Version May 2024
Seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder: Patients weighing >28 kg:
Week 1: Oral: 150 mg 3 times daily.
Week 2: Oral: 300 mg 3 times daily.
Week 3: Oral: 450 mg 3 times daily.
Week 4 and thereafter: Oral: 600 mg 3 times daily.
Maximum dose: 1.8 g/day (Ref).
Discontinuation of therapy: Unless safety concerns require a more rapid withdrawal, withdraw gradually to minimize the risk of increased seizure frequency and/or status epilepticus.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, renal elimination is minimal.
Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.
Severe hepatic impairment (Child-Pugh class C) in patients weighing >28 kg:
Week 1: Oral: 50 mg 3 times daily.
Week 2: Oral: 100 mg 3 times daily.
Week 3: Oral: 150 mg 3 times daily.
Week 4 and thereafter: Oral: 200 mg 3 times daily.
Use with caution (has not been studied).
(For additional information see "Ganaxolone: Pediatric drug information")
Seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD):
Note: Dose should be titrated as tolerated no more frequently than every 7 days according to the following schedule (Ref).
Children ≥2 years and Adolescents weighing ≤28 kg:
Days 1 to 7: Oral: Initial: 6 mg/kg/dose 3 times daily.
Days 8 to 14: Oral: 11 mg/kg/dose 3 times daily.
Days 15 to 21: Oral: 16 mg/kg/dose 3 times daily.
≥22 days: Oral: 21 mg/kg/dose 3 times daily maintenance dose.
Children ≥2 years and Adolescents weighing >28 kg:
Days 1 to 7: Oral: Initial: 150 mg 3 times daily.
Days 8 to 14: Oral: 300 mg 3 times daily.
Days 15 to 21: Oral: 450 mg 3 times daily.
≥22 days: Oral: 600 mg 3 times daily maintenance dose.
Discontinuation of therapy: There is currently no standard method for the withdrawal of antiseizure medications. Successful discontinuation of an antiseizure medication is dependent on several factors including but not limited to: Time of seizure freedom, underlying reason for the epilepsy, neuroimaging abnormalities, underlying neurodevelopmental status, duration, and dose of medication to be withdrawn (Ref). The dose of ganaxolone should be gradually decreased when discontinuing treatment. Regardless of dose, abrupt discontinuation should be avoided given the possibility of increasing seizure frequency or status epilepticus unless a safety concern requires a more rapid withdrawal.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered kidney function: There are no dosage adjustments provided in the manufacturer's labeling; has not been studied. Renal excretion is not a major elimination pathway; impairment is unlikely to increase ganaxolone exposure.
There are no specific dosage adjustments provided in the manufacturer's labeling; has not been studied, however, hepatic impairment is likely to increase ganaxolone exposure due to significant hepatic clearance; monitor closely; dose reduction may be necessary.
Ganaxolone may commonly cause dose-dependent CNS depression, including drowsiness, hypersomnia, lethargy, and sedated state. CNS depression may impair physical or mental abilities, and result in accidental injury, including falls.
Mechanism: Dose-related; related to pharmacologic action (positive allosteric modulation of GABA-A receptors; increases the inhibitory effect of GABA on CNS).
Risk factors:
• Concomitant use of alcohol or other CNS depressants (eg, opioids, antidepressants)
Antiseizure medications have been associated with suicidal ideation and suicidal tendencies. However, the FDA meta-analysis has been criticized due to several limitations (Ref). The risk of suicide is increased in epilepsy (Ref), but the occurrence of suicidal ideation/tendencies in epilepsy is multifactorial. While some antiepileptic drugs (AEDs) (but not all) have been associated with treatment-emergent psychiatric effects such as anxiety and depression, other factors such as postictal suicidal behavior and pertinent patient history must also be evaluated to provide an accurate assessment of risk for any individual drug (Ref).
Onset: Varied; peak incidence of suicidality across AEDs (not specific to individual agents) has been noted to occur between 1 and 12 weeks of therapy (Ref). A review of clinical trials noted that risk extended from 1 week to 24 weeks of therapy, corresponding to the duration of most trials.
Risk factors:
• History of depression (Ref)
• Use in conditions other than epilepsy, depression, or bipolar disorder (Ref)
• Family and psychiatric history (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in children, adolescents, and young adults and may include coadministration with other antiseizure drugs.
