DRUGS & SUPPLEMENTS
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Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death .
WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS
See full prescribing information for complete boxed warning.
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death (5.1, 7.1).
Boxed Warning 12/2016
Contraindications (5.1) 12/2016
Frisium® (clobazam) is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older.
Frisium is a benzodiazepine indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older (1)
A daily dose of Frisium greater than 5 mg should be administered in divided doses twice daily; a 5 mg daily dose can be administered as a single dose. Dose patients according to body weight. Individualize dosing within each body weight group, based on clinical efficacy and tolerability. Each dose in Table 1 (e.g. 5 to 20 mg in ≤30 kg weight group) has been shown to be effective, although effectiveness increases with increasing dose . Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of Frisium and its active metabolite require 5 and 9 days, respectively, to reach steady-state.
|≤30 kg Body Weight||>30 kg Body Weight|
|Starting Dose||5 mg||10 mg|
|Starting Day 7||10 mg||20 mg|
|Starting Day 14||20 mg||40 mg|
As with all antiepileptic drugs and benzodiazepines, withdraw Frisium gradually. Taper by decreasing the total daily dose by 5-10 mg/day on a weekly basis until discontinued .
Instruct patients to read the "Instructions for Use" carefully for complete directions on how to properly dose and administer Frisium oral suspension.
Frisium Tablet Oral Administration
Frisium tablets can be taken with or without food.
Frisium tablets can be administered whole, broken in half along the score, or crushed and mixed in applesauce.
Frisium Oral Suspension Oral Administration
Frisium oral suspension can be taken with or without food.
Shake Frisium Oral Suspension well before every administration. When administering the oral suspension, use only the oral dosing syringe provided with the product. Each carton includes two syringes, but only one syringe should be used for dosing. The second oral syringe is reserved as a replacement in case the first syringe is damaged or lost. Insert the provided adapter firmly into the neck of the bottle before first use and keep the adapter in place for the duration of the usage of the bottle. To withdraw the dose, insert the dosing syringe into the adapter and invert the bottle then slowly pull back the plunger to prescribed dose. After removing the syringe from the bottle adapter, slowly squirt Frisium Oral Suspension into the corner of the patient's mouth. Replace the cap after each use. The cap fits over the adapter when the adapter is properly placed. See Frisium Oral Suspension "Instructions for Use" for complete instruction on how to properly dose and administer the Frisium Oral Suspension.
Plasma concentrations at any given dose are generally higher in the
Elderly: proceed slowly with dose escalation. The starting dose should be 5 mg/day for all elderly patients. Then titrate elderly patients according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose may be started on day 21 .
In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam's active metabolite, will be increased. Therefore, in patients known to be CYP2C19 poor metabolizers, the starting dose should be 5 mg/day and dose titration should proceed slowly according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group) may be started on day 21 .
No dose adjustment is required for patients with mild and moderate renal impairment. There is no experience with Frisium in patients with severe renal impairment or end stage renal disease. It is not known if Frisium or its active metabolite, N-desmethylclobazam, is dialyzable .
Frisium is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of Frisium. For this reason, proceed slowly with dosing escalations. For patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), the starting dose should be 5 mg/day in both weight groups. Then titrate patients according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, start an additional titration on day 21 to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group). There is inadequate information about metabolism of Frisium in patients with severe hepatic impairment. Therefore no dosing recommendation in those patients can be given .
Tablets: 10 mg and 20 mg with a functional score for oral administration.
Each Frisium tablet 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.
Oral Suspension: 2.5 mg/mL for oral administration. Each bottle contains 120 mL of an off-white suspension.
Frisium iscontraindicated in patients with a history of hypersensitivity to the drug orits ingredients. Hypersensitivity reactions have included seriousdermatological reactions .
History of hypersensitivity to the drug or its ingredients (4)
Concomitantuse of benzodiazepines, including Frisium, and opioids may result in profoundsedation, respiratory depression, coma, and death. Because of these risks,reserve concomitant prescribing of benzodiazepines and opioids for use inpatients for whom alternative treatment options are inadequate.
Observationalstudies have demonstrated that concomitant use of opioid analgesics and benzodiazepinesincreases the risk of drug-related mortality compared to use of opioids alone. Ifa decision is made to prescribe Frisium concomitantly with opioids, prescribe thelowest effective dosages and minimum durations of concomitant use, and followpatients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depressionand sedation when Frisium is used with opioids [seeDrug Interactions (7.1)].
