Topiramate

Template:Short description Template:Use dmy dates Template:Cs1 config Template:Main other {{#invoke:Infobox|infobox}}Template:Template other{{#invoke:TemplatePar |check |template=Template:Infobox_drug |all= |opt= pronounce= pronounce_ref= pronounce_comment= ATC_prefix= ATC_suffix= ATC_supplemental= ATCvet= biosimilars= CAS_number_Ref= CAS_number= CAS_supplemental= ChEBI= ChEBI_Ref= ChEMBL_Ref= ChEMBL= ChemSpiderID= ChemSpiderID_Ref= chirality= class= container_only= DailyMedID= data_page= DrugBank_Ref= DrugBank= Drugs.com= duration_of_action= INN= INN_EMA= IUPAC_name= IUPHAR_ligand= KEGG_Ref= KEGG= MedlinePlus= NIAID_ChemDB= PDB_ligand= PubChemSubstance= PubChem= StdInChIKey_Ref= StdInChIKey= StdInChI_Ref= StdInChI_comment= StdInChI= UNII_Ref= UNII= DTXSID= Verifiedfields= Watchedfields= addiction_liability= alt2= altL= altR= alt= bioavailability= boiling_high= boiling_notes= boiling_point= captionLR= caption= caption2= charge= chemical_formula= chemical_formula_ref= chemical_formula_comment= class1= class2= class3= class4= class5= class6= component1= component2= component3= component4= component5= component6= density= density_notes= dependency_liability= drug_name= elimination_half-life= engvar= excretion= image2= imageL= imageR= image= image_class= image_class2= image_classL= image_classR= Jmol= legal_AU= legal_BR= legal_CA= legal_DE= legal_EU= legal_NZ= legal_UK= legal_UN= legal_US= legal_AU_comment= legal_BR_comment= legal_CA_comment= legal_DE_comment= legal_UK_comment= legal_NZ_comment= legal_US_comment= legal_UN_comment= legal_EU_comment= legal_status= licence_CA= licence_EU= licence_US= license_CA= license_EU= license_US= mab_type= melting_high= melting_notes= melting_point= metabolism= metabolites= molecular_weight= molecular_weight_round= molecular_weight_unit= molecular_weight_ref= molecular_weight_comment= onset= pregnancy_AU= pregnancy_AU_comment= pregnancy_category= protein_bound= routes_of_administration= SMILES= smiles= solubility= sol_units= source= specific_rotation= synonyms= target= tradename= type= vaccine_type= verifiedrevid= width2= widthL= widthR= width= AAN= BAN= JAN= USAN= source_tissues= target_tissues= receptors= agonists= antagonists= precursor= biosynthesis= gt_target_gene= gt_vector= gt_nucleic_acid_type= gt_editing_method= gt_delivery_method= sec_combustion= Ac=Ag=Al=Am=Ar=As=At=Au=B=Ba=Be=Bh=Bi=Bk=Br=C=Ca=Cd=Ce=Cf=Cl=Cm=Cn=Co=Cr=Cs=Cu= D=Db=Ds=Dy=Er=Es=Eu=F=Fe=Fl=Fm=Fr=Ga=Gd=Ge=H=He=Hf=Hg=Ho=Hs=I=In=Ir=K=Kr=La=Li=Lr=Lu=Lv= Mc=Md=Mg=Mn=Mo=Mt=N=Na=Nb=Nd=Ne=Nh=Ni=No=Np=O=Og=Os=P=Pa=Pb=Pd=Pm=Po=Pr=Pt=Pu=Ra=Rb=Re=Rf=Rg=Rh=Rn=Ru=S=Sb=Sc=Se=Sg=Si=Sm=Sn=Sr=Ta=Tb=Tc=Te=Th=Ti=Tl=Tm=Ts=U=V=W=Xe=Y=Yb=Zn=Zr= index_label= index2_label= index_comment= index2_comment= CAS_number2= CAS_supplemental2= ATC_prefix2= ATC_suffix2= ATC_supplemental2= PubChem2= PubChemSubstance2= IUPHAR_ligand2= DrugBank2= ChemSpiderID2= UNII2= KEGG2= ChEBI2= ChEMBL2= PDB_ligand2= NIAID_ChemDB2= SMILES2= smiles2= StdInChI2= StdInChIKey2= CAS_number2_Ref= ChEBI2_Ref= ChEMBL2_Ref= ChemSpiderID2_Ref= DrugBank2_Ref= KEGG2_Ref= StdInChI2_Ref= StdInChIKey2_Ref= UNII2_Ref= DTXSID2= QID= QID2=PLLR= pregnancy_US= pregnancy_US_comment= |cat=Pages using infobox drug with unknown parameters |format=0|errNS=0

