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  • CLASSES

    Anticonvulsants, GABA-T Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral anticonvulsant for partial seizures; unique MOA; inhibits reuptake of GABA; a therapeutic range for plasma concentrations has not been established; does not appear to affect hepatic microsomal enzymes; close monitoring for emerging or worsening suicidal thoughts/behavior or depression is recommended.

    COMMON BRAND NAMES

    Gabitril

    HOW SUPPLIED

    Gabitril/Tiagabine Hydrochloride Oral Tab: 2mg, 4mg, 12mg, 16mg

    DOSAGE & INDICATIONS

    For the adjunctive treatment of partial seizures.
    NOTE: Dosage adjustment of tiagabine should be considered whenever a change in patient's enzyme-inducing status occurs as a result of the addition, discontinuation, or dose change of the enzyme-inducing agent. The systemic exposure after a tiagabine dose of 32 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 12 mg/day in a NON-induced population. Similarly, the systemic exposure after a dose of 56 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 22 mg/day in a NON-induced population.
    Oral dosage
    Induced Adults (i.e., patients who are already taking enzyme-inducing antiepileptic drugs (AEDs) (e.g., carbamazepine, phenytoin, primidone, and phenobarbital)

    Initially, 4 mg orally once daily. After 1 week, increase by 4 to 8 mg/day at weekly intervals until clinical response is achieved or up to 56 mg per day. The total daily dose should be given in 2 to 4 divided doses. The usual adult maintenance dose is 32 to 56 mg/day in 2 to 4 divided doses. Most of the clinical experience with tiagabine has been obtained in patients taking at least 1 concomitant enzyme-inducing antiepilepsy drug (AED). If tiagabine is used in a patient who is NOT taking an enzyme-inducing AED (e.g., patients receiving valproate monotherapy), lower doses or a slower dose titration schedule is necessary. A therapeutic range for tiagabine plasma concentrations has not been established.

    Induced Adolescents >= 12 years (i.e., patients who are already taking enzyme-inducing antiepileptic drugs (AEDs) (e.g., carbamazepine, phenytoin, primidone, and phenobarbital)

    Initially, 4 mg orally once daily. Increase by 4 mg at the beginning of week 2. Thereafter, may increase by 4 to 8 mg/day at weekly intervals; the daily dosage should be given in 2 to 4 divided doses. Doses higher than 32 mg/day have been tolerated in a small number of adolescents for a relatively short duration. Most of the clinical experience with tiagabine has been obtained in patients taking at least 1 concomitant enzyme-inducing antiepilepsy drug (AED). If tiagabine is used in a patient who is NOT taking an enzyme-inducing AED (e.g., patients receiving valproate monotherapy), lower doses or a slower dose titration schedule is necessary. A therapeutic range for tiagabine plasma concentrations has not been established.

    Children 2—11 years†

    Published data are limited; off-label experience suggests an initial dosage of 0.1 mg/kg/day orally titrated every 2 weeks by 0.1 mg/kg/day up to a target dosage of 0.4 to 0.6 mg/kg/day orally in patients NOT currently taking enzyme-inducing antiepileptic drugs (AEDs) concurrently. In pediatric patients taking at least 1 concomitant enzyme-inducing AED, upward titration may occur every 1 to 2 weeks, with a higher target dosage of 0.7 to 1 mg/kg/day orally.

    MAXIMUM DOSAGE

    Adults

    56 mg/day PO, dependent on concomitant drug therapy.

    Elderly

    56 mg/day PO, dependent on concomitant drug therapy.

    Adolescents

    >=12 years: 32 mg/day PO, dependent on concomitant drug therapy.

    Children

    2—11 years: 0.6—1 mg/kg/day PO suggested, dependent on concomitant drug therapy.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific dosing guidelines have not been established. Because the half-life of tiagabine is prolonged in patients with hepatic disease, dosage reduction and/or a less frequent dosing interval may be necessary.

    Renal Impairment

    No initial dosage adjustment is required. Adjust dosage as per recommended titration schedules according to patient response and tolerance.