Since Frisium has a central nervous system depressant effect, patients or their caregivers should be cautioned against simultaneous use with other CNS depressant drugs or alcohol, and cautioned that the effects of other CNS depressant drugs or alcohol may be potentiated .
ONFIcauses somnolence and sedation. In clinical trials, somnolence or sedation wasreported at all effective doses and was dose-related.
Ingeneral, somnolence and sedation begin within the first month of treatment andmay diminish with continued treatment. Prescribers should monitor patients for somnolenceand sedation, particularly with concomitant use of other central nervous systemdepressants. Prescribers should caution patients against engaging in hazardous activitiesrequiring mental alertness, such as operating dangerous machinery or motorvehicles, until the effect of Frisium is known.
Abrupt discontinuation of Frisium should be avoided. Frisium should betapered by decreasing the dose every week by 5-10 mg/day until discontinuation .
Withdrawal symptomsoccurred following abrupt discontinuation of Frisium; the risk of withdrawalsymptoms is greater with higher doses.
As with allantiepileptic drugs, Frisium should be withdrawn gradually to minimize the risk ofprecipitating seizures, seizure exacerbation, or status epilepticus.
Withdrawalsymptoms (e.g., convulsions, psychosis, hallucinations, behavioral disorder, tremor,and anxiety) have been reported following abrupt discontinuance ofbenzodiazepines. The more severe withdrawal symptoms have usually been limitedto patients who received excessive doses over an extended period of time,followed by an abrupt discontinuation. Generally milder withdrawal symptoms(e.g., dysphoria, anxiety, and insomnia) have been reported following abruptdiscontinuance of benzodiazepines taken continuously at therapeutic doses forseveral months.
Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with Frisium in both children and adults during the post-marketing period. Patients should be closely monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment initiation or when re-introducing therapy. Frisium should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered .
Patients with a history of substance abuse should be under careful surveillance when receiving Frisium or other psychotropic agents because of the predisposition of such patients to habituation and dependence [see Drug Abuse and Dependence ].
Antiepileptic drugs (AEDs), including Frisium, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
|Indication|| Placebo Patients with |
Events per 1000 Patients
| Drug Patients with |
Events per 1000 Patients
| Relative Risk: Incidence of Drug |
Events in Drug Patients/Incidence
in Placebo Patients
| Risk Difference: Additional |
Drug Patients with Events
per 1000 Patients
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing Frisium or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Clinically significant adverse reactions that appear in other sections of the labeling include the following:
Adverse reactions that occurred at least 10% more frequently than placebo in any Frisium dose included constipation, somnolence or sedation, pyrexia, lethargy, and drooling (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck at 1-800-455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
During its development for the adjunctive treatment of seizures associated with LGS, Frisium was administered to 333 healthy volunteers and 300 patients with a current or prior diagnosis of LGS, including 197 patients treated for 12 months or more. The conditions and duration of exposure varied greatly and included single- and multiple-dose clinical pharmacology studies in healthy volunteers and two double-blind studies in patients with LGS (Study 1 and 2) . Only Study 1 included a placebo group, allowing comparison of adverse reaction rates on Frisium at several doses to placebo.
Adverse Reactions Leading to Discontinuation in an LGS Placebo Controlled Clinical Trial (Study 1)
The adverse reactions associated with Frisium treatment discontinuation in ≥1% of patients in decreasing order of frequency included lethargy, somnolence, ataxia, aggression, fatigue, and insomnia.
Most Common Adverse Reactions in an LGS Placebo Controlled Clinical Trial (Study 1)
Table 3 lists the adverse reactions that occurred in ≥5% of ONFI-treated patients (at any dose), and at a rate greater than placebo-treated patients, in the randomized, double-blind, placebo-controlled, parallel group clinical study of adjunctive AED therapy for 15 weeks (Study 1).
| aMaximum daily dose of 5 mg for ≤30 kg body weight; 10 mg for >30 kg body weight |
bMaximum daily dose of 10 mg for ≤30 kg body weight; 20 mg for >30 kg body weight
cMaximum daily dose of 20 mg for ≤30 kg body weight; 40 mg for >30 kg body weight
| Placebo |
|Frisium Dose Level|| All Frisium |
| Lowa |
| Mediumb |
| Highc |
|General Disorders and Administration Site Conditions|
|Infections and Infestations|
|Upper respiratory tract infection||10||10||13||14||12|
|Urinary tract infection||0||2||5||5||4|
|Metabolism and Nutrition Disorders|
|Nervous System Disorders|
|Somnolence or Sedation||15||17||27||32||26|
These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are categorized by system organ class.