|preview=

}}{{Infobox drug/maintenance categoriesTemplate:Yesno | drug_name = | INN = | _drugtype =

| _has_physiological_data= | _has_gene_therapy=

| vaccine_type= | mab_type= | _number_of_combo_chemicals={{#invoke:ParameterCount |main |component1 |component2 |component3 |component4|component5|component6 }} | _vaccine_data= | _mab_data= | _mab_vaccine_data= | _mab_other_data=122118O=S(=O)(OC[C@@]21OC(O[C@H]1[C@@H]3OC(O[C@@H]3CO2)(C)C)(C)C)N1S/C12H21NO8S/c1-10(2)18-7-5-16-12(6-17-22(13,14)15)9(8(7)19-10)20-11(3,4)21-12/h7-9H,5-6H2,1-4H3,(H2,13,14,15)/t7-,8-,9+,12+/m1/s1KJADKKWYZYXHBB-XBWDGYHZSA-NTemplate:StdinchiciteTemplate:Stdinchicite | _combo_data= | _physiological_data= | _clinical_data=Template:Drugs.coma697012Topiramate DOralTopamax, Trokendi XR, Qudexy XR, othersN03Template:ATC | _legal_data=S4<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>C1Rx-only<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Rx-onlyPOM<ref name="Trokendi FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Topamax FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Qsymia FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Qudexy FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Eprontia FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Rx-only

| _other_data=2,3:4,5-Bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate

| _image_0_or_2 = Topiramate structure.svgTopiramate 3D.png | _image_LR =

| _datapage = Topiramate (data page) | _vaccine_target={{#ifeq: | vaccine | | _type_not_vaccine }} | _legal_all=S4C1Rx-onlyPOMRx-onlyRx-only | _ATC_prefix_supplemental=N03Template:ATC | _has_EMA_link = | CAS_number=97240-79-4 | PubChem=5284627 | ChemSpiderID=4447672 | ChEBI= | ChEMBL=220492 | DrugBank=DB00273 | KEGG=D00537 | _hasInChI_or_Key={{#if:1S/C12H21NO8S/c1-10(2)18-7-5-16-12(6-17-22(13,14)15)9(8(7)19-10)20-11(3,4)21-12/h7-9H,5-6H2,1-4H3,(H2,13,14,15)/t7-,8-,9+,12+/m1/s1KJADKKWYZYXHBB-XBWDGYHZSA-N |yes}} | UNII=0H73WJJ391 | _hasJmol02 = |_hasMultipleCASnumbers = |_hasMultiplePubChemCIDs = |_hasMultipleChEBIs =

| _countSecondIDs={{#invoke:ParameterCount |main |CAS_number2 |ATC_prefix2 |PubChem2 |PubChemStructure2 |IUPHAR_ligand2 |DrugBank2 |ChemSpiderID2 |UNII2 |KEGG2 |ChEBI2 |ChEMBL2 |PDB_ligand2 |NIAID_ChemDB2 |SMILES2 |smiles2 |StdInChI2 |StdInChIKey2 |DTXCID2}} | _countIndexlabels={{#invoke:ParameterCount |main |index_label |index2_label}} | _trackListSortletter= |QID = |QID2 = |Verifiedfields=changed |Watchedfields=changed |verifiedrevid=408971931}}

