Ozap

Each vial of Ozap powder for solution for injection contains 10 mg Ozap. After reconstitution each mL of the solution contains 5 mg Ozap.

Ozap Zydis orodispersible tablets are freeze-dried, rapid-dispersing preparations to be placed in the mouth or alternatively, to be dispersed in water or other suitable beverage for administration.

Excipients/Inactive Ingredients: Ozap: 5-mg and 10-mg Coated Tablet: Tablet Core: Lactose monohydrate (156 mg and 312 mg, respectively), hyprolose, crospovidone, microcrystalline cellulose and magnesium stearate. Tablet Coat: Hypromellose, color mixture white (hypromellose, titanium dioxide E171, macrogol, polysorbate 80), carnauba wax, edible blue ink (shellac, anhydrous ethanol, isopropyl alcohol, butyl alcohol, propylene glycol, ammonium hydroxide, indigo carmine E132).

Powder for Injection: Lactose monohydrate, hydrochloric acid, tartaric acid, E334, sodium hydroxide.

Ozap Zydis: Orodispersible 5-mg Tablet: Gelatin, mannitol (E421), aspartame (E951) 0.60 mg, sodium methyl parahydroxybenzoate (E219) 0.1125 mg, sodium propyl parahydroxybenzoate (E217) 0.0375 mg.

Orodispersible 10-mg Tablet: Gelatin, mannitol (E421), aspartame (E951) 0.80 mg, sodium methyl parahydroxybenzoate (E219) 0.15 mg, sodium propyl parahydroxybenzoate (E217) 0.05 mg.

Schizophrenia

Oral Ozap Tablets, USP are indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial. In adolescent patients with schizophrenia (ages 13 to 17), efficacy was established in one 6-week trial.

When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents.

Bipolar I Disorder (Manic or Mixed Episodes)

Monotherapy —

Oral Ozap Tablets, USP are indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one monotherapy maintenance trial. In adolescent patients with manic or mixed episodes associated with bipolar I disorder (ages 13 to 17), efficacy was established in one 3-week trial.

When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents.

Adjunctive Therapy to Lithium or Valproate —

Oral Ozap Tablets, USP are indicated for the treatment of manic or mixed episodes associated with bipolar I disorder as an adjunct to lithium or valproate. Efficacy was established in two 6-week clinical trials in adults. The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials.

Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder

Pediatric schizophrenia and bipolar I disorder are serious mental disorders; however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, pediatric patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar I disorder should be part of a total treatment program that often includes psychological, educational and social interventions.

Ozap Tablets and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder

Oral Ozap Tablets, USP and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolar I disorder, based on clinical studies. When using Ozap Tablets, USP and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.

Ozap Tablets, USP monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

Ozap is used to treat nervous, emotional, and mental conditions (e.g., schizophrenia). It may also be used alone or with other medicines (e.g., lithium or valproate) to treat bipolar disorder (manic-depressive illness) or mania that is part of bipolar disorder. Ozap should not be used to treat behavioral problems in older adult patients who have dementia or Alzheimer's disease.

Ozap is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although this use is not included in product labeling, Ozap is used in certain patients with the following medical condition:

• Prevention of nausea and vomiting caused by cancer medicines.

Schizophrenia

Adults

Dose Selection —

Oral Ozap should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 to 10 mg initially, with a target dose of 10 mg/day within several days. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1 week, since steady state for Ozap would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.

Efficacy in schizophrenia was demonstrated in a dose range of 10 to 15 mg/day in clinical trials. However, doses above 10 mg/day were not demonstrated to be more efficacious than the 10 mg/day dose. An increase to a dose greater than the target dose of 10 mg/day (i.e., to a dose of 15 mg/day or greater) is recommended only after clinical assessment. Ozap is not indicated for use in doses above 20 mg/day.

Dosing in Special Populations — The recommended starting dose is 5 mg in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of Ozap (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to Ozap. When indicated, dose escalation should be performed with caution in these patients.

Maintenance Treatment — The effectiveness of oral Ozap, 10 mg/day to 20 mg/day, in maintaining treatment response in schizophrenic patients who had been stable on Ozap Tablets for approximately 8 weeks and were then followed for relapse has been demonstrated in a placebo-controlled trial. The physician who elects to use Ozap Tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Adolescents

Dose Selection —

Oral Ozap should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with schizophrenia was demonstrated based on a flexible dose range of 2.5 to 20 mg/day in clinical trials, with a mean modal dose of 12.5 mg/day (mean dose of 11.1 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are recommended.

The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials.

Maintenance Treatment — The efficacy of Ozap Tablets for the maintenance treatment of schizophrenia in the adolescent population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of Ozap pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

Bipolar I Disorder (Manic or Mixed Episodes)

Adults

Dose Selection for Monotherapy —

Oral Ozap should be administered on a once-a-day schedule without regard to meals, generally beginning with 10 or 15 mg. Dosage adjustments, if indicated, should generally occur at intervals of not less than 24 hours, reflecting the procedures in the placebo-controlled trials. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.

