved by American Association for the Study of Liver Diseases (AASLD) and American College of Gastroenterology (ACG). Shoen below is an algorithm depicting the management of actively bleeding varices based on the practice guidelines approved by American Association for the Study of Liver Diseases (AASLD) and American College of Gastroenterology (ACG).

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/index.php/Varicose_veins

# Varicose veins History and Symptoms | Physical Examination | Laboratory Findings | CT | MRI | Ultrasound | Other Imaging Findings | Other Diagnostic Studies

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/index.php/Varicose_veins_(patient_information)

# Varicose veins (patient information) In normal veins, valves in the vein keep blood moving forward toward the heart. With varicose veins, the valves do not function properly, allowing blood to remain in the vein. Pooling of blood in a vein causes it to enlarge. Primary varicose veins occur because of congenitally defective valves, or without a known cause. Secondary varicose veins occur because of another condition, such as when a pregnant woman develops varicose veins. Standing for a long time and having increased pressure in the abdomen may make you more likely to develop varicose veins, or may make the condition worse. At times a physician may order a duplex ultrasound exam of the extremity to see blood flow in the veins, and to rule out other disorders of the legs (such as a blood clot). Rarely, an angiogram of the legs may be performed to rule out other disorders. Vein stripping is surgery to remove varicose veins in the legs. It is usually reserved for patients who are having a lot of pain or who have skin ulcers.

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/index.php/Varicose_veins_CT

# Varicose veins CT Diagnostic test of choice for varicose veins is duplex ultrasound. CT is not recommended. While it can help diagnose varicose veins, sensitivity is relative low. CT can be used in conjunction with Ultrasonography to diagnose hidden Varicose Veins, assess the root cause of recurrent varicose veins and perform a pre-operative assessment of varicose veins . Using a contrast such as iodine, CT Angiography can help quickly locate malformations, structural abnormalities and blockages of the vascular system. 3-D CT Venography technology can improve the accuracy and clarity of the images further.

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/index.php/Varicose_veins_MRI

# Varicose veins MRI Varicose veins can at times present with nothing but lower limb edema. Magnetic Resonance Venography(MRV) is the most sensitive and specific imaging study that can be used to detect deep as well as superficial venous pathologies that might not be clinically apparent otherwise . It is useful in clarifying situations where clinical picture of edema and leg pain might falsely suggest venous insufficiency .

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/index.php/Varicose_veins_causes

# Varicose veins causes Varicose veins are more common in women than in men, and are linked with heredity. Other related factors are pregnancy, obesity, menopause, aging, prolonged standing, leg injury and abdominal straining. Varicose veins are bulging veins that are larger than spider veins, typically 3 mm or more in diameter. Varicose veins are distinguished from reticular veins (blue veins) and telangiectasias (spider veins) which also involve valvular insufficiency, by the size and location of the veins. The causes of varicose veins are not clearly understood. In some cases, it is caused by weak or damaged valves that are usually present in veins. These valves help ensure that blood in veins down not flow in the backward direction. However, when these valves are weak or damaged, blood tends to flow backward . This increases the pressure inside the veins, causing them to become ballooned and tortuous over time. In some other cases, walls of veins are already weak and they might form outpouchings from the pooling and pressure of blood . There are no clearly established causes of varicose veins. However, there are a few established risk factors such as Pregnancy, obesity, age, sex, family history etc. To review the risk factor please refer to the relevant section.

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/index.php/Varicose_veins_classification

# Varicose veins classification The CEAP (Clinical, Etiological, Anatomical, and Pathophysiological) Classification has been developed to help in diagnosis, staging, and treating Varicose veins/Chronic Venous Insufficiency. The patients with Varicose veins can present with symptoms ranging from discomfort, itching, ulceration, swelling to DVT (Deep vein thrombosis) depending on the severity of the disease. This classification helps us stage the disease, while also providing useful information about the anatomy, cause, and the pathophysiology of the disease which with help in deciding the method of management. The CEAP classification has four major categories(Clinical, Etiological, Anatomical, and Pathophysiological); each of them divided into multiple subcategories .

