Gemplex

Gemplex is an atypical antipsychotic which is present in Gemplex as its monohydrate polymorphic form. Gemplex monohydrate is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy]-3,4 dihydrocarbostyril monohydrate. The empirical formula is C₂₃H₂₇Cl₂N₃O₂·H₂O and its molecular weight is 466.40.

Gemplex (Gemplex) is an extended release injectable suspension available in 400-mg or 300-mg strength pre-filled dual chamber syringes. The labeled strengths are calculated based on the anhydrous form (Gemplex).

Inactive ingredients (per administered dose) for 400 mg and 300 mg strength products, respectively, include carboxymethyl cellulose sodium (16.64 mg and 12.48 mg), mannitol (83.2 mg and 62.4 mg), sodium phosphate monobasic monohydrate (1.48 mg and 1.11 mg) and sodium hydroxide (pH adjuster).

Schizophrenia: Treatment of schizophrenia. The efficacy of Gemplex in the treatment of schizophrenia was established in short-term (4- and 6-week) controlled trials of schizophrenic inpatients.

The efficacy of Gemplex in maintaining stability in patients with schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of ≥3 months, were discontinued from those other medications, and were then administered Gemplex 15 mg/day and observed for relapse during a period of up to 26 weeks was demonstrated in a placebo-controlled trial. The physician who elects to use Gemplex for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Bipolar Disorder: Treatment of acute manic and mixed episodes associated with bipolar disorder.

The efficacy of Gemplex was established in 2 placebo-controlled trials (3 weeks) of inpatients with DSM-IV criteria for bipolar I disorder who were experiencing an acute manic or mixed episode with or without psychotic features.

The efficacy of Gemplex in maintaining efficacy in patients with bipolar I disorder with a recent manic or mixed episode who had been stabilized and then maintained for at least 6 weeks, was demonstrated in a double-blind, placebo-controlled trial. Prior to entering the double-blind, randomization phase of this trial, patients were clinically stabilized and maintained their stability for 6 consecutive weeks on Gemplex.

Following this 6-week maintenance phase, patients were randomized to either placebo or Gemplex and monitored for relapse. Physicians who elect to use Gemplex for extended periods ie, >6 weeks, should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Gemplex is an antipsychotic medication. It works by changing the actions of chemicals in the brain.

Gemplex is used to treat the symptoms of psychotic conditions such as schizophrenia and bipolar I disorder (manic depression). It is not known if Gemplex is safe or effective in children younger than 13 with schizophrenia, or children younger than 10 with bipolar disorder.

Gemplex is also used together with other medicines to treat major depressive disorder in adults.

Gemplex is also used in children 6 years or older who have Tourette's disorder, or symptoms of autistic disorder (irritability, aggression, mood swings, temper tantrums, and self-injury).

Gemplex may also be used for purposes not listed in this medication guide.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Prefilled Syringe,

Intramuscular:

Gemplex: 1064 mg/3.9 mL (3.9 mL); 441 mg/1.6 mL (1.6 mL); 662 mg/2.4 mL (2.4 mL); 882 mg/3.2 mL (3.2 mL)

Prefilled Syringe,

Intramuscular [preservative free]:

Gemplex Initio: 675 mg/2.4 mL (2.4 mL)

Dosing: Adult

Note: Formulations: Gemplex lauroxil is a prodrug of Gemplex formulated as an ER suspension for IM injection. Another ER suspension for IM injection is available as Gemplex monohydrate. All doses, for all routes of administration, are expressed as the equivalent amounts of Gemplex base in both monographs. When initiating Gemplex lauroxil or restarting after missed doses, a 675 mg nanocrystal dispersion preparation of Gemplex lauroxil (Gemplex Initio) is an option for one-time use. The 675 mg nanocrystal dispersion (Gemplex Initio) is not to be used for repeated dosing due to pharmacokinetic differences with other Gemplex lauroxil strengths.

Schizophrenia: IM: Note: Establish tolerability with oral Gemplex prior to initiating treatment. Avoid use of 675 mg nanocrystal dispersion (Gemplex Initio) in known CYP2D6 poor metabolizers.

Initial dose options:

1-day oral overlap using Gemplex Initio: Administer a single oral Gemplex 30 mg dose, a single 675 mg dose of nanocrystal dispersion (Gemplex Initio), plus the first dose of Gemplex lauroxil based on current oral Gemplex dose with or within 10 days after administering the 675 mg dose.

or

21-day oral overlap: Administer oral Gemplex for 21 days in conjunction with first dose of Gemplex lauroxil based on the current oral Gemplex dose.