Blood Disorders: Anemia, eosinophilia, leukopenia, thrombocytopenia
Eye Disorders: Diplopia, vision blurred
Gastrointestinal Disorders: Abdominal distention
General Disorders and Administration Site Conditions: Hypothermia
Investigations: Hepatic enzyme increased
Musculoskeletal: Muscle spasms
Psychiatric Disorders: Agitation, anxiety, apathy, confusional state, depression, delirium, delusion, hallucination
Renal and Urinary Disorders: Urinary retention
Respiratory Disorders: Aspiration, respiratory depression
Skin and Subcutaneous Tissue Disorders: Rash, urticaria, angioedema, and facial and lip edema
The concomitant use of benzodiazepines and opioidsincreases the risk of respiratory depression because of actions at differentreceptor sites in the CNS that control respiration. Benzodiazepines interact atGABAA sites, and opioids interact primarily at mu receptors. Whenbenzodiazepines and opioids are combined, the potential for benzodiazepines tosignificantly worsen opioid-related respiratory depression exists. Limit dosageand duration of concomitant use of benzodiazepines and opioids, and followpatients closely for respiratory depression and sedation .
Concomitant use of Frisium with other CNS depressants may increase the risk of sedation and somnolence .
Alcohol, as a CNS depressant, will interact with Frisium in a similar way and also increases clobazam's maximum plasma exposure by approximately 50%. Therefore, caution patients or their caregivers against simultaneous use with other CNS depressant drugs or alcohol, and caution that the effects of other CNS depressant drugs or alcohol may be potentiated .
Frisium is a weak CYP3A4 inducer. As some hormonal contraceptives are metabolized by CYP3A4, their effectiveness may be diminished when given with Frisium. Additional non-hormonal forms of contraception are recommended when using Frisium .
Drugs Metabolized by CYP2D6
Frisium inhibits CYP2D6. Dose adjustment of drugs metabolized by CYP2D6 may be necessary .
Strong and moderate inhibitors of CYP2C19
Strong and moderate inhibitors of CYP2C19 may result in increased exposure to N-desmethylclobazam, the active metabolite of Frisium. This may increase the risk of dose-related adverse reactions. Dosage adjustment of Frisium may be necessary when co-administered with strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole) .
Pregnancy: Based on animal data, may cause fetal harm
Pregnancy Category C.
There are no adequate and well-controlled studies of Frisium in pregnant women. In animal studies, administration of Frisium during pregnancy resulted in developmental toxicity, including increased incidences of fetal malformations, at plasma exposures for Frisium and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients. Frisium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Available human data on the risk of teratogenicity associated with benzodiazepines are inconclusive. There is insufficient evidence in humans to assess the effect of benzodiazepine exposure during pregnancy on neurodevelopment. Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding. In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period.
Data for other benzodiazepines suggest the possibility of adverse developmental effects (including long-term effects on neurobehavioral and immunological function) in animals following prenatal exposure to benzodiazepines at clinically relevant doses.
In a study in which Frisium (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 Frisium 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 Frisium (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 Frisium and N-desmethylclobazam lower than those in humans at the MRHD.
Oral administration of Frisium (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 Frisium and N-desmethylclobazam lower than those in humans at the MRHD.
To provide information regarding the effects of in utero exposure to Frisium, physicians are advised to recommend that pregnant patients taking Frisium enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves or their caregiver. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/
Frisium is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Frisium, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in patients less than 2 years of age have not been established.
In a study in which Frisium 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 Frisium and its major active metabolite, N-desmethylclobazam, less than those expected at therapeutic doses in pediatric patients.
Clinical studies of Frisium 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 Frisium 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 .
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 .
The pharmacokinetics of Frisium 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 Frisium in patients with severe renal impairment or ESRD. It is not known if Frisium or its active metabolite, N-desmethylclobazam, is dialyzable .
Frisium is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of Frisium. 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 Frisium in patients with severe hepatic impairment .