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/index.php/Varicose_veins_differential_diagnosis

# Varicose veins differential diagnosis Varicose veins maybe differentiated from other diseases that cause swelling in the lower limb, such as femoral hernia, inguinal hernia, femoral artery aneurysm, lymphadenopathy and lipoma.

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/index.php/Varicose_veins_epidemiology_and_demographics

# Varicose veins epidemiology and demographics Varicose veins are a common disease. Its reported prevalence all over the world varies between 10% to 30% . The majority of the cases are reported in developed and industrialised countries. The prevalence of varicose veins in the USA is estimated to be 23% of the adult population. It is more common in women than in men. The prevalence increases with age. Heredity seems to play a major role in development of Varicose veins. 50% of the patients have a family history of the disease. The children with two affected parents are at almost 90% risk . Prevalence: Worldwide the prevalence varies between 10-30% of the population. In the USA, the prevalence is around 4500/100,000 . It affects around 22 million women and 11 million men . Region: Varicose Veins are more common in western and industrialized countries compared to the developing countries . The paper noted that the prevalence rates between Egypt and England was upwards of five-fold after standardization for age. Gender: Females are twice as likely to be affected by varicose veins as compared to males. Although, males are nearly twice as likely to have visible disease . Race: The San Diego Population Study, a first of its kind multi-ethnic study of Chronic venous disease noted that the prevalence of visible varicose veins was significantly higher in Hispanics; while it was lowest in Asians .

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/index.php/Varicose_veins_historical_perspective

# Varicose veins historical perspective The first mention of Varicose veins can be traced back to the Papyrus of Ebers. Depending on the severity, treatment ranging from compression stocking to operative procedures are available. Its treatment methods have evolved over time from procedures with very high mortality( such as stripping of veins through long incisions) to procedures that can be performed without any anesthesia such as EVLT.

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/index.php/Varicose_veins_history_and_symptoms

# Varicose veins history and symptoms ## Symptoms Besides cosmetic problems, varicose veins are often painful, especially when standing or walking. They often itch, and scratching them can cause ulcers. The symptoms such as heaviness, aching, cramping, etc. are often due to venous hypertension. The symptoms are often worse at the starting of the disease, mild at the middle of the disease, and again worsen in the advanced stages of the disease. Patients often get used to having the symptoms and might need some thorough interviewing to get the information .

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/index.php/Varicose_veins_medical_therapy

