ONFI- clobazam tablet ONFI- clobazam suspension

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

CLOBAZAM (UNII: 2MRO291B4U) (CLOBAZAM - UNII:2MRO291B4U)

Available from:

Lundbeck Pharmaceuticals LLC

INN (International Name):

CLOBAZAM

Composition:

CLOBAZAM 10 mg

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

ONFI® (clobazam) is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. ONFI is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients. Hypersensitivity reactions have included serious dermatological reactions [see Warnings and Precautions (5.6 , 5.7)] . Pregnancy Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as ONFI, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women taking ONFI enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or online at  http://www.aedpregnancyregistry.org/. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and  Precautions (5.9) and Clinical Considerations] . Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ). Administration of clobazam to pregnant rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation resulted in developmental toxicity, including increased incidences of fetal malformations and mortality, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients [see Animal Data ]. Data for other benzodiazepines suggest the possibility of long-term effects on neurobehavioral and immunological function in animals following prenatal exposure to benzodiazepines at clinically relevant doses. ONFI should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Advise a pregnant woman and women of childbearing age of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.  Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to ONFI during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to ONFI during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.9)] .  Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. Animal Data In a study in which clobazam (0, 150, 450, or 750 mg/kg/day) was orally administered to pregnant rats throughout the period of organogenesis, embryofetal mortality and incidences of fetal skeletal variations were increased at all doses. The low-effect dose for embryofetal developmental toxicity in rats (150 mg/kg/day) was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, lower than those in humans at the maximum recommended human dose (MRHD) of 40 mg/day. Oral administration of clobazam (0, 10, 30, or 75 mg/kg/day) to pregnant rabbits throughout the period of organogenesis resulted in decreased fetal body weights, and increased incidences of fetal malformations (visceral and skeletal) at the mid and high doses, and an increase in embryofetal mortality at the high dose. Incidences of fetal variations were increased at all doses. The highest dose tested was associated with maternal toxicity (ataxia and decreased activity). The low-effect dose for embryofetal developmental toxicity in rabbits (10 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD. Oral administration of clobazam (0, 50, 350, or 750 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased embryofetal mortality at the high dose, decreased pup survival at the mid and high doses and alterations in offspring behavior (locomotor activity) at all doses. The low-effect dose for adverse effects on pre- and postnatal development in rats (50 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD. Risk Summary ONFI is excreted in human milk (see Data) . There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data on the effects of clobazam on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ONFI and any potential adverse effects on the breastfed infant from ONFI or from the underlying maternal condition. Clinical Considerations Adverse reactions such as somnolence and difficulty feeding have been reported in infants during breastfeeding in postmarketing experience with ONFI. Infants exposed to ONFI through breast milk should be monitored for sedation, poor feeding and poor weight gain. Data Scientific literature on ONFI use during lactation is limited. After short-term administration, clobazam and N-desmethylclobazam are transferred into breast milk. Administration of clobazam to rats prior to and during mating and early gestation resulted in adverse effects on fertility and early embryonic development at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those in humans at the MRHD [see Nonclinical Toxicology (13.1)] . Safety and effectiveness in patients less than 2 years of age have not been established. In a study in which clobazam (0, 4, 36, or 120 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 14 to 48), adverse effects on growth (decreased bone density and bone length) and behavior (altered motor activity and auditory startle response; learning deficit) were observed at the high dose. The effect on bone density, but not on behavior, was reversible when drug was discontinued. The no-effect level for juvenile toxicity (36 mg/kg/day) was associated with plasma exposures (AUC) to clobazam and its major active metabolite, N-desmethylclobazam, less than those expected at therapeutic doses in pediatric patients. Clinical studies of ONFI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, elderly subjects appear to eliminate clobazam more slowly than younger subjects based on population pharmacokinetic analysis. For these reasons, the initial dose in elderly patients should be 5 mg/day. Patients should be titrated initially to 10-20 mg/day. Patients may be titrated further to a maximum daily dose of 40 mg if tolerated [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)] . Concentrations of clobazam's active metabolite, N-desmethylclobazam, are higher in CYP2C19 poor metabolizers than in extensive metabolizers. For this reason, dosage modification is recommended [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)] . The pharmacokinetics of ONFI were evaluated in patients with mild and moderate renal impairment. There were no significant differences in systemic exposure (AUC and Cmax ) between patients with mild or moderate renal impairment and healthy subjects. No dose adjustment is required for patients with mild and moderate renal impairment. There is essentially no experience with ONFI in patients with severe renal impairment or ESRD. It is not known if clobazam or its active metabolite, N-desmethylclobazam, is dialyzable [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)] . ONFI is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of ONFI. For this reason, dosage adjustment is recommended in patients with mild to moderate hepatic impairment (Child-Pugh score 5-9). There is inadequate information about metabolism of ONFI in patients with severe hepatic impairment [see Dosage and Administration (2.7), Clinical Pharmacology (12.3)] . ONFI contains clobazam, a Schedule IV controlled substance. ONFI is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)] . The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.     The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol). The World Health Organization epidemiology database contains reports of drug abuse, misuse, and overdoses associated with clobazam. Physical Dependence ONFI may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)] .In clinical trials, cases of dependency were reported following abrupt discontinuation of ONFI. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue ONFI or reduce the dosage [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)] . Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.    Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance Tolerance to ONFI may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of ONFI may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

Product summary:

Each ONFI tablet contains 10 mg or 20 mg of clobazam and is a white to off-white, oval tablet with a functional score on one side and either a "1" and "0" or a "2" and "0" debossed on the other side. NDC 67386-314-01: 10 mg scored tablet, Bottles of 100 NDC 67386-315-01: 20 mg scored tablet, Bottles of 100 ONFI oral suspension is a berry flavored off-white liquid supplied in a bottle with child-resistant closure.  The oral suspension is packaged with a dispenser set which contains two calibrated oral dosing syringes and a bottle adapter.  Store and dispense ONFI oral suspension in its original bottle in an upright position.  Use within 90 days of first opening the bottle, then discard any remainder. NDC 67386-313-21: 2.5 mg/mL supplied in a bottle containing 120 mL of suspension. Store tablets and oral suspension at 20°C to 25°C (68°F to 77°F). See USP controlled room temperature.