    ADMINISTRATION

     
    A MedGuide is available that discusses the risks associated with the use of anticonvulsant medications, including suicidal thoughts and behaviors.

    Oral Administration

    Tiagabine should be taken with food.
    Tiagabine should be withdrawn gradually to minimize the potential for increased seizure frequency upon drug withdrawal.

    STORAGE

    Gabitril:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Bipolar disorder, children, infants, mania, neonates, seizures, status epilepticus

    The FDA and the manufacturer are strongly discouraging the use of tiagabine for any off-label use. Tiagabine use has been associated with an increased risk for new onset seizures or other seizure disorders (status epilepticus) in patients without seizure disorders. An increased incidence of cognitive/neuropsychiatric events have been associated with patients with a history of EEG abnormalities consisting of spike and wave discharges. This raises the possibility that some of these events may be manifestations of underlying seizure activity. These adverse events usually begin during initial titration and may be dose related. Slow initial titration may help to minimize these central nervous system effects. Many of the patients in whom new onset seizures were reported were prescribed the drug for indications other than partial seizure (e.g., off-label psychiatric indications, like mania or bipolar disorder). In non-epileptic patients who develop seizures, tiagabine should be discontinued and patients should be evaluated for an underlying seizure disorder. In February, 2005 the manufacturer added a bolded warning to the product label to warn of the elevated risk of seizures in patients being treated for conditions other than epilepsy; at that time, the FDA had received roughly 30 such reports. The tiagabine dosing recommendations for treatment of epilepsy were based on studies of patients that were taking enzyme-inducing antiepileptic drugs (AEDs; e.g., carbamazepine, phenytoin, primidone and phenobarbital) which lower plasma levels of tiagabine by inducing its metabolism. Use of tiagabine without enzyme-inducing drugs results in blood levels about twice those attained in the studies on which current dosing recommendations are based. Use in non-induced patients requires lower dose and possibly slower titration of tiagabine. However, seizures have been reported in patients taking daily doses of tiagabine as low as 4 mg/day. In most cases, patients were using concomitant medications (antidepressants, antipsychotics, stimulants, narcotics) that may lower the seizure threshold. Some seizures occurred near the time of a dose increase, even after periods of prior stable dosing. Tiagabine is approved for use only as adjunctive therapy in adults and children 12 years and older in the treatment of partial seizures. The safe and effective use of tiagabine has not been established in neonates, infants, and children below the age of 12 years.

    Depression, suicidal ideation

    In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). This alert followed an initial request by the FDA in March 2005 for manufacturers of marketed anticonvulsants to provide data from existing controlled clinical trials for analysis. Prior to this request, preliminary evidence had suggested a possible link between anticonvulsant use and suicidality. The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (>= 5 years of age). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2—2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Data were analyzed from drugs with adequately designed clinical trials including carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, this is considered to be a class effect. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Anticonvulsants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    Abrupt discontinuation

    Abrupt discontinuation of tiagabine may increase seizure frequency. In initial clinical studies, tiagabine was tapered over a period of four weeks to reduce the potential for withdrawal seizures.

    Hepatic disease

    Tiagabine should be used with caution in patients with hepatic disease. In patients with moderate hepatic impairment (Child-Pugh Class B), clearance of tiagabine was reduced by about 60%. Thus, dosage reduction and/or less frequent dosing may be necessary.

    Driving or operating machinery

    Tiagabine can cause dizziness, drowsiness, and impaired cognition. Patients should be advised to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of whether tiagabine adversely affects their mental and/or motor performance.

    Pregnancy

    Tiagabine is classified as FDA pregnancy risk category C. Tiagabine has been shown to have adverse effects on embryo-fetal development, including teratogenic effects, when administered to pregnant rats and rabbits at dosages greater than the human therapeutic dose. An increased incidence of malformed fetuses (various craniofacial, appendicular, and visceral defects) was observed when tiagabine was administered to pregnant rats during organogenesis; decreased fetal weights and transient maternal weight loss were also noted. When tiagabine was given to female rats during late gestation and throughout parturition and lactation, decreased maternal weight gain, an increase in stillbirths, and decreased postnatal offspring viability were found. Thus, tiagabine should be used during pregnancy only if clearly needed. The effects of tiagabine during labor and delivery are unknown; no data are available. Physicians are advised to recommend that pregnant patients receiving tiagabine enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry.