Conversion of oral Gemplex to IM Gemplex lauroxil (Gemplex):

Oral Gemplex 10 mg/day: Initial IM Gemplex lauroxil (Gemplex) dose: 441 mg per month.

Oral Gemplex 15 mg/day: Initial IM Gemplex lauroxil (Gemplex) dose: 662 mg per month or 882 mg every 6 weeks or 1,064 mg every 2 months.

Oral Gemplex ≥20 mg/day: Initial IM Gemplex lauroxil (Gemplex) dose: 882 mg every month.

Dosage adjustment: Adjust Gemplex lauroxil dose as needed; if a dose is required earlier than the recommended interval(s), do not administer <14 days after the previous injection.

Missed dose: Administer missed dose as soon as possible. Supplemental dose(s) may be appropriate; see table below. In patients who require oral supplemental dose(s), administer the same dose of oral Gemplex that the patient was receiving prior to initiation of Gemplex lauroxil, unless otherwise indicated.

Table was converted to the following text:

Supplemental Dose Recommendations Following Missed Doses

Current dose of Gemplex lauroxil (Gemplex): 441 mg

Last injection occurred ≤6 weeks ago: Administer Gemplex lauroxil (Gemplex) immediately; no Gemplex supplementation required.

Last injection occurred >6 and ≤7 weeks ago: Administer Gemplex lauroxil (Gemplex) immediately in conjunction with:

Oral Gemplex supplementation for 7 days

or

Single dose of Gemplex lauroxil nanocrystal dispersion (Gemplex Initio) 675 mg

Last injection occurred >7 weeks ago: Administer Gemplex lauroxil (Gemplex) immediately in conjunction with:

Oral Gemplex supplementation for 21 days

or

Single dose of Gemplex lauroxil nanocrystal dispersion (Gemplex Initio) 675 mg and a single dose of oral Gemplex 30 mg

Current dose of Gemplex lauroxil (Gemplex): 662 mg or 882 mg

Last injection occurred ≤8 weeks ago: Administer Gemplex lauroxil (Gemplex) immediately; no Gemplex supplementation required

Last injection occurred >8 and ≤12 weeks ago: Administer Gemplex lauroxil (Gemplex) immediately in conjunction with:

Oral Gemplex supplementation for 7 days

i

Single dose of Gemplex lauroxil nanocrystal dispersion (Gemplex Initio) 675 mg

Last injection occurred >12 weeks ago: Administer Gemplex lauroxil (Gemplex) immediately in conjunction with:

Oral Gemplex supplementation for 21 days

or

Single dose of Gemplex lauroxil nanocrystal dispersion (Gemplex Initio) 675 mg and a single dose of oral Gemplex 30 mg

Current dose of Gemplex lauroxil (Gemplex): 1,064 mg

Last injection occurred ≤10 weeks ago: Administer Gemplex lauroxil (Gemplex) immediately; no Gemplex supplementation required

Last injection occurred >10 and ≤12 weeks ago: Administer Gemplex lauroxil (Gemplex) immediately in conjunction with:

Oral Gemplex supplementation for 7 days

or

Single dose of Gemplex lauroxil nanocrystal dispersion (Gemplex Initio) 675 mg

Last injection occurred >12 weeks ago: Administer Gemplex lauroxil (Gemplex) immediately in conjunction with:

Oral Gemplex supplementation for 21 days

or

Single dose of Gemplex lauroxil nanocrystal dispersion (Gemplex Initio) 675 mg and a single dose of oral Gemplex 30 mg

Discontinuation of therapy: Gradual dose reduction is advised to avoid withdrawal symptoms (ie, insomnia, headache, GI symptoms) unless discontinuation is due to significant adverse effects. Generally, when discontinuing antipsychotic therapy for a chronic psychiatric disorder (eg, schizophrenia), decreasing the dose gradually over months with close monitoring may be appropriate and may enable clinicians to detect prodromal symptoms of disease recurrence (APA [Lehman 2004]; CPA 2005).

Switching antipsychotics: An optimal, universal strategy for switching antipsychotic drugs has not been established. Strategies include: Cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). In patients with schizophrenia at high risk of relapse, the current medication may be maintained at full dose as the new medication is increased (ie, overlap); once the new medication is at therapeutic dose, the first medication is gradually decreased and discontinued over 1 to 2 weeks (Cerovecki 2013; Remington 2005; Takeuchi 2017). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Post 2019; Stroup 2019).

See also:
What is the most important information I should know about Gemplex?

Gemplex is not for use in psychotic conditions that are related to dementia. Gemplex may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions.