Topiramate, sold under the brand name Topamax among others, is a medication used to treat epilepsy and prevent migraines.<ref name=AHFS2019/> It has also been used for alcohol dependence and essential tremor.<ref name=AHFS2019>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> For epilepsy, this includes treatment for generalized or focal seizures.<ref name=BNF76/> It is taken orally (by mouth).<ref name=AHFS2019/>

Common side effects include tingling, feeling tired, loss of appetite, abdominal pain, weight loss,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and decreased cognitive function such as trouble concentrating.<ref name=AHFS2019/><ref name=BNF76>Template:Cite book</ref> Serious side effects may include suicide, increased ammonia levels resulting in encephalopathy, and kidney stones.<ref name=AHFS2019/> Topiramate can cause birth defects, including cleft lip and palate.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Risks/benefits should be carefully discussed with the full treatment team. Topiramate is considered "probably compatible" with lactation and is not contraindicated for breastfeeding, though monitoring of the infant for diarrhea or poor weight gain may be considered.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite book</ref> The mechanism of action is unclear.<ref name=AHFS2019/>

Topiramate was approved for medical use in the United States in 1996.<ref name=AHFS2019/> It is available as a generic medication.<ref name=BNF76/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 2022, it was the 84th most commonly prescribed medication in the United States, with more than 8Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

File:Topimax 25mg.jpg

A package of topiramate 25mg from Norway

Topiramate is used to treat epilepsy in children and adults, and it was originally used as an anticonvulsant.<ref name="Topamax Rx info" /> In children, it is indicated for the treatment of Lennox-Gastaut syndrome, a disorder that causes seizures and developmental delay. It is most frequently prescribed for the prevention of migraines,<ref name="Topamax Rx info">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> as it decreases the frequency of attacks.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Topiramate is used to treat medication overuse headache and is recommended by the European Federation of Neurological Societies as one of the few medications showing effectiveness for this indication.<ref name="European Neurology">Template:Cite journal</ref>

Pain

A 2018 review found topiramate of no use in chronic low back pain.<ref>Template:Cite journal</ref> Topiramate has not been shown to work as a pain medicine in diabetic neuropathy, the only neuropathic condition for which it has been adequately tested.<ref>Template:Cite journal</ref>

Other

One common off-label use for topiramate is in the treatment of bipolar disorder.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> A review published in 2010 suggested a benefit of topiramate in the treatment of symptoms of borderline personality disorder; however, the authors noted that this was based only on one randomized controlled trial and requires replication.<ref>Template:Cite journal</ref>

Topiramate has been used as a treatment for alcoholism.<ref>Template:Cite journal</ref> The U.S. Veterans Affairs and Department of Defense 2015 guidelines on substance use disorders list topiramate as a "strong for" in its recommendations for alcohol use disorder.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Other uses include treatment of obesity<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and binge eating disorder,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and off-setting weight gain induced by taking antipsychotic medications.<ref>Template:Cite journal</ref> In 2012, the combination of phentermine/topiramate was approved in the United States for weight loss.

Adverse effects

People taking topiramate should be aware of the following risks:

• Avoid activities requiring mental alertness and coordination until drug effects are realized.
• Topiramate may impair heat regulation,<ref name="side-effects" /> especially in children. Use caution with activities leading to an increased core temperature, such as strenuous exercise, exposure to extreme heat, or dehydration.
• Topiramate may cause visual field defects.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• Topiramate may decrease the effectiveness of oestrogen-containing oral contraceptives.
• Taking topiramate in the first trimester of pregnancy may increase the risk of cleft lip/cleft palate in infants.<ref name="fda.gov"/>
• As is the case for all antiepileptic drugs, it is advisable not to suddenly discontinue topiramate, as there is a theoretical risk of rebound seizures.
• Some studies have attributed loss of appetite and upper respiratory tract infection to topiramate, but studies have concluded these adverse events are not difficult to tolerate for most individuals.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