    Breast-feeding

    According to the manufacturer, it is unknown if tiagabine is excreted into human breast milk, and the drug should be used only if the benefits to the mother clearly outweigh the potential risks to the nursing infant. Studies in rats have shown that tiagabine and/or its metabolites are excreted in breast milk. The molecular weight and half-life of the drug suggest that excretion into human breast milk is likely. Because of the possibility that tiagabine may be excreted in breast milk, patients should be advised to notify those providing care to themselves and their children if they intend to breast-feed or are breast-feeding an infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    Because few patients 65 years of age or older (n = approximately 20) were exposed to tiagabine during its clinical evaluation, no specific statements about the safety or effectiveness of the drug in geriatric patients could be made. According to the Beers Criteria, anticonvulsants such as tiagabine are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, with the exception of treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If tiagabine must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, some anticonvulsants may be used to treat disorders other than seizures (e.g., bipolar disorder, schizoaffective disorder, chronic neuropathic pain, migraine prevention). The need for indefinite continuation in treating any condition should be based on confirmation of the condition and its potential cause(s). Determining effectiveness and tolerability through evaluation of symptoms should be used to adjust doses. Therapeutic drug monitoring is not required or available for most anticonvulsants. In addition, significant signs and symptoms of toxicity can occur at normal or low serum concentrations, and symptom control for seizures or behavior can occur at subtherapeutic serum concentrations. Obtaining serum medication concentrations may assist in identifying toxicity. High or toxic serum concentrations should become a consideration for dosage adjustments. Anticonvulsants may cause liver dysfunction, blood dyscrasias, and serious skin rashes requiring treatment discontinuation. Anticonvulsants may also cause nausea/vomiting, dizziness, ataxia, somnolence/lethargy, incoordination, blurred or double vision, restlessness, toxic encephalopathy, anorexia, and headaches; these effects can increase the risk for falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / 0.1-1.0
    coma / Early / 0.1-1.0
    cholecystitis / Delayed / 0.1-1.0
    GI bleeding / Delayed / 0.1-1.0
    exfoliative dermatitis / Delayed / 0.1-1.0
    myocardial infarction / Delayed / 0.1-1.0
    apnea / Delayed / 0.1-1.0
    bronchospasm / Rapid / 0.1-1.0
    hearing loss / Delayed / 0.1-1.0
    keratoconjunctivitis / Early / 0.1-1.0
    renal failure (unspecified) / Delayed / 0.1-1.0
    visual impairment / Early / 1.0
    seizures / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    fetal abortion / Delayed / Incidence not known