Stop using Gemplex and call your doctor at once if you have the following symptoms: fever with stiff muscles and rapid heart rate; uncontrolled muscle movements; symptoms that come on suddenly such as numbness or weakness, severe headache, and problems with vision, speech, or balance.

Gemplex may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid drinking alcohol, which can increase some of the side effects of Gemplex.

Before you take Gemplex, tell your doctor if you regularly use other medicines that make you sleepy (such as cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by Gemplex.

Avoid becoming overheated or dehydrated. Drink plenty of fluids, especially in hot weather and during exercise. It is easier to become dangerously overheated and dehydrated while you are taking Gemplex.

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

• Gemplex orally disintegrating tablets comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Gemplex orally disintegrating tablets refilled.
• Take Gemplex orally disintegrating tablets by mouth with or without food.
• Taking Gemplex orally disintegrating tablets at the same time each day will help you remember to take it.
• Take Gemplex orally disintegrating tablets on a regular schedule to get the most benefit from it.
• Do not remove the tablet from the blister until you are ready to take a dose. To open the blister, peel back the foil to expose the tablet. Do not push the tablet through the blister. This could damage the tablet.
• Make sure your hands are dry before you handle the tablet. Do not break, crush, or chew the tablet. Place the entire tablet on your tongue and allow it to dissolve.
• It is recommended that Gemplex orally disintegrating tablets be taken without liquid. However, it may be taken with liquid if needed.
• Continue to take Gemplex orally disintegrating tablets even if you feel well. Do not miss any doses.
• If you miss a dose of Gemplex 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 Gemplex orally disintegrating tablets.

Extended-release Gemplex injection is used to treat a mental/mood disorder called schizophrenia. This medication can decrease hallucinations (hearing/seeing things that are not there) and improve your concentration. It also helps you to think more clearly, feel less nervous, and take a more active part in everyday life. Extended-release Gemplex injection is a long-acting psychiatric medication known as an atypical antipsychotic. It works by helping to restore the balance of certain natural substances in the brain.

How to use Gemplex intramuscular

Read the Medication Guide provided by your pharmacist before you start using Gemplex and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

The extended-release injection should only be used if you have already taken Gemplex by mouth without any serious side effects.

Gemplex is given by injection into the buttock or upper arm muscle by a health care professional, usually once every month. Some doses of some brands of this medication may also be given once every 6 weeks. Do not rub/massage the injection site after your dose.

After your first injection, your doctor may direct you to continue to take your antipsychotic medication by mouth (such as Gemplex tablet/solution) for 2 to 3 weeks. This will help maintain the right level of medication in your body as you switch from receiving medication by mouth to receiving it by injection. Follow your doctor's instructions carefully.

The dosage is based on your medical condition, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

It may take several weeks to get the full benefit of this medication. Use this medication regularly to get the most benefit from it. To help you remember, mark the days on the calendar when you need to receive the medication.

Tell your doctor if your condition does not improve or if it worsens.

See also:
What other drugs will affect Gemplex?

Given the primary CNS effects of Gemplex, caution should be used when Gemplex is taken in combination with other centrally acting drugs and alcohol. Due to its α₁-adrenergic receptor antagonism, Gemplex has the potential to enhance the effect of certain antihypertensive agents.

Potential for Other Drugs to Affect Gemplex: Gemplex is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2E1 enzymes. Gemplex also does not undergo direct glucuronidation. This suggests that an interaction of Gemplex with inhibitors or inducers of these enzymes or other factors eg, smoking is unlikely.

Both CYP3A4 and CYP2D6 are responsible for Gemplex metabolism. Agents that induce CYP3A4 (eg, carbamazepine) could cause an increase in Gemplex clearance and lower blood levels. Inhibitors of CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, quinidine, fluoxetine or paroxetine) can inhibit Gemplex elimination and cause increased blood levels.

Ketoconazole: Co-administration of ketoconazole (200 mg/day for 14 days) with a 15-mg single dose of Gemplex increased the AUC of Gemplex and its active metabolite by 63% and 77%, respectively. The effect of a higher ketoconazole dose (400 mg/day) has not been studied. When concomitant administration of ketoconazole with Gemplex occurs, Gemplex dose should be reduced to ½ of its normal dose. Other strong inhibitors of CYP3A4 (itraconazole) would be expected to have similar effects and need similar dose reductions; weaker inhibitors (erythromycin, grapefruit juice) have not been studied. When the CYP3A4 inhibitor is withdrawn from the combination therapy, Gemplex dose should then be increased.

