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

MAXIMUM DOSAGE

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

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

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

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

DOSING CONSIDERATIONS

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.

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.

STORAGE

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

CONTRAINDICATIONS / PRECAUTIONS

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.

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 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.

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.

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.

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.

Because few geriatric patients 65 years of age or older (n = approximately 20) were exposed to tiagabine during preapproval clinical trials, no specific statements about safety or effectiveness in the elderly could be made.[30809] 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, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If tiagabine must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; the use of any anticonvulsant for any condition should be based on confirmation of the condition and its potential cause(s). Determine effectiveness and tolerability by evaluating symptoms, and use these as the basis for dosage adjustment for most patients. Therapeutic drug monitoring is not required or available for most anticonvulsants. Serum medication concentrations (when available) may assist in identifying toxicity. Monitor the treated patient for drug efficacy and side effects. Anticonvulsants can cause a variety of side effects; some adverse reactions can increase the risk of 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 as outlined in the OBRA guidelines.[60742]

ADVERSE REACTIONS

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

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

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

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.
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.
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.
Meperidine; 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.
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.
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.
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.
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.
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.
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.

PREGNANCY AND LACTATION

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.

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.