    Moderate

    ataxia / Delayed / 5.0-9.0
    amblyopia / Delayed / 4.0-9.0
    depression / Delayed / 1.0-7.0
    confusion / Early / 5.0-5.0
    hostility / Early / 2.0-5.0
    dysarthria / Delayed / 4.0-4.0
    memory impairment / Delayed / 4.0-4.0
    nystagmus / Delayed / 2.0-2.0
    peripheral vasodilation / Rapid / 2.0-2.0
    psychosis / Early / 0.1-1.0
    dystonic reaction / Delayed / 0.1-1.0
    choreoathetosis / Delayed / 0.1-1.0
    encephalopathy / Delayed / 0.1-1.0
    hyperreflexia / Delayed / 0.1-1.0
    neuritis / Delayed / 0.1-1.0
    glossitis / Early / 0.1-1.0
    dysphagia / Delayed / 0.1-1.0
    cholelithiasis / Delayed / 0.1-1.0
    gastritis / Delayed / 0.1-1.0
    oral ulceration / Delayed / 1.0-1.0
    gingival hyperplasia / Delayed / 0.1-1.0
    melena / Delayed / 0.1-1.0
    fecal incontinence / Early / 0.1-1.0
    hepatomegaly / Delayed / 0.1-1.0
    elevated hepatic enzymes / Delayed / 0.1-1.0
    esophagitis / Delayed / 0.1-1.0
    contact dermatitis / Delayed / 0.1-1.0
    furunculosis / Delayed / 0.1-1.0
    skin ulcer / Delayed / 0.1-1.0
    atopic dermatitis / Delayed / 0.1-1.0
    psoriasis / Delayed / 0.1-1.0
    hypotension / Rapid / 0.1-1.0
    orthostatic hypotension / Delayed / 0.1-1.0
    angina / Early / 0.1-1.0
    phlebitis / Rapid / 0.1-1.0
    myasthenia / Delayed / 1.0-1.0
    hemoptysis / Delayed / 0.1-1.0
    thrombocytopenia / Delayed / 0.1-1.0
    leukopenia / Delayed / 0.1-1.0
    anemia / Delayed / 0.1-1.0
    hyperacusis / Delayed / 0.1-1.0
    photophobia / Early / 0.1-1.0
    blepharitis / Early / 0.1-1.0
    hypothyroidism / Delayed / 0.1-1.0
    goiter / Delayed / 0.1-1.0
    hypoglycemia / Early / 0.1-1.0
    hypercholesterolemia / Delayed / 0.1-1.0
    dehydration / Delayed / 0.1-1.0
    hyponatremia / Delayed / 0.1-1.0
    hypokalemia / Delayed / 0.1-1.0
    hyperglycemia / Delayed / 0.1-1.0
    hyperlipidemia / Delayed / 0.1-1.0
    cystitis / Delayed / 0.1-1.0
    hematuria / Delayed / 0.1-1.0
    vaginal bleeding / Delayed / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    impotence (erectile dysfunction) / Delayed / 0.1-1.0
    euphoria / Early / 1.0
    hallucinations / Early / 1.0
    myoclonia / Delayed / 1.0
    migraine / Early / 1.0
    hypertonia / Delayed / 1.0
    hypotonia / Delayed / 1.0
    stomatitis / Delayed / 1.0
    palpitations / Early / 1.0
    sinus tachycardia / Rapid / 1.0
    hypertension / Early / 1.0
    dyspnea / Early / 1.0
    lymphadenopathy / Delayed / 1.0
    peripheral edema / Delayed / 1.0
    edema / Delayed / 1.0
    vaginitis / Delayed / 1.0
    urinary incontinence / Early / 1.0
    dysuria / Early / 1.0
    chest pain (unspecified) / Early / 1.0
    EEG changes / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    blurred vision / Early / Incidence not known