Frisium contains Frisium which is a Schedule IV controlled substance.
Frisium can be abused in a similar manner as other benzodiazepines, such as diazepam.
The pharmacological profile of Frisium is similar to that of other benzodiazepines listed in Schedule IV of the Controlled Substance Act, particularly in its potentiation of GABAergic transmission through its action on GABAA receptors, which leads to sedation and somnolence.
The World Health Organization epidemiology database contains reports of drug abuse, misuse, and overdoses associated with Frisium.
Drug abuse is the intentional non-therapeutic use of a drug, repeatedly or even sporadically, for its rewarding psychological or physiological effects.
Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood levels of the drug, and/or administration of an antagonist. In clinical trials, cases of dependency were reported following abrupt discontinuation of Frisium.
The risk of dependence is present even with use of Frisium at the recommended dose range over periods of only a few weeks. The risk of dependence increases with increasing dose and duration of treatment. The risk of dependence is increased in patients with a history of alcohol or drug abuse.
Abrupt discontinuation of Frisium causes withdrawal symptoms. As with other benzodiazepines, Frisium should be withdrawn gradually .
In Frisium clinical pharmacology trials in healthy volunteers, the most common withdrawal symptoms after abrupt discontinuation were headache, tremor, insomnia, anxiety, irritability, drug withdrawal syndrome, palpitations, and diarrhea .
Other withdrawal reactions to Frisium reported in the literature include restlessness, panic attacks, profuse sweating, difficulty in concentrating, nausea and dry retching, weight loss, blurred vision, photophobia, and muscle pain and stiffness. In general, benzodiazepine withdrawal may cause seizures, psychosis, and hallucinations .
Overdose and intoxication with benzodiazepines, including Frisium, may lead to CNS depression, associated with drowsiness, confusion and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and, rarely, coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol.
The management of Frisium overdose may include gastric lavage and/or administration of activated charcoal, intravenous fluid replenishment, early control of airway and general supportive measures, in addition to monitoring level of consciousness and vital signs. Hypotension can be treated by replenishment with plasma substitutes and, if necessary, with sympathomimetic agents.
The efficacy of supplementary administration of physostigmine (a cholinergic agent) or of flumazenil (a benzodiazepine antagonist) in Frisium overdose has not been assessed. The administration of flumazenil in cases of benzodiazepine overdose can lead to withdrawal and adverse reactions. Its use in patients with epilepsy is typically not recommended.
|Dosage Forms:||Tablet and Oral Suspension|
|Route of Administration:||Oral|
|Established Pharmacologic Class of Drug:||Benzodiazepine|
|Chemical Name:||7-Chloro-1-methyl-5-phenyl-1H-1,5 benzodiazepine-2,4(3H,5H)-dione|
|Structural Formula:|| |
Frisium is a white or almost white, crystalline powder with a slightly bitter taste; is slightly soluble in water, sparingly soluble in ethanol, and freely soluble in methylene chloride. The melting range of Frisium is from 182ºC to 185ºC. The molecular formula is C16H13O2N2Cl and the molecular weight is 300.7.
Each Frisium tablet contains 10 mg or 20 mg of Frisium. Tablets also contain as inactive ingredients: modified corn starch, lactose monohydrate, magnesium stearate, silicon dioxide, and talc.
Frisium is also available for oral administration as an off-white suspension containing Frisium at a concentration of 2.5 mg/mL. Inactive ingredients include magnesium aluminum silicate, xanthan gum, citric acid monohydrate, disodium hydrogen phosphate dihydrate, simethicone emulsion, polysorbate 80, methylparaben, propylparaben, propylene glycol, sucralose, maltitol solution, berry flavor, purified water.
The exact mechanism of action for Frisium, a 1,5-benzodiazepine, is not fully understood but is thought to involve potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABAA receptor.
Effects on Electrocardiogram
The effect of Frisium 20 mg and 80 mg administered twice daily on QTc interval was evaluated in a randomized, evaluator-blinded, placebo-, and active-controlled parallel thorough QT study in 280 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on the Fridericia correction method was below 10 ms, the threshold for regulatory concern. Thus, at a dose two times the maximum recommended dose, Frisium did not prolong the QTc interval to any clinically relevant extent.