# Varicose veins medical therapy Non-surgical treatments include sclerotherapy, elastic stockings, elevating the legs, and exercise. The traditional surgical treatment has been vein stripping to remove the affected veins. Newer surgical treatments are less invasive (see radiofrequency ablation) and are slowly replacing traditional surgical treatments . Since most of the blood in the legs is returned by the deep veins, and the superficial veins only return about 10%, they can be removed or ablated without serious harm. A commonly performed non-surgical treatment for varicose and "spider" leg veins is sclerotherapy. It has been used in the treatment of varicose veins for over 150 years. Sclerotherapy is often used for telangiectasias (spider veins) and varicose veins that persist or recur after vein stripping. Sclerotherapy can also be performed using microfoam sclerosants under ultrasound guidance to treat larger varicose veins, including the greater and short saphenous veins. A study by Kanter and Thibault in 1996 reported a 76% success rate at 24 months in treating saphenofemoral junction and great saphenous vein incompetence with STS 3% solution. A Cochrane Collaboration review concluded sclerotherapy was better than surgery in the short term (1 year) for its treatment success, complication rate and cost, but surgery was better after 5 years, although the research is weak. A Health Technology Assessment found that sclerotherapy provided less benefit than surgery, but is likely to provide a small benefit in varicose veins without reflux. Complications of sclerotherapy are rare but can include blood clots and ulceration. Anaphylactic reactions are "extraordinarily rare but can be life-threatening," and doctors should have resuscitation equipment ready. There has been one reported case of stroke after ultrasound guided sclerotherapy when an unusually large dose of sclerosant foam was injected. The Australian Medical Services Advisory Committee (MSAC) in 2008 has determined that endovenous laser treatment for varicose veins "appears to be more effective in the short term, and at least as effective overall, as the comparative procedure of junction ligation and vein stripping for the treatment of varicose veins." It also found in its assessment of available literature, that "occurrence rates of more severe complications such as DVT, nerve injury and paresthesia, post-operative infections and hematomas, appears to be greater after ligation and stripping than after EVLT". Complications for endovenous laser treatment include minor skin burns (0.4%) and temporary paresthesia (2.1%). The longest study of endovenous laser ablation is 39 months. Two prospective randomized trials found speedier recovery and fewer complications after radiofrequency obliteration (AKA radiofrequency ablation) compared to open surgery. Myers wrote that open surgery for small saphenous vein reflux is obsolete. Myers said these veins should be treated with endovenous techniques, citing high recurrence rates after surgical management, and risk of nerve damage up to 15%. In comparison, radiofrequency ablation has been shown to control 80% of cases of small saphenous vein reflux at 4 years, said Myers. Complications for radiofrequency ablation include burns, paresthesia, clinical phlebitis, and slightly higher rates of deep vein thrombosis (0.57%) and pulmonary embolism (0.17%). One 3-year study compared radiofrequency, with a recurrence rate of 33%, to open surgery, which had a recurrence rate of 23%. Endovenous laser and radiofrequency ablation require specialized training for doctors and expensive equipment. Endovenous laser treatment is performed as an outpatient procedure and does not require the use of an operating theater, nor does the patient need a general anesthetic. Doctors must use ultrasound during the procedure to see what they are doing. Some practitioners also perform phlebectomy or ultrasound guided sclerotherapy at the time of endovenous treatment. Follow-up treatment to smaller branch varicose veins is often needed in the weeks after the initial procedure.

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/index.php/Varicose_veins_natural_history,_complications_and_prognosis

# Varicose veins natural history, complications and prognosis The progression of chronic venous insufficiency over time is not well understood. The progression follows quite a variable path. Some patients might initially have varicose veins but not have any clinical symptoms; others might develop clinical symptoms(such as heaviness,eczema, etc.) without any clinically visible disease. Without treatment most patients will show worsening of the condition over time . The natural history of varicose veins is not well understood. This has been a roadblock in prioritizing patients on the basis of stage of clinical disease. For different patients, the disease progresses in different manners. The progression of the varicose veins is driven by a cycle of venous hypertension, inflammation, capillary damage, and edema . In a study by Lee et al , it was found that almost half(57%) the patients who develop some level of chronic venous disease initially would show a progression of the disease when followed over time. 98% of the patients who had both varicose veins and chronic venous insufficiency at baseline showed deterioration with time. While the progression was affected by a family history of varicose veins, age, history of DVT, being overweight; gender did not seem to play a role in determining the rate of progression. On duplex ultrasonography scanning, venous reflux especially, superficial combined with deep vein reflux was found to be associated with higher rates of disease progression. Even though Varicose veins are a chronic condition, the prognosis is often benign. Most of the mortality associated with varicose veins is due to venous thromboembolism. The possibility of DVT should always be considered in patients with varicose veins. In a 14 year study conducted in Taiwan during the year 2018, the incidence of DVT was found to be 5 times higher in subjects with varicose veins as compared to without . This can be prevented with timely intervention.

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/index.php/Varicose_veins_other_diagnostic_studies

# Varicose veins other diagnostic studies Varicose veins usually occur in the superficial veins due to failure of venous valve system (which protects the superficial veins from high pressure of the deep vein system). The convenience of Duplex Ultrasonography for Varicose veins has driven down the demand and importance of Physiologic testing. Some physiologic tests for varicose veins are Maximal venous outflow(MVO), Venous refill time(VRT), and Calf Muscle pump Ejection fraction(MPEF) .

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/index.php/Varicose_veins_overview

# Varicose veins overview Varicose veins are veins that have become enlarged and twisted. The term commonly refers to the veins on the leg, although varicose veins occur elsewhere. Veins have leaflet valves to prevent blood from flowing backwards (retrograde). Leg muscles pump the blood in veins to return it to the heart. When veins become enlarged, the leaflets of the valves no longer meet properly, and the valves don't work. A common cause of valve failure is Deep Vein Thrombosis (DVT), which can cause permanent damage to the valves. The blood collects in the veins and they enlarge even more. Varicose veins are common in the superficial veins of the legs, which are subject to high pressure when standing. These often occur in people who are involved in work requiring prolonged periods of standing. The high pressure that builds up during those periods cause the veins to become tortuous and their valves to fail. With time, these varicosities can enlarge and cause swelling as well as pain of legs at the end of the day. Eventually, these can become associated with superficial ulcers which can bleed and/or get infected. Stagnation of the venous blood in these veins can also lead to formation of blood clots. Serious complications are rare but severe varicosities can lead to major complications such as thrombophlebitis, venous ulcers & clotting of blood , due to the poor circulation through the affected limb. Besides cosmetic problems, varicose veins are often tortuous and painful, especially when standing or walking. They often itch, and scratching them can cause ulcers. Non-surgical treatments include sclerotherapy, elastic stockings, elevating the legs, and exercise. The traditional surgical treatment has been vein stripping to remove the affected veins. Newer surgical treatments are less invasive (see radiofrequency ablation) and are slowly replacing traditional surgical treatments. Since most of the blood in the legs is returned by the deep veins, and the superficial veins only return about 10%, they can be removed or ablated without serious harm. Several techniques have been performed for over a century, from the more invasive named "saphenous stripping" up to mini invasives like superficial phlectomies and CHIVA cure.

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# Varicose veins pathophysiology Varicose veins are normal veins that have become dilated beyond 3mm. They usually occur in lower limbs. The superficial and deep veins are connected by perforating veins (also have valves), which also prevent the backflow of blood from deep to superficial veins. Due to obesity, pregnancy, intra-abdominal mass, post-thrombotic destruction of the perforating veins' valves, etc. sustained high pressures can develop in superficial veins. This causes dilation of superficial veins and the development of varicose veins over time. If unattended, they worsen over time and might be associated with pain, discomfort, localized dermatitis, discoloration, and/or ulceration. Because of slowed blood flow, they can also be associated with the formation of blood clots in the dilated veins. Varicose veins originate from sustained raised blood pressure in the superficial veins. Veins are normally gated by a one-way bicuspid valve system that prevents the backward flow of blood. The venous system of limbs is divided by fascia into two sub-systems- Superficial veins and Deep veins. These two venous systems are connected intermittently by perforating veins that travel across fascia. The deep veins are a high-pressure system supported by muscle and deep fascia, which prevent abnormal dilatation of these veins. Additionally, the muscles surrounding the deep veins help in pumping blood towards the heart. The one-way valves and the negative pressure generated by the emptying of deep veins help the blood in superficial veins flow into the deep veins via the perforant/perforating collateral veins . The superficial veins are not supported by fascia. The valves in perforating collateral veins allow blood to flow from superficial to deep veins only. They inhibit backward blood flow from deep to superficial veins. Even though the pressure inside them is low, they are prone to dilation when exposed to high pressure. The pathogenesis of varicose veins is multifactorial. Most of the risk factors for varicose veins either cause the weakening/destruction of valves of perforating veins or cause raise the overall pressure in the veins. There are several risk factors for varicose veins :

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