>10%:
Nervous system: Drowsiness (38%; including hypersomnia and lethargy) (table 1)
|
Drug (Ganaxolone) |
Placebo |
Number of Patients (Ganaxolone) |
Number of Patients (Placebo) |
|---|---|---|---|
|
38% |
20% |
50 |
51 |
Miscellaneous: Fever (18%)
1% to 10%:
Gastrointestinal: Sialorrhea (6%)
Hypersensitivity: Seasonal allergy (6%)
Infection: Influenza (4%)
Nervous system: Abnormal gait (4%), sedated state (6%) (table 2)
|
Drug (Ganaxolone) |
Placebo |
Number of Patients (Ganaxolone) |
Number of Patients (Placebo) |
|---|---|---|---|
|
6% |
4% |
50 |
51 |
Respiratory: Bronchitis (4%), nasal congestion (4%), upper respiratory tract infection (10%)
Frequency not defined: Nervous system: Suicidal ideation, suicidal tendencies
There are no contraindications listed in the manufacturer's labeling.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with preexisting liver impairment.
Other warnings/precautions:
• Withdrawal: Antiseizure medications should not be discontinued abruptly because of the possibility of increasing seizure frequency and status epilepticus; therapy should be withdrawn gradually unless safety concerns require a more rapid withdrawal.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, Oral:
Ztalmy: 50 mg/mL (110 mL) [contains methylparaben, propylparaben, sodium benzoate]
No
Suspension (Ztalmy Oral)
50 mg/mL (per mL): $28.02
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C-V
Oral: Administer with food. Shake well for 1 minute prior to use, then let stand for 1 minute before measuring to allow foam to settle. Measure dose using provided oral syringe. A household teaspoon or tablespoon is not an adequate measuring device and should not be used.
Oral: Administer with food. Shake bottle for 1 minute, then wait another minute prior to measuring and administering dose. Administer with an oral dosing syringe; do not use a household teaspoon (overdosage may occur).
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Ganaxolone may cause teratogenicity.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Ztalmy: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215904s003s004lbl.pdf#page=16
Seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder: Treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients ≥2 years of age.
Substrate of CYP2B6 (minor), CYP2C19 (minor), CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): Ganaxolone may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Ganaxolone. Management: Avoid concomitant use of ganaxolone and moderate CYP3A4 inducers whenever possible. If combined, consider increasing the dose of ganaxolone, but do not exceed the maximum recommended daily dose. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May decrease the serum concentration of Ganaxolone. Management: Avoid concomitant use of ganaxolone and strong CYP3A4 inducers whenever possible. If combined, consider increasing the dose of ganaxolone, but do not exceed the maximum recommended daily dose. Risk D: Consider therapy modification
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Doxylamine: CNS Depressants may enhance the CNS depressant effect of Doxylamine. Risk C: Monitor therapy
DroPERidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification
Administration with a high-fat meal increases Cmax and AUC by 3-fold and 2-fold, respectively, compared to fasting administration. Management: Administer with food.
Adverse events were observed in animal reproduction studies following oral administration of ganaxolone in doses lower than the maximum recommended human doses.
Data collection to monitor pregnancy and infant outcomes following exposure to ganaxolone is ongoing. Health care providers are encouraged to enroll patients exposed to ganaxolone during pregnancy in the North American Antiepileptic Drug (NAAED) Pregnancy Registry (1-888-233-2334 or http://www.aedpregnancyregistry.org/).
Ganaxolone is present in breast milk.
Data related to the presence of ganaxolone in breast milk is available from a study conducted in 5 breastfeeding women. Following an oral dose of ganaxolone 300 mg, breast milk concentrations were ~4 times those in the maternal plasma. The estimated daily infant dose via breast milk was calculated to be 0.157 mg/kg/day providing a relative infant dose (RID) of 0.24% compared to a pediatric therapeutic dose of 63 mg/kg/day. Additional details not provided in the manufacturer's labeling.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).
Changes in behavior for depression or suicidal thoughts or ideation; mental alertness.
The precise mechanism by which ganaxolone exerts its therapeutic effects in the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder is unknown, but its anticonvulsant effects are thought to result from positive allosteric modulation of the gamma-aminobutyric acid type A (GABAA) receptor in the CNS.
Absorption: Administration with a high-fat meal increases Cmax and AUC by 3-fold and 2-fold, respectively, compared to fasting administration.
Protein binding: ~99%.
Metabolism: Hepatically metabolized via CYP3A4/5, CYP2B6, CYP2C19, and CYP2D6.
Half-life elimination: 34 hours.
Time to peak: 2 to 3 hours.
Excretion: Feces: 55% (2% as unchanged drug); urine: 18%.
Hepatic impairment: Following a single 300 mg oral dose, the Cmax and AUC increased by 38% and 8%, respectively, in subjects with mild hepatic impairment (Child-Pugh class A); 45% and 50%, respectively, in subjects with moderate hepatic impairment (Child-Pugh class B); 148% and 269%, respectively, in subjects with severe hepatic impairment (Child-Pugh class C) compared to subjects with normal hepatic function.
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