The peak plasma levels (Cmax) and the area under the curve (AUC) of Frisium are dose-proportional over the dose range of 10-80 mg following single- or multiple-dose administration of Frisium. Based on a population pharmacokinetic analysis, the pharmacokinetics of Frisium are linear from 5-160 mg/day. Frisium is converted to N-desmethylclobazam which has about 1/5 the activity of Frisium. The estimated mean elimination half-lives (t1/2) of Frisium and N-desmethylclobazam were 36-42 hours and 71-82 hours, respectively.
Frisium is rapidly and extensively absorbed following oral administration. The time to peak concentrations (Tmax) of Frisium tablets under fasted conditions ranged from 0.5 to 4 hours after single- or multiple-dose administrations. The relative bioavailability of Frisium tablets compared to an oral solution is approximately 100%. After single dose administration of the oral suspension under fasted conditions, the Tmax ranged from 0.5 to 2 hours. Based on exposure (Cmax and AUC) of Frisium, Frisium tablets and suspension were shown to have similar bioavailability under fasted conditions. The administration of Frisium tablets with food or when crushed in applesauce does not affect absorption. Although not studied, the oral bioavailability of the oral suspension is unlikely to be affected under fed conditions.
Frisium is lipophilic and distributes rapidly throughout the body. The apparent volume of distribution at steady state was approximately 100 L. The in vitro plasma protein binding of Frisium and N-desmethylclobazam is approximately 80-90% and 70%, respectively.
Metabolism and Excretion
Frisium is extensively metabolized in the liver, with approximately 2% of the dose recovered in urine and 1% in feces as unchanged drug. The major metabolic pathway of Frisium involves N-demethylation, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. N-desmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3-5 times higher than those of the parent compound. Based on animal and in vitro receptor binding data, estimates of the relative potency of N-desmethylclobazam compared to parent compound range from 1/5 to equal potency. N-desmethylclobazam is extensively metabolized, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine. Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.
The polymorphic CYP2C19 is the major contributor to the metabolism of the pharmacologically active N-desmethylclobazam . In CYP2C19 poor metabolizers, levels of N-desmethylclobazam were 5-fold higher in plasma and 2- to 3-fold higher in the urine than in CYP2C19 extensive metabolizers.
Pharmacokinetics in Specific Populations
Population pharmacokinetic analyses showed that the clearance of Frisium is lower in elderly subjects compared to other age groups (ages 2 to 64). Dosing should be adjusted in the elderly .
Population pharmacokinetic analyses showed no difference in the clearance of Frisium between women and men.
Population pharmacokinetic analyses including Caucasian (75%), African American (15%), and Asian (9%) subjects showed that there is no evidence of clinically significant effect of race on the clearance of Frisium.
The effect of renal impairment on the pharmacokinetics of Frisium was evaluated in patients with mild (creatinine clearance [CLCR] >50 to 80 mL/min; N=6) and moderate (CLCR=30 to 50 mL/min; N=6) renal dysfunction, with matching healthy controls (N=6), following administration of multiple doses of Frisium 20 mg/day. There were insignificant changes in Cmax (3-24%) and AUC (≤13%) for Frisium or N-desmethylclobazam in patients with mild or moderate renal impairment compared to patients with normal renal function. Patients with severe renal impairment or ESRD were not included in this study.
There are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of Frisium. In a small study, the pharmacokinetics of a 20 mg single oral dose of Frisium in 9 patients with liver impairment were compared to healthy controls (N=6). The Cmax and the mean plasma clearance of Frisium, as well as the Cmax of N-desmethylclobazam, showed no significant change compared to the healthy controls. The AUC values of N-desmethylclobazam in these patients were not available. Adjust dosage in patients with hepatic impairment .
Drug Interaction Studies
In vitro studies :
Frisium did not inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A4, UGT1A6, or UGT2B4 in vitro. N-desmethylclobazam showed weak inhibition of CYP2C9, UGT1A4, UGT1A6 and UGT2B4.
Frisium and N-desmethylclobazam did not significantly increase CYP1A2 or CYP2C19 activities, but did induce CYP3A4 activity in a concentration-dependent manner. Frisium and N-desmethylclobazam also increased UGT1A1 mRNA but at concentrations much higher than therapeutic levels. The potential for Frisium or N-desmethylclobazam to induce CYP2B6 and CYP2C8 has not been evaluated.