    Mild

    dizziness / Early / 27.0-31.0
    asthenia / Delayed / 18.0-23.0
    drowsiness / Early / 18.0-21.0
    tremor / Early / 9.0-21.0
    infection / Delayed / 10.0-19.0
    nausea / Early / 11.0-11.0
    diarrhea / Early / 2.0-10.0
    influenza / Delayed / 6.0-9.0
    pharyngitis / Delayed / 7.0-8.0
    abdominal pain / Early / 5.0-7.0
    vomiting / Early / 7.0-7.0
    insomnia / Early / 5.0-6.0
    ecchymosis / Delayed / 0-6.0
    rash (unspecified) / Early / 5.0-5.0
    myalgia / Early / 2.0-5.0
    paresthesias / Delayed / 4.0-4.0
    cough / Delayed / 4.0-4.0
    emotional lability / Early / 3.0-3.0
    appetite stimulation / Delayed / 2.0-2.0
    pruritus / Rapid / 2.0-2.0
    agitation / Early / 1.0-1.0
    libido increase / Delayed / 0.1-1.0
    libido decrease / Delayed / 0.1-1.0
    hypersalivation / Early / 0.1-1.0
    eructation / Early / 0.1-1.0
    xerostomia / Early / 0.1-1.0
    dental caries / Delayed / 0.1-1.0
    polydipsia / Early / 0.1-1.0
    halitosis / Early / 0.1-1.0
    hirsutism / Delayed / 0.1-1.0
    maculopapular rash / Early / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    skin discoloration / Delayed / 0.1-1.0
    photosensitivity / Delayed / 0.1-1.0
    weakness / Early / 1.0-1.0
    pallor / Early / 0.1-1.0
    pelvic pain / Delayed / 0.1-1.0
    muscle cramps / Delayed / 0.1-1.0
    hiccups / Early / 0.1-1.0
    laryngitis / Delayed / 0.1-1.0
    hyperventilation / Early / 0.1-1.0
    petechiae / Delayed / 0.1-1.0
    parosmia / Delayed / 0.1-1.0
    dysgeusia / Early / 0.1-1.0
    ocular pain / Early / 0.1-1.0
    menorrhagia / Delayed / 0.1-1.0
    polyuria / Early / 0.1-1.0
    mastalgia / Delayed / 0.1-1.0
    urinary urgency / Early / 0.1-1.0
    breast enlargement / Delayed / 0.1-1.0
    amenorrhea / Delayed / 0.1-1.0
    nocturia / Early / 0.1-1.0
    paranoia / Early / 1.0
    hyporeflexia / Delayed / 1.0
    hypoesthesia / Delayed / 1.0
    hyperkinesis / Delayed / 1.0
    vertigo / Early / 1.0
    gingivitis / Delayed / 1.0
    xerosis / Delayed / 1.0
    alopecia / Delayed / 1.0
    hyperhidrosis / Delayed / 1.0
    syncope / Early / 1.0
    arthralgia / Delayed / 1.0
    epistaxis / Delayed / 1.0
    otalgia / Early / 1.0
    tinnitus / Delayed / 1.0
    dysmenorrhea / Delayed / 1.0
    chills / Rapid / 1.0
    malaise / Early / 1.0
    vesicular rash / Delayed / Incidence not known