Frequency

Adverse effects by incidence:<ref name = TGA>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name = MSR>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=EMC>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name = DM>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Very common (>10% incidence) adverse effects include: Template:Columns-list

Rarely, the inhibition of carbonic anhydrase may be strong enough to cause metabolic acidosis of clinical importance.<ref>Template:Cite journal</ref>

The U.S. Food and Drug Administration (FDA) has notified prescribers that topiramate can cause acute myopia and secondary angle closure glaucoma in a small subset of people who take topiramate regularly.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The symptoms, which typically begin in the first month of use, include blurred vision and eye pain. Discontinuation of topiramate may halt the progression of the ocular damage and may reverse the visual impairment.

Preliminary data suggests that, as with several other anti-epileptic drugs, topiramate carries an increased risk of congenital malformations.<ref name="pmid18645165">Template:Cite journal</ref> This might be particularly important for women who take topiramate to prevent migraine attacks. In March 2011, the FDA notified healthcare professionals and patients of an increased risk of development of cleft lip and/or cleft palate (oral clefts) in infants born to women treated with Topamax (topiramate) during pregnancy and placed it in Pregnancy Category D.<ref name="fda.gov">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Cognitive and word-finding difficulties, which may occur in some patients, may respond to piracetam.<ref>Berthier, M.L. and Dávila, G., 2023. Pharmacotherapy for post-stroke aphasia: what are the options?. Expert Opinion on Pharmacotherapy, (just-accepted).</ref><ref>Cumbo, E. and Ligori, L.D., 2010. Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer’s disease. Epilepsy & Behavior, 17(4), pp.461-466.</ref>

Carbonation dysgeusia (distortion of the sense of taste-sensation of carbonation) may respond to and/or be prevented with zinc.<ref>Charbonneau, M., Doyle-Campbell, C., Laskey, C. and Capoccia, K., 2020. Carbonation dysgeusia associated with topiramate. American Journal of Health-System Pharmacy, 77(14), pp.1113-1116.</ref>

Topiramate has been associated with a statistically significant increase in suicidality,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and "suicidal thoughts or actions" is now listed as one of the possible side effects of the drug "in a very small number of people, about 1 in 500."<ref name="side-effects">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Overdose

Symptoms of acute and acute on chronic exposure to topiramate range from asymptomatic to status epilepticus, including in patients with no seizure history.<ref name=clintox>Template:Cite journal</ref><ref name=wills>Template:Cite journal</ref> In children, overdose may also result in hallucinations.<ref name=wills/> Topiramate has been deemed the primary substance that led to fatal overdoses in cases that were complicated by polydrug exposure.<ref name=lofton>Template:Cite journal</ref> The most common signs of overdose are dilated pupils, somnolence, dizziness, psychomotor agitation, and abnormal, uncoordinated body movements.<ref name=clintox/><ref name=wills/><ref name=lofton/>

Interactions

Topiramate has many drug-drug interactions. Some of the most common are listed below:

• As topiramate inhibits carbonic anhydrase, use with other inhibitors of carbonic anhydrase (e.g. acetazolamide) increases the risk of kidney stones.Template:Citation needed
• Enzyme inducers (e.g. carbamazepine) can increase the elimination of topiramate, possibly necessitating dose escalations of topiramate.Template:Citation needed
• Topiramate may increase the plasma levels of phenytoin.
• Topiramate itself is a weak inhibitor of CYP2C19 and induces CYP3A4; a decrease in plasma levels of estrogens and digoxin has been noted during topiramate therapy. This can reduce the effectiveness of oral contraceptives (birth control pills); use of alternative birth control methods is recommended.<ref name=Martindale_OC>Template:Cite book</ref> Neither intrauterine devices (IUDs) nor Depo-Provera are affected by topiramate.<ref name=Martindale_OC/>
• Alcohol may cause increased sedation or drowsiness, and increase the risk of having a seizure.
• As topiramate may result in acidosis, other treatments that also do so may worsen this effect.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• Oligohidrosis and hyperthermia were reported in post-marketing reports about topiramate; antimuscarinic drugs (like trospium) can aggravate these disorders.Template:Citation needed

Pharmacology

File:Topiramate (chair style).svg

Chair-style representation of skeletal formula

The topiramate molecule is a sulfamate modified sugar – more specifically, fructose diacetonide, an unusual chemical structure for a pharmaceutical.

Topiramate is quickly absorbed after oral use. It has a half-life of 21 hours and a steady state of the drug is reached in 4 days in patients with normal renal function.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Most of the drug (70%) is excreted in the urine unchanged. The remainder is extensively metabolized by hydroxylation, hydrolysis, and glucuronidation. Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose.

Several cellular targets have been proposed to be relevant to the therapeutic activity of topiramate.<ref>Template:Cite book</ref> These include (1) voltage-gated sodium channels; (2) high-voltage-activated calcium channels; (3) GABA-A receptors; (4) AMPA/kainate receptors; and (5) carbonic anhydrase isoenzymes. There is evidence that topiramate may alter the activity of its targets by modifying their phosphorylation state instead of by direct action.<ref>Template:Cite journal</ref> The effect on sodium channels could be of particular relevance for seizure protection. Although topiramate does inhibit high-voltage-activated calcium channels, its relevance to clinical activity is uncertain. Effects on specific GABA-A receptor isoforms could also contribute to the antiseizure activity of the drug. Topiramate selectively inhibits cytosolic (type II) and membrane-associated (type IV) forms of carbonic anhydrase. Its action on carbonic anhydrase isoenzymes may contribute to the drug's side effects, including its propensity to cause metabolic acidosis and calcium phosphate kidney stones.

Topiramate inhibits maximal seizure activity in electroconvulsive therapy and in pentylenetetrazol-induced seizures as well as partial and secondarily generalized tonic-clonic seizures in the kindling model, findings predictive of a broad spectrum of activities clinically. Its action on mitochondrial permeability transition pores has been proposed as a mechanism.<ref name="pmid15571505">Template:Cite journal</ref>

While many anticonvulsants have been associated with apoptosis in young animals, animal experiments have found that topiramate is one of the very few anticonvulsants [see: levetiracetam, carbamazepine, lamotrigine] that do not induce apoptosis in young animals at doses needed to produce an anticonvulsant effect.<ref name="Czuczwar-2004">Template:Cite journal</ref>

Detection in body fluids

Blood, serum, or plasma topiramate concentrations may be measured using immunoassay or chromatographic methods to monitor therapy, confirm a diagnosis of poisoning in hospitalized patients, or assist in a medicolegal death investigation. Plasma levels are usually less than 10 mg/L during therapeutic administration, but can range from 10 to 150 mg/L in overdose victims.<ref name="pmid19593736">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite book</ref>

History

Topiramate was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil Pharmaceuticals.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Topiramate was first sold in 1996.<ref>Template:Cite book</ref> Mylan Pharmaceuticals was granted final approval by the FDA for the sale of generic topiramate in the United States and the generic version was made available in September 2006.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The last patent for topiramate in the U.S. was for use in children and expired on 28 February 2009.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Research

Topiramate is being studied as a potential treatment for post-traumatic stress disorder (PTSD).<ref>Template:Cite journal</ref>

There is some evidence for the use of topiramate in the management of cravings related to withdrawal from dextromethorphan.<ref>Template:Cite journal</ref>

A 2023 systematic review of seizure treatment for infants aged 1 to 36 months identified three studies that evaluated the use of topiramate. Though its adverse effects, including upper respiratory tract infection and loss of appetite, were rarely severe enough for the medication to be discontinued in this age group, its effectiveness in reducing seizures was inconclusive. The available research suffers from small sample sizes, inconsistent findings, and inadequate comparison groups.<ref>Template:Cite report</ref>

External links

Template:Anticonvulsants {{#invoke:Navbox|navbox}} Template:Ion channel modulators Template:GABAA receptor positive modulators Template:Ionotropic glutamate receptor modulators Template:Portal bar Template:Authority control