Frisium and N-desmethylclobazam do not inhibit P-glycoprotein (P-gp), but are P-gp substrates.
In vivo studies :
Potential for Frisium to Affect Other Drugs
The effect of repeated 40 mg once-daily doses of Frisium on the pharmacokinetic profiles of single-dose dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), caffeine (CYP1A2 substrate), and tolbutamide (CYP2C9 substrate), was studied when these probe substrates were given as a drug cocktail (N=18).
Frisium increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively, reflecting its inhibition of CYP2D6 in vivo. Drugs metabolized by CYP2D6 may require dose adjustment when used with Frisium.
Frisium decreased the AUC and Cmax of midazolam by 27% and 24%, respectively, and increased the AUC and Cmax of the metabolite 1-hydroxymidazolam by 4-fold and 2-fold, respectively. This level of induction does not call for dosage adjustment of drugs that are primarily metabolized by CYP3A4 when used concomitantly with Frisium. Some hormonal contraceptives are metabolized by CYP3A4 and their effectiveness may be diminished when given with Frisium . Repeated Frisium doses had no effect on caffeine and tolbutamide.
A population pharmacokinetic analysis indicated Frisium did not affect the exposure of valproic acid (a CYP2C9/2C19 substrate) or lamotrigine (a UGT substrate).
Potential for Other Drugs to Affect Frisium
Co-administration of ketoconazole (a strong CYP3A4 inhibitor) 400 mg once-daily for 5 days increased Frisium AUC by 54%, with an insignificant effect on Frisium Cmax. There was no significant change in AUC and Cmax of N-desmethylclobazam (N=18).
Strong (e.g., fluconazole, fluvoxamine, ticlopidine) and moderate (e.g., omeprazole) inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam, the active metabolite of Frisium, based on extrapolation from pharmacogenomic data . Dosage adjustment of Frisium may be necessary when co-administered with strong or moderate CYP2C19 inhibitors .
The effects of concomitant antiepileptic drugs that are CYP3A4 inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C19 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), and CYP2C19 inhibitors (felbamate and oxcarbazepine) were evaluated using data from clinical trials. Results of population pharmacokinetic analysis show that these concomitant antiepileptic drugs did not significantly alter the pharmacokinetics of Frisium or N-desmethylclobazam at steady-state.
Alcohol has been reported to increase the maximum plasma exposure of Frisium by approximately 50%. Alcohol may have additive CNS depressant effects when taken with Frisium .
The polymorphic CYP2C19 is the main enzyme that metabolizes the pharmacologically active N-desmethylclobazam. Compared to CYP2C19 extensive metabolizers, N-desmethylclobazam AUC and Cmax are approximately 3-5 times higher in poor metabolizers (e.g., subjects with *2/*2 genotype) and 2 times higher in intermediate metabolizers (e.g., subjects with *1/*2 genotype). The prevalence of CYP2C19 poor metabolism differs depending on racial/ethnic background. Dosage in patients who are known CYP2C19 poor metabolizers may need to be adjusted .
The systemic exposure of Frisium is similar for both CYP2C19 poor and extensive metabolizers.
The carcinogenic potential of Frisium has not been adequately assessed.
In a limited study in rats, oral administration of Frisium (4, 20, and 100 mg/kg/day) for 2 years resulted in an increased incidence of thyroid follicular cell adenomas in males at the high dose.
Frisium and the major active metabolite, N-desmethylclobazam, were negative for genotoxicity, based on data from a battery of in vitro (bacteria reverse mutation, mammalian clastogenicity) and in vivo (mouse micronucleus) assays.
Impairment of Fertility
In a study in which Frisium (50, 350, or 750 mg/kg/day) was orally administered to male and female rats prior to and during mating and continuing in females to gestation day 6, increases in abnormal sperm and pre-implantation loss were observed at the highest dose tested. The no effect level for fertility and early embryonic development in rats was associated with plasma exposures (AUC) for Frisium and its major active metabolite, N-desmethylclobazam, less than those in humans at the maximum recommended human dose of 40 mg/day.
The effectiveness of Frisium for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome was established in two multicenter controlled studies (Study 1 and Study 2). Both studies were similar in terms of disease characteristics and concomitant AED treatments. The most common concomitant AED treatments at baseline included: valproate, lamotrigine, levetiracetam, and topiramate.