Authorization status:

New Drug Application

Patient Information leaflet

ONFI- CLOBAZAM TABLET
ONFI- CLOBAZAM SUSPENSION
Lundbeck Pharmaceuticals LLC
----------
MEDICATION GUIDE
ONFI® (ON-fee)
(clobazam)
tablets and oral suspension, C-IV
What is the most important information I should know about ONFI?
•
ONFI is a benzodiazepine medicine. Taking benzodiazepines with opioid
medicines, alcohol, or other
central nervous system (CNS) depressants (including street drugs) can
cause severe drowsiness,
breathing problems (respiratory depression), coma, and death. Get
emergency help right away if any
of the following happens:
•
shallow or slowed breathing
•
breathing stops (which may lead to the heart stopping)
•
excessive sleepiness (sedation)
Do not drive or operate heavy machinery until you know how taking ONFI
with opioids affects you.
•
Risk of abuse, misuse, and addiction. There is a risk of abuse,
misuse, and addiction with
benzodiazepines, including ONFI, which can lead to overdose and
serious side effects including coma
and death.
•
Serious side effects including coma and death have happened in people
who have abused or
misused benzodiazepines, including ONFI. These serious side effects
may also include
delirium, paranoia, suicidal thoughts or actions, seizures, and
difficulty breathing. Call your
healthcare provider or go to the nearest hospital emergency room right
away if you get any of
these serious side effects.
•
You can develop an addiction even if you take ONFI as prescribed by
your healthcare
provider.
•
Take ONFI exactly as your healthcare provider prescribed.
•
Do not share your ONFI with other people.
•
Keep ONFI in a safe place and away from children.
•
Physical dependence and withdrawal reactions. ONFI can cause physical
dependence and withdrawal
reactions.
•
Do not suddenly stop taking ONFI. Stopping ONFI suddenly can cause
serious and life-
threatening side effects, including, unusual movements, responses, or
expressions, seizures,
sudden and severe mental or nervous system changes, depression, seeing
or hearing things that
others do not see or

Summary of Product characteristics

ONFI- CLOBAZAM TABLET
ONFI- CLOBAZAM SUSPENSION
LUNDBECK PHARMACEUTICALS LLC
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE ONFI
SAFELY AND
EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR ONFI.
ONFI (CLOBAZAM) TABLETS, FOR ORAL USE, CIV
ONFI (CLOBAZAM) ORAL SUSPENSION, CIV
INITIAL U.S. APPROVAL: 2011
WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND
ADDICTION; AND DEPENDENCE AND WITHDRAWAL REACTIONS
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
CONCOMITANT USE OF BENZODIAZEPINES AND OPIOIDS MAY RESULT IN PROFOUND
SEDATION,
RESPIRATORY DEPRESSION, COMA, AND DEATH. RESERVE CONCOMITANT
PRESCRIBING OF THESE
DRUGS FOR PATIENTS FOR WHOM ALTERNATIVE TREATMENT OPTIONS ARE
INADEQUATE. LIMIT
DOSAGES AND DURATIONS TO THE MINIMUM REQUIRED. FOLLOW PATIENTS FOR
SIGNS AND
SYMPTOMS OF RESPIRATORY DEPRESSION AND SEDATION (5.1, 7.1).
THE USE OF BENZODIAZEPINES, INCLUDING ONFI, EXPOSES USERS TO RISKS OF
ABUSE,
MISUSE, AND ADDICTION, WHICH CAN LEAD TO OVERDOSE OR DEATH. BEFORE
PRESCRIBING
ONFI AND THROUGHOUT TREATMENT, ASSESS EACH PATIENT’S RISK FOR ABUSE,
MISUSE, AND
ADDICTION (5.2).
ABRUPT DISCONTINUATION OR RAPID DOSAGE REDUCTION OF ONFI AFTER
CONTINUED USE MAY
PRECIPITATE ACUTE WITHDRAWAL REACTIONS, WHICH CAN BE LIFE-THREATENING.
TO REDUCE THE
RISK OF WITHDRAWAL REACTIONS, USE A GRADUAL TAPER TO DISCONTINUE ONFI
OR REDUCE THE
DOSAGE (2.2, 5.3).
RECENT MAJOR CHANGES
Warnings and Precautions (5.7)
3/2024
INDICATIONS AND USAGE
ONFI is a benzodiazepine indicated for adjunctive treatment of
seizures associated with Lennox-Gastaut
syndrome (LGS) in patients 2 years of age or older (1)
DOSAGE AND ADMINISTRATION
For doses above 5 mg/day administer in two divided doses (2.1)
Patients ≤30 kg body weight: Initiate at 5 mg daily and titrate as
tolerated up to 20 mg daily (2.1)
Patients >30 kg body weight: Initiate at 10 mg daily and titrate as
tolerated up to 40 mg daily (2.1)
Dosage adjustment needed in following groups:
Geriatric