Short-term (3 to 4 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials.

Maintenance Monotherapy — The benefit of maintaining bipolar I patients on monotherapy with oral Ozap Tablets at a dose of 5 to 20 mg/day, after achieving a responder status for an average duration of 2 weeks, was demonstrated in a controlled trial. The physician who elects to use Ozap Tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Dose Selection for Adjunctive Treatment — When administered as adjunctive treatment to lithium or valproate, oral Ozap dosing should generally begin with 10 mg once-a-day without regard to meals.

Antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials.

Adolescents

Dose Selection —

Oral Ozap should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with bipolar I disorder (manic or mixed episodes) was demonstrated based on a flexible dose range of 2.5 to 20 mg/day in clinical trials, with a mean modal dose of 10.7 mg/day (mean dose of 8.9 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are recommended.

The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials.

Maintenance Treatment — The efficacy of Ozap Tablets for the maintenance treatment of bipolar I disorder in the adolescent population has not been evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of Ozap pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

Ozap Tablets and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder

​When using Ozap Tablets and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. When using Ozap Tablets and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

​Adults

​Oral Ozap should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral Ozap and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral Ozap 5 to 12.5 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with Ozap Tablets and fluoxetine in combination in adult patients with a dose range of Ozap 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of co-administration of doses above 18 mg Ozap with 75 mg fluoxetine has not been evaluated in clinical studies.

Oral Ozap should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral Ozap and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral Ozap 5 to 12.5 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with Ozap Tablets and fluoxetine in combination in adult patients with a dose range of Ozap 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of co-administration of doses above 18 mg Ozap with 75 mg fluoxetine has not been evaluated in clinical studies.

Children and Adolescents (10 to 17 years of age)

​ Dosage and Administration information for pediatric patients (10 to 17) is approved for Eli Lilly and Company's Ozap Tablets. However, due to Eli Lilly and Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

​Safety and efficacy of Ozap Tablets and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of Ozap Tablets and fluoxetine). Symbyax is dosed between 3 mg/25 mg (Ozap/fluoxetine) per day and 12 mg/50 mg (Ozap/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of Ozap Tablets and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

Safety and efficacy of Ozap Tablets and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of Ozap Tablets and fluoxetine). Symbyax is dosed between 3 mg/25 mg (Ozap/fluoxetine) per day and 12 mg/50 mg (Ozap/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of Ozap Tablets and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

• Table 1: Approximate Dose Correspondence Between Symbyax a and the Combination of Ozap Tablets and Fluoxetine

​While there is no body of evidence to answer the question of how long a patient treated with Ozap Tablets and fluoxetine in combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring chronic treatment. The physician should periodically reexamine the need for continued pharmacotherapy. While there is no body of evidence to answer the question of how long a patient treated with Ozap Tablets and fluoxetine in combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring chronic treatment. The physician should periodically reexamine the need for continued pharmacotherapy.

​Ozap Tablets monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder. Ozap Tablets monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

Ozap Tablets and Fluoxetine in Combination: Dosing in Special Populations

The starting dose of oral Ozap 2.5 to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of Ozap or fluoxetine in combination (female gender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive to Ozap. Dosing modification may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. Ozap Tablets and fluoxetine in combination have not been systematically studied in patients over 65 years of age or in patients under <10 years of age.

Use Ozap orally disintegrating tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Ozap orally disintegrating tablets comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Ozap orally disintegrating tablets refilled.
• Take Ozap orally disintegrating tablets by mouth with or without food.
• Make sure that your hands are dry before you touch Ozap orally disintegrating tablets.
• Ozap orally disintegrating tablets may come in a bottle or a blister pack. If it comes in a blister pack, do not remove the blister from the outer pouch until you are ready to take Ozap orally disintegrating tablets. Do not push the tablet through the foil. Peel back the foil on the blister pack and place the tablet on your tongue. Take the tablet immediately after opening the blister pack. Do not store the removed tablet for future use.
• The tablet dissolves quickly and can be swallowed with saliva. Ozap orally disintegrating tablets may be taken with or without water.
• Drinking extra fluids while you are taking Ozap orally disintegrating tablets is recommended. Check with your doctor for instructions.
• Continue to take Ozap orally disintegrating tablets even if you feel well. Do not miss any doses.
• If you miss a dose of Ozap orally disintegrating tablets, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Ozap orally disintegrating tablets.

Use: Labeled Indications

Agitation/Aggression (acute) associated with psychiatric disorders (short-acting IM): Treatment of acute agitation associated with schizophrenia and bipolar I mania.

Bipolar disorder (oral): Treatment of acute manic or mixed episodes of bipolar I disorder (as monotherapy or in combination with lithium or valproate) and maintenance treatment; treatment of bipolar depression in combination with fluoxetine.

Major depressive disorder (unipolar), treatment resistant (oral): Treatment of treatment-resistant depression in combination with fluoxetine.

Schizophrenia (oral, ER IM): Treatment of the manifestations of schizophrenia.

Off Label Uses

Agitation/Aggression and psychosis associated with dementia

Data from randomized, double-blind, controlled trials support the use of Ozap in the treatment of psychosis and agitation related to dementia.

Based on the APA practice guideline for the treatment of patients with major depressive disorder and the WFSBP guidelines for biological treatment of unipolar depressive disorders, in patients with psychotic depression, the combination of an antidepressant and antipsychotic is recommended at the onset of treatment.

See also:
What other drugs will affect Ozap?

The risks of using Ozap in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of Ozap, caution should be used when Ozap is taken in combination with other centrally acting drugs and alcohol.

Because of its potential for inducing hypotension, Ozap may enhance the effects of certain antihypertensive agents.

Ozap may antagonize the effects of levodopa and dopamine agonists.

The Effect of Other Drugs on Ozap — Agents that induce CYP1A2 or glucuronyl transferase enzymes, such as omeprazole and rifampin, may cause an increase in Ozap clearance. Inhibitors of CYP1A2 could potentially inhibit Ozap clearance. Although Ozap is metabolized by multiple enzyme systems, induction or inhibition of a single enzyme may appreciably alter Ozap clearance. Therefore, a dosage increase (for induction) or a dosage decrease (for inhibition) may need to be considered with specific drugs.

Charcoal — The administration of activated charcoal (1 g) reduced the Cmax and AUC of oral Ozap by about 60%. As peak Ozap levels are not typically obtained until about 6 hours after dosing, charcoal may be a useful treatment for Ozap overdose.

Cimetidine and Antacids — Single doses of cimetidine (800 mg) or aluminum- and magnesium-containing antacids did not affect the oral bioavailability of Ozap.

Carbamazepine — Carbamazepine therapy (200 mg bid) causes an approximately 50% increase in the clearance of Ozap. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in Ozap clearance.

Ethanol — Ethanol (45 mg/70 kg single dose) did not have an effect on Ozap pharmacokinetics.

Fluoxetine — Fluoxetine (60 mg single dose or 60 mg daily for 8 days) causes a small (mean 16%) increase in the maximum concentration of Ozap and a small (mean 16%) decrease in Ozap clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended.

Fluvoxamine — Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of Ozap. This results in a mean increase in Ozap Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in Ozap AUC is 52% and 108%, respectively. Lower doses of Ozap should be considered in patients receiving concomitant treatment with fluvoxamine.

Warfarin — Warfarin (20 mg single dose) did not affect Ozap pharmacokinetics.

Lithium — Multiple doses of Ozap (10 mg for 8 days) did not influence the kinetics of lithium. Therefore, concomitant Ozap administration does not require dosage adjustment of lithium.

Valproate —In vivo administration of Ozap (10 mg daily for 2 weeks) did not affect the steady state plasma concentrations of valproate. Therefore, concomitant Ozap administration does not require dosage adjustment of valproate.

The co-administration of either diazepam or ethanol with Ozap potentiated the orthostatic hypotension observed with Ozap. Multiple doses of Ozap did not affect the pharmacokinetics of theophylline or its metabolites.

See also:
What are the possible side effects of Ozap?

Clinical Trials Experience

The information below for Ozap RELPREVV is derived primarily from a clinical trial database consisting of 2058 patients with approximately 1948 patient years of exposure to Ozap RELPREVV. This database includes safety data from 6 open-label studies and 2 double-blind comparator studies, conducted in patients with schizophrenia or schizoaffective disorder. Additionally, data obtained from patients treated with oral Ozap are also presented below. Adverse reactions were assessed by the collection of adverse reactions, vital signs, weights, laboratory analytes, ECGs, and the results of physical and ophthalmologic examinations. In the tables and tabulations that follow for Ozap RELPREVV, the MedDRA terminology has been used to classify reported adverse reactions. Data obtained from oral Ozap studies was reported using the COSTART and MedDRA dictionaries.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions listed elsewhere in labeling may not be repeated below. The entire label should be read to gain a complete understanding of the safety profile of Ozap RELPREVV.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.

Adverse Reactions Associated With Discontinuation Of Treatment In A Short-Term, Placebo-Controlled Trial

Overall, there was no difference in the incidence of discontinuation due to adverse reactions between Ozap RELPREVV (4%; 13/306 patients) and placebo (5%; 5/98 patients) in an 8-week trial.

Commonly Observed Adverse Reactions In A Short-Term, Placebo-Controlled Trial

In an 8-week trial, treatment-emergent adverse reactions with an incidence of 5% or greater in at least one of the Ozap RELPREVV treatment groups (210 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks) and greater than placebo were: headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting.

Adverse Reactions Occurring At An Incidence Of 2% Or More Among Ozap RELPREVV-Treated Patients In A Short-Term, Placebo-Controlled Trial

Table 9 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with Ozap RELPREVV and with incidence greater than placebo who participated in the 8-week, placebo-controlled trial.

Table 9: Treatment-Emergent Adverse Reactions: Incidence in a Short-Term, Placebo-Controlled Clinical Trial with Ozap RELPREVV