    DRUG INTERACTIONS

    Alprazolam: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Amitriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Amitriptyline; Chlordiazepoxide: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Amoxapine: (Moderate) Amoxapine, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Some anticonvulsants, such as phenobarbital or carbamazepine, may potentially induce the metabolism of amoxapine as well. Monitor patients for side effects or altered responses to drug therapy.
    Amphetamines: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if tiagabine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in tiagabine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tiagabine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of tiagabine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Atazanavir: (Moderate) The plasma concentrations of tiagabine may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor, while tiagabine is a CYP3A4 substrate.
    Atazanavir; Cobicistat: (Moderate) The plasma concentrations of tiagabine may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor, while tiagabine is a CYP3A4 substrate. (Moderate) The plasma concentrations of tiagabine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while tiagabine is a CYP3A4 substrate.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Population pharmacokinetic analyses indicate that tiagabine clearance is increased by about 60 percent when taken concomitantly with phenobarbital.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Population pharmacokinetic analyses indicate that tiagabine clearance is increased by about 60 percent when taken concomitantly with phenobarbital.
    Benzodiazepines: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering tiagabine with boceprevir due to an increased potential for tiagabine-related adverse events. If tiagabine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of tiagabine. Tiagabine is metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated tiagabine plasma concentrations.
    Brigatinib: (Moderate) Monitor for decreased efficacy of tiagabine if coadministration with brigatinib is necessary. Tiagabine is a CYP3A substrate and brigatinib induces CYP3A in vitro. Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking a strong CYP3A4 inducer; brigatinib may also decrease tiagabine exposure.
    Bupropion: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Bupropion; Naltrexone: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Chlordiazepoxide: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Chlordiazepoxide; Clidinium: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Chlorpromazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Clomipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Clonazepam: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Clorazepate: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Cobicistat: (Moderate) The plasma concentrations of tiagabine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while tiagabine is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of tiagabine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while tiagabine is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of tiagabine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while tiagabine is a CYP3A4 substrate.
    Colesevelam: (Moderate) Colesevelam may decrease the bioavailability of tiagabine if coadministered. To minimize potential for interactions, consider administering oral anticonvulsants such as tiagabine at least 1 hour before or at least 4 hours after colesevelam.
    Conivaptan: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as tiagabine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with tiagabine. Treatment with tiagabine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Moderate) Monitor for an increase in tiagabine-related adverse reactions if coadministration with crizotinib is necessary. It may be useful to obtain plasma concentrations of tiagabine before and after changes are made in the therapeutic regimen, but a therapeutic range has not been established. Tiagabine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
    Darunavir: (Moderate) The plasma concentrations of tiagabine may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while tiagabine is a CYP3A4 substrate.
    Darunavir; Cobicistat: (Moderate) The plasma concentrations of tiagabine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while tiagabine is a CYP3A4 substrate. (Moderate) The plasma concentrations of tiagabine may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while tiagabine is a CYP3A4 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of tiagabine with ritonavir may result in elevated tiagabine plasma concentrations. Tiagabine is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Desipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Diazepam: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Doxepin: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Tiagabine is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Elbasvir; Grazoprevir: (Moderate) Administering tiagabine with elbasvir; grazoprevir may result in elevated tiagabine plasma concentrations. Tiagabine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Enzalutamide: (Moderate) Monitor for decreased efficacy of tiagabine if coadministration with enzalutamide is necessary. Tiagabine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking another strong CYP3A4 inducer.
    Estazolam: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Ethanol: (Major) Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    Fluphenazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Flurazepam: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Hydantoins: (Moderate) Population pharmacokinetic analyses indicate that tiagabine clearance is increased by about 60% when taken concomitantly with phenytoin (or fosphenytoin) or other hepatic enzyme-inducing antiepileptic drugs. Tiagabine had no effect on the steady-state plasma concentrations of phenytoin when evaluated in patients with epilepsy. Tiagabine does not appear to be an inducer or inhibitor of the hepatic microsomal enzyme system. Use of tiagabine WITHOUT enzyme-inducing antiepileptic drugs results in blood levels about two times those attained in the studies on which dosing recommendations for partial seizures are based. If tiagabine is used in patients that are not taking enzyme-inducing drugs, whether it be for the partial seizure indication or for other off-label uses, the dose of tiagabine must be adjusted down. Paradoxical seizures have occurred in patients receiving tiagabine for off-label (primarily psychiatric) indications; these seizures may be dose-related. However, many of these patients were also taking medications that can lower the seizure threshold and the FDA strongly discourage the use of tiagabine for off-label indications.
    Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as tiagabine. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with tiagabine, a CYP3A substrate, as tiagabine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Imipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Isavuconazonium: (Moderate) The plasma concentrations of tiagabine may be elevated when administered concurrently with isavuconazonium. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Tiagabine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme.
    Isocarboxazid: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Kava Kava, Piper methysticum: (Major) The German Commission E warns that any substances that act on the CNS, including anticonvulsants, may interact with kava kava. While the interactions can be pharmacodynamic in nature, kava kava has been reported to inhibit many CYP isozymes (i.e., CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11) and important pharmacokinetic interactions with CNS-active agents that undergo oxidative metabolism via these CYP isozymes are also possible. Persons taking an anticonvulsant should discuss the use of herbal supplements with their health care professional prior to consuming them.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tiagabine; monitor for potential reduction in efficacy. Tiagabine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tiagabine; monitor for potential reduction in efficacy. Tiagabine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of tiagabine with ritonavir may result in elevated tiagabine plasma concentrations. Tiagabine is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Lorazepam: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Maprotiline: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Mefloquine: (Moderate) Coadministration of mefloquine and anticonvulsants may result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the anticonvulsant serum concentration is recommended. Dosage adjustments may be required during and after therapy with mefloquine.
    Mesoridazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Midazolam: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Mitotane: (Major) Use caution if mitotane and tiagabine are used concomitantly, and monitor for decreased efficacy of tiagabine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and tiagabine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of tiagabine.
    Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
    Monoamine oxidase inhibitors: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Netupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as tiagabine. The plasma concentrations of tiagabine can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
    Nortriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of tiagabine with ritonavir may result in elevated tiagabine plasma concentrations. Tiagabine is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Oritavancin: (Moderate) Tiagabine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of tiagabine may be reduced if these drugs are administered concurrently.
    Orlistat: (Moderate) Seizures have been reported in patients treated concomitantly with orlistat and anticonvulsants. Patients should be monitored for possible changes in the frequency and/or severity of convulsions. A mechanism for the potential interaction has not been stated.
    Oxazepam: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and tiagabine, a CYP3A4 substrate, may cause an increase in systemic concentrations of tiagabine. Use caution when administering these drugs concomitantly.
    Pemoline: (Major) A reduction in seizure threshold has been reported following concomitant administration of pemoline with anticonvulsant agents. Dosage adjustments of anticonvulsants may be necessary during simultaneous use of these drugs.
    Perphenazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Perphenazine; Amitriptyline: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Phenelzine: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Phenobarbital: (Moderate) Population pharmacokinetic analyses indicate that tiagabine clearance is increased by about 60 percent when taken concomitantly with phenobarbital.
    Phenothiazines: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant tiagabine, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Posaconazole: (Major) Posaconazole and tiagabine should be coadministered with caution due to an increased potential for tiagabine-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of tiagabine. These drugs used in combination may result in elevated tiagabine plasma concentrations, causing an increased risk for tiagabine-related adverse events.
    Prochlorperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Protriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Quazepam: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with tiagabine is necessary, as the systemic exposure of tiagabine may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and tiagabine is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with tiagabine is necessary, as the systemic exposure of tiagabine may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and tiagabine is a CYP3A4 substrate.
    Ritonavir: (Moderate) Concurrent administration of tiagabine with ritonavir may result in elevated tiagabine plasma concentrations. Tiagabine is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Selegiline: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tiagabine, which is a CYP3A4 substrate. Monitor patients for adverse effects of tiagabine, such as CNS effects.
    St. John's Wort, Hypericum perforatum: (Moderate) Monitor for potential reduction in tiagabine efficacy if administered concomitantly with St. John's Wort, Hypericum perforatum. St. John's Wort is a potent inducer of CYP3A4 isoenzyme and tiagabine is a substrate for CYP3A4. Increased metabolism of tiagabine may occur when St. John's Wort is administered concomitantly.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering tiagabine with telaprevir due to an increased potential for tiagabine-related adverse events. If tiagabine dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of tiagabine. Tiagabine is metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated tiagabine plasma concentrations.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and tiagabine is necessary, as the systemic exposure of tiagabine may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of tiagabine; consider increasing the dose of tiagabine if necessary. Tiagabine is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temazepam: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Thiethylperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Thioridazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Topiramate: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant tiagabine, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Tranylcypromine: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Trazodone: (Moderate) Trazodone can lower the seizure threshold of anticonvulsants, although the overall risk is low at therapeutic doses. Patients may require increased concentrations of anticonvulsants to achieve equivalent effects if trazodone is added.
    Triazolam: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Tricyclic antidepressants: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Trifluoperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Trimipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Valproic Acid, Divalproex Sodium: (Moderate) Tiagabine causes a slight decrease (about 10%) in steady state valproic acid concentrations. The addition of tiagabine to patients taking valproic acid chronically has no effect on tiagabine pharmacokinetics. However, valproic acid has been shown to decrease tiagabine protein binding in vitro from 96.3% to 94.8%, resulting in a 40% increase in free tiagabine concentration; the clinical significance of this finding is not known. Because dosing recommendations for tiagabine were based on use in patients taking enzyme-inducing drugs, patients receiving valproic acid monotherapy may require lower doses or slower dose titration of tiagabine.
    Vemurafenib: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as tiagabine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of tiagabine when coadministered with vemurafenib.
    Voriconazole: (Moderate) Voriconazole is an inhibitor of CYP3A4 isoenzyme and tiagabine is a substrate for CYP3A4. Reduced metabolism of tiagabine may occur when voriconazole is administered concomitantly. The clinical significance of this potential interaction is not known.

    PREGNANCY AND LACTATION

    Pregnancy

    Tiagabine is classified as FDA pregnancy risk category C. Tiagabine has been shown to have adverse effects on embryo-fetal development, including teratogenic effects, when administered to pregnant rats and rabbits at dosages greater than the human therapeutic dose. An increased incidence of malformed fetuses (various craniofacial, appendicular, and visceral defects) was observed when tiagabine was administered to pregnant rats during organogenesis; decreased fetal weights and transient maternal weight loss were also noted. When tiagabine was given to female rats during late gestation and throughout parturition and lactation, decreased maternal weight gain, an increase in stillbirths, and decreased postnatal offspring viability were found. Thus, tiagabine should be used during pregnancy only if clearly needed. The effects of tiagabine during labor and delivery are unknown; no data are available. Physicians are advised to recommend that pregnant patients receiving tiagabine enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry.

    According to the manufacturer, it is unknown if tiagabine is excreted into human breast milk, and the drug should be used only if the benefits to the mother clearly outweigh the potential risks to the nursing infant. Studies in rats have shown that tiagabine and/or its metabolites are excreted in breast milk. The molecular weight and half-life of the drug suggest that excretion into human breast milk is likely. Because of the possibility that tiagabine may be excreted in breast milk, patients should be advised to notify those providing care to themselves and their children if they intend to breast-feed or are breast-feeding an infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Tiagabine inhibits neuronal and glial uptake of gamma aminobutyric acid (GABA) by binding to recognition sites associated with the GABA uptake carrier. Tiagabine inhibits the reuptake of GABA while vigabatrin inhibits enzymatic metabolism of GABA. GABA is the major inhibitory neurotransmitter in the central nervous system and acts on postsynaptic membranes to open chloride channels, thereby leading to membrane hyperpolarization and preventing propagation of neural impulses. By blocking GABA reuptake into presynaptic neurons, tiagabine allows more GABA to be available for receptor binding on post-synaptic cells. Tiagabine does not inhibit the uptake of dopamine, norepinephrine, serotonin, glutamate, or choline. Unlike tiagabine and vigabatrin, the mechanisms of action of other drugs indicated for adjunctive treatment of partial seizures (e.g., lamotrigine, gabapentin, topiramate) are not primarily mediated through GABA transmission.

    PHARMACOKINETICS

    Tiagabine is administered orally. It is extensively bound to plasma proteins (96%), mainly to serum albumin and alpha1-acid glycoprotein.
     
    Although the metabolism has not been completely elucidated, studies indicate that the drug undergoes both oxidation and glucuronidation; at least one inactive metabolite, 5-oxo-tiagabine, has been identified. Tiagabine is thought to be metabolized primarily by the hepatic cytochrome P450 isoenzyme CYP3A4. Systemic clearance in patients receiving enzyme-inducing drugs (e.g., carbamazepine, phenytoin, primidone, phenobarbital) is approximately 60% greater resulting in lower plasma concentrations and an elimination half-life of 2 to 5 hours. Given this difference in clearance, the systemic exposure after a dose of 32 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 12 mg/day in a non-induced population. Similarly, the systemic exposure after a dose of 56 mg/day in an induced population is expected to be comparable to the systemic exposure after a dose of 22 mg/day in a non-induced population. About 2% of a dose is excreted unchanged, with 25% and 63% of the remaining dose excreted into urine and feces, respectively, as metabolites. Average elimination half-life for healthy adults is 7—9 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  CYP3A4
    Tiagabine does not inhibit or induce the hepatic CYP450 microsomal enzymes or UGT (UDP-glucuronosyltransferase). It is a substrate of CYP3A4.

    Oral Route

    After oral administration, the drug is rapidly and nearly completely absorbed (about 95%) with an absolute bioavailability of about 90%. In the fasting state, peak plasma concentrations are achieved about 45 minutes after an oral dose. A high fat meal decreases the rate but not the extent of absorption. The pharmacokinetics of tiagabine are linear over a single dose range of 2—24 mg. A therapeutic range for tiagabine plasma concentrations has not been established; trough plasma concentrations observed with therapeutic doses of 30—56 mg per day ranged from <1 ng/ml to 234 ng/ml. A dose-response effect was seen with tiagabine during initial clinical trials in patients with complex partial seizures: 16 mg/day led to an 8% reduction in seizures, while doses of 32 mg/day and 56 mg/day reduced seizure frequency by 20% and 29%, respectively.