Study 1 (N=238) was a randomized, double-blind, placebo-controlled study consisting of a 4-week baseline period followed by a 3-week titration period and 12-week maintenance period. Patients age 2-54 years with a current or prior diagnosis of LGS were stratified into 2 weight groups (12.5 kg to ≤30 kg or >30 kg) and then randomized to placebo or one of three target maintenance doses of Frisium according to Table 5.
|≤30 kg Body Weight||>30 kg Body Weight|
|Low Dose||5 mg daily||10 mg daily|
|Medium Dose||10 mg daily||20 mg daily|
|High Dose||20 mg daily||40 mg daily|
Doses above 5 mg/day were administered in two divided doses.
The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to 12-week maintenance period.
The pre-dosing baseline mean weekly drop seizure frequency was 98, 100, 61, and 105 for the placebo, low-, medium-, and high-dose groups, respectively. Figure 1 presents the mean percent reduction in weekly drop seizures from this baseline. All dose groups of Frisium were statistically superior (p≤0.05) to the placebo group. This effect appeared to be dose dependent.
Figure 1. Mean Percent Reduction from Baseline in Weekly Drop Seizure Frequency (Study 1)
Figure 2 shows changes from baseline in weekly drop seizure frequency by category for patients treated with Frisium and placebo in Study 1. Patients in whom the seizure frequency increased are shown at left as "worse." Patients in whom the seizure frequency decreased are shown in five categories.
Figure 2. Drop Seizure Response by Category for Frisium and Placebo (Study 1)
There was no evidence that tolerance to the therapeutic effect of Frisium developed during the 3-month maintenance period.
Study 2 (N=68) was a randomized, double-blind comparison study of high- and low-dose Frisium, consisting of a 4-week baseline period followed by a 3-week titration period and 4-week maintenance period. Patients age 2-25 years with a current or prior diagnosis of LGS were stratified by weight, then randomized to either a low or high dose of Frisium, and then entered a 3-week titration period.
The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to the 4-week maintenance period.
A statistically significantly greater reduction in seizure frequency was observed in the high-dose group compared to the low-dose group (median percent reduction of 93% vs 29%; p<0.05).
Each Frisium tablet contains 10 mg or 20 mg of Frisium 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
Frisium 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 Frisium 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.
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Risks from Concomitant Use with Opioids
Inform patients and caregivers that potentially fatal additive effects may occur if Frisium is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider .
Somnolence or Sedation
Advise patients or caregivers to check with their healthcare provider before Frisium is taken with other CNS depressants such as other benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or alcohol .
If applicable, caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that Frisium does not affect them adversely (e.g., impair judgment, thinking or motor skills).
Increasing or Decreasing the Frisium Dose
Inform patients or caregivers to consult their healthcare provider before increasing the Frisium dose or abruptly discontinuing Frisium. Advise patients or caregivers that abrupt withdrawal of AEDs may increase their risk of seizure .
Inform patients or caregivers that Frisium is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients .
Interactions with Hormonal Contraceptives
Counsel women to also use non-hormonal methods of contraception when Frisium is used with hormonal contraceptives and to continue these alternative methods for 28 days after discontinuing Frisium to ensure contraceptive reliability .
Serious Dermatological Reactions
Advise patients or caregivers that serious skin reactions have been reported in patients taking Frisium. Serious skin reactions, including SJS/TEN, may need to be treated in a hospital and may be life-threatening. If a skin reaction occurs while taking Frisium, patients or caregivers should consult with healthcare providers immediately .
Suicidal Thinking and Behavior
Counsel patients, their caregivers, and their families that AEDs, including Frisium, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Patients should report behaviors of concern immediately to healthcare providers .
Use in Pregnancy
Instruct patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org .
Use in Nursing
Instruct patients to notify their physician if they are breast feeding or intend to breast feed during therapy .
Tablets manufactured by: Catalent Pharma Solutions, LLC
Winchester, KY 40391, U.S.A.
Oral suspension manufactured by: Rosemont Pharmaceuticals, Ltd.
Leeds, West Yorkshire LS11 9XE, U.K.
Deerfield, IL 60015, U.S.A.
Frisium is a registered trademark of Lundbeck
Tablets and Oral Suspension, CIV
What is the most important information I should know about Frisium?
Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
How can I watch for early symptoms of suicidal thoughts and actions?
Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
What is Frisium?
Frisium is a prescription medicine used along with other medicines to treat seizures associated with Lennox-Gastaut syndrome in people 2 years of age or older.
It is not known if Frisium is safe and effective in children less than 2 years old.
Do not take Frisium if you:
Before you take Frisium, tell your healthcare provider about all your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking Frisium with certain other medicines can cause side effects or affect how well Frisium or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.
How should I take Frisium?
What should I avoid while taking Frisium?
What are the possible side effects of Frisium?
Frisium may cause serious side effects, including: See "What is the most important information I should know about Frisium?"
The most common side effects of Frisium include:
These are not all the possible side effects of Frisium. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Frisium?
General Information about the safe and effective use of Frisium.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Frisium for a condition for which it was not prescribed. Do not give Frisium to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Frisium that is written for health professionals.
What are the ingredients in Frisium?
Active ingredient: Frisium
Inactive ingredients: modified corn starch, lactose monohydrate, magnesium stearate, silicon dioxide, and talc.
Active ingredient: Frisium
Inactive ingredients: magnesium aluminum silicate, xanthan gum, citric acid monohydrate, disodium hydrogen phosphate dihydrate, simethicone emulsion, polysorbate 80, methylparaben, propylparaben, propylene glycol, sucralose, maltitol solution, berry flavor, purified water.
Marketed by: Lundbeck, Deerfield, IL 60015, U.S.A.
Frisium is a registered trademark of Lundbeck
For more information about Frisium, go to www. ONFI.com or call Lundbeck at 1-866-402-8520
This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 12/2016
Instructions for Use
Read this Instructions for Use before using Frisium oral suspension and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or treatment.
Prepare Frisium Oral Suspension Dose
You will need the following supplies: See Figure A
Step 1. Remove the Frisium oral suspension bottle, bottle adapter, and 1 syringe from the box.
Step 2. Shake the bottle well before each use. See Figure B
Step 3. Uncap the bottle and firmly insert the bottle adapter into the bottle until the adapter top is even with the bottle top. See Figure C
Once the bottle adapter is in place, it should not be removed.
Step 4. Check your dose in milliliters (mL) as prescribed by your healthcare provider. Find this number on the syringe. Do not take more than the prescribed total dose in 1 day. See Figure D
Step 5. Push the plunger all the way down and then insert the syringe into the upright bottle through the opening in the bottle adapter. See Figure E
Step 6. With the syringe in place, turn the bottle upside down. Pull the plunger to the number of mLs needed (the amount of liquid medicine in Step 4). See Figure F
Measure the mLs of medicine using the black ring on the white plunger. See Figure G
Step 7. Remove the syringe from the bottle adapter. Slowly squirt Frisium oral suspension directly into the corner of your mouth or your child's mouth until all of the liquid medicine in the syringe is given. See Figure H
Step 8. Cap the bottle tightly with the adapter in place. If the cap does not fit securely, check to see if the adapter is fully inserted. See Figure I
Step 9. Wash the oral syringe after each use.
This Instruction for Use has been approved by the U.S. Food and Drug Administration.
Marketed by: Lundbeck, Deerfield, IL 60015, U.S.A.
Frisium is a registered trademark of Lundbeck
logo onfi-04 onfi-05 onfi-06 onfi-07 onfi-08 onfi-09 onfi-10 onfi-11 onfi-12 logo
PRINCIPAL DISPLAY PANEL - 10 MG TABLET SCORED
10 mg C-IV
DISPENSE THE ENCLOSED MEDICATION GUIDE WITH EACH PRESCRIPTION.
10 mg principal display panel
PRINCIPAL DISPLAY PANEL - 20 MG TABLET SCORED
20 mg C-IV
DISPENSE THE ENCLOSED MEDICATION GUIDE WITH EACH PRESCRIPTION.
20 mg principal display panel
PRINCIPAL DISPLAY PANEL - 2.5 MG/ML ORAL SUSPENSION
2.5 mg/mL C-IV
FOR ORAL ADMINISTRATION ONLY.
DISPENSE THE ENCLOSED MEDICATION GUIDE AND INSTRUCTIONS FOR USE WITH EACH PRESCRIPTION.
2.5 mg oral suspension principal display panel
Depending on the reaction of the Frisium after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Frisium not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Frisium addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology