Gabitril

Browse PDR's full list of drug information

Gabitril

Classes

Anticonvulsants, GABA-T Inhibitors

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Tiagabine should be withdrawn gradually to minimize the potential for increased seizure frequency upon drug withdrawal.

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
spontaneous fetal abortion / Delayed / Incidence not known
teratogenesis / 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 / 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

Common Brand Names

Gabitril

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.

Dosage And 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.

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.

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.
Apalutamide: (Moderate) Monitor for decreased efficacy of tiagabine if coadministration with apalutamide is necessary. Tiagabine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking another strong CYP3A4 inducer.
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.
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.
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; Amitriptyline: (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.
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.
Codeine; Phenylephrine; Promethazine: (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.
Codeine; Promethazine: (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.
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.
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.
Darunavir; Cobicistat; 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. (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.
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.
Elvitegravir; Cobicistat; 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.
Elvitegravir; Cobicistat; 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.
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) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
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) Additive CNS depression is possible if monoamine oxidase inhibitors (MAOIs) and tiagabine are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
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, if the drug is monitored via therapeutic drug monitoring, is recommended. Mefloquine may cause CNS side effects that may cause seizures or alter moods or behaviors. Some, but not all anticonvulsants, induce CYP3A4 and may increase the metabolism of mefloquine. Use of enzyme-inducing anticonvulsants can reduce the clinical efficacy of mefloquine, increasing the risk of Plasmodium falciparum resistance during treatment of malaria.
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) Additive CNS depression is possible if monoamine oxidase inhibitors (MAOIs) and tiagabine are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
Netupitant, Fosnetupitant; 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.
Nirmatrelvir; 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.
Nortriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
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.
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.
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) Additive CNS depression is possible if monoamine oxidase inhibitors (MAOIs) and tiagabine are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
Phenobarbital: (Moderate) Population pharmacokinetic analyses indicate that tiagabine clearance is increased by about 60 percent when taken concomitantly with phenobarbital.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (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.
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.
Promethazine: (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.
Promethazine; Dextromethorphan: (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.
Promethazine; Phenylephrine: (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.
Remimazolam: (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.
Rifapentine: (Moderate) Monitor for decreased efficacy of tiagabine if coadministration with rifapentine is necessary. Tiagabine is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking another strong CYP3A4 inducer.
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.
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.
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.
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.
Tranylcypromine: (Moderate) Additive CNS depression is possible if monoamine oxidase inhibitors (MAOIs) and tiagabine are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
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.

How Supplied

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

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.

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.

Pregnancy And Lactation
Pregnancy

Tiagabine should be used during pregnancy only if clearly needed. 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. The effects of tiagabine during labor and delivery are unknown; no data are available. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to tiagabine; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.

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.