Quinidine: Co-administration of a 10-mg single dose of Gemplex with quinidine (166 mg/day for 13 days), a potent inhibitor of CYP2D6, increased the AUC of Gemplex by 112% but decreased the AUC of its active metabolite, dehydro-Gemplex, by 35%. Gemplex dose should be reduced to ½ of its normal dose when concomitant administration of quinidine with Gemplex occurs. Other significant inhibitors of CYP2D6 eg, fluoxetine or paroxetine, would be expected to have similar effects and therefore, should be accompanied by similar dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, Gemplex dose should then be increased.

Carbamazepine: Co-administration of carbamazepine (200 mg twice daily), a potent CYP3A4 inducer, with Gemplex (30 mg once daily) resulted in an approximate 70% decrease in C_max and AUC values of both Gemplex and its active metabolite, dehydro-Gemplex. When carbamazepine is added to Gemplex therapy, Gemplex dose should be doubled. Additional dose increases should be based on clinical evaluation. When carbamazepine is withdrawn from the combination therapy, Gemplex dose should then be reduced.

No clinically significant effect of famotidine, valproate or lithium was seen on the pharmacokinetics of Gemplex.

Potential for Gemplex to Affect Other Drugs: Gemplex is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P-450 enzymes. In in vivo studies, 10- to 30-mg/day doses of Gemplex had no significant effect on metabolism by CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin) and CYP3A4 (dextromethorphan) substrates. Additionally, Gemplex and dehydro-Gemplex did not show potential for altering CYP1A2-mediated metabolism in vitro.

Alcohol: There was no significant difference between Gemplex co-administered with ethanol and placebo co-administered with ethanol on performance of gross motor skills or stimulus response in healthy subjects. As with most psychoactive medications, patients should be advised to avoid alcohol while taking Gemplex.

No effect of Gemplex was seen on the pharmacokinetics of lithium or valproate.

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

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.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis

• Cerebrovascular Adverse Events, Including Stroke

• Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

• Neuroleptic Malignant Syndrome (NMS)

• Tardive Dyskinesia

• Metabolic Changes

• Orthostatic Hypotension

• Leukopenia, Neutropenia, and Agranulocytosis

• Seizures/Convulsions

• Potential for Cognitive and Motor Impairment

• Body Temperature Regulation

• Suicide

• Dysphagia

The most common adverse reactions in adult patients in clinical trials (≥10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness.

The most common adverse reactions in the pediatric clinical trials (≥10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased.

Gemplex has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, bipolar disorder, major depressive disorder, Dementia of the Alzheimer’s type, Parkinson’s disease, and alcoholism, and who had approximately 7619 patient-years of exposure to oral Gemplex. A total of 3390 patients were treated with oral Gemplex for at least 180 days and 1933 patients treated with oral Gemplex had at least 1 year of exposure.

Gemplex has been evaluated for safety in 1,686 patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, autistic disorder, or Tourette’s disorder and who had approximately 1,342 patient-years of exposure to oral Gemplex. A total of 959 pediatric patients were treated with oral Gemplex for at least 180 days and 556 pediatric patients treated with oral Gemplex had at least 1 year of exposure.

The conditions and duration of treatment with Gemplex (monotherapy and adjunctive therapy with antidepressants or mood stabilizers) included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed- and flexible-dose studies, and short- and longer-term exposure.

6.1 Clinical Trials Experience

Adult Patients with Schizophrenia

The following findings are based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral Gemplex was administered in doses ranging from 2 mg/day to 30 mg/day.

Commonly Observed Adverse Reactions

The only commonly observed adverse reaction associated with the use of Gemplex in patients with schizophrenia (incidence of 5% or greater and Gemplex incidence at least twice that for placebo) was akathisia (Gemplex 8%; placebo 4%).

Adult Patients with Bipolar Mania

Monotherapy

The following findings are based on a pool of 3-week, placebo-controlled, bipolar mania trials in which oral Gemplex was administered at doses of 15 mg/day or 30 mg/day.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of Gemplex in patients with bipolar mania (incidence of 5% or greater and Gemplex incidence at least twice that for placebo) are shown in Table 16.

Table 16: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Adult Patients with Bipolar Mania Treated with

Oral Gemplex Monotherapy

Less Common Adverse Reactions in Adults

Table 17 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania), including only those reactions that occurred in 2% or more of patients treated with Gemplex (doses ≥2 mg/day) and for which the incidence in patients treated with Gemplex was greater than the incidence in patients treated with placebo in the combined dataset.

Table 17: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with

Oral Gemplex

a Adverse reactions reported by at least 2% of patients treated with oral Gemplex, except adverse reactions which had an incidence equal to or less than placebo.

An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race.

Adult Patients with Adjunctive Therapy with Bipolar Mania

The following findings are based on a placebo-controlled trial of adult patients with bipolar disorder in which Gemplex was administered at doses of 15 mg/day or 30 mg/day as adjunctive therapy with lithium or valproate.

Adverse Reactions Associated with Discontinuation of Treatment

In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 12% for patients treated with adjunctive Gemplex compared to 6% for patients treated with adjunctive placebo. The most common adverse drug reactions associated with discontinuation in the adjunctive Gemplex-treated compared to placebo-treated patients were akathisia (5% and 1%, respectively) and tremor (2% and 1%, respectively).

Commonly Observed Adverse Reactions

The commonly observed adverse reactions associated with adjunctive Gemplex and lithium or valproate in patients with bipolar mania (incidence of 5% or greater and incidence at least twice that for adjunctive placebo) were: akathisia, insomnia, and extrapyramidal disorder.

Less Common Adverse Reactions in Adult Patients with Adjunctive Therapy in Bipolar Mania

Table 18 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute treatment (up to 6 weeks), including only those reactions that occurred in 2% or more of patients treated with adjunctive Gemplex (doses of 15 mg/day or 30 mg/day) and lithium or valproate and for which the incidence in patients treated with this combination was greater than the incidence in patients treated with placebo plus lithium or valproate.

Table 18: Adverse Reactions in a Short-Term, Placebo-Controlled Trial of Adjunctive Therapy in Patients with Bipolar Disorder

a Adverse reactions reported by at least 2% of patients treated with oral Gemplex, except adverse reactions which had an incidence equal to or less than placebo.

* Lithium or Valproate

Pediatric Patients (13 to 17 years) with Schizophrenia

The following findings are based on one 6-week, placebo-controlled trial in which oral Gemplex was administered in doses ranging from 2 mg/day to 30 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between Gemplex-treated and placebo-treated pediatric patients (13 to 17 years) was 5% and 2%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of Gemplex in adolescent patients with schizophrenia (incidence of 5% or greater and Gemplex incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor.

Pediatric Patients (10 to 17 years) with Bipolar Mania

The following findings are based on one 4-week, placebo-controlled trial in which oral Gemplex was administered in doses of 10 mg/day or 30 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between Gemplex-treated and placebo-treated pediatric patients (10 to 17 years) was 7% and 2%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of Gemplex in pediatric patients with bipolar mania (incidence of 5% or greater and Gemplex incidence at least twice that for placebo) are shown in Table 19.

Table 19: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (10 to 17 years) with Bipolar Mania Treated with

Oral Gemplex

Pediatric Patients (6 to 17 years) with Autistic Disorder

The following findings are based on two 8-week, placebo-controlled trials in which oral Gemplex was administered in doses of 2 mg/day to 15 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between Gemplex-treated and placebo-treated pediatric patients (6 to 17 years) was 10% and 8%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of Gemplex in pediatric patients with autistic disorder (incidence of 5% or greater and Gemplex incidence at least twice that for placebo) are shown in Table 20.

Table 20: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) with Autistic Disorder Treated with

Oral Gemplex

Pediatric Patients (6 to 18 years) with Tourette's Disorder

The following findings are based on one 8-week and one 10-week, placebo-controlled trials in which oral Gemplex was administered in doses of 2 mg/day to 20 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between Gemplex-treated and placebo-treated pediatric patients (6 to 18 years) was 7% and 1%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of Gemplex in pediatric patients with Tourette's disorder (incidence of 5% or greater and Gemplex incidence at least twice that for placebo) are shown in Table 21.

Table 21: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) with Tourette's Disorder Treated with

Oral Gemplex

Less Common Adverse Reactions in Pediatric Patients (6 to 18 years) with Schizophrenia, Bipolar Mania, Autistic Disorder, or Tourette’s Disorder

Table 22 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia, up to 4 weeks in bipolar mania, up to 8 weeks in autistic disorder, and up to 10 weeks in Tourette’s disorder), including only those reactions that occurred in 2% or more of pediatric patients treated with Gemplex (doses ≥2 mg/day) and for which the incidence in patients treated with Gemplex was greater than the incidence in patients treated with placebo.

Table 22: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) Treated with

Oral Gemplex

Adult Patients Receiving Aripiprazoleas Adjunctive Treatment of Major Depressive Disorder

The following findings are based on a pool of two placebo-controlled trials of patients with major depressive disorder in which Gemplex was administered at doses of 2 mg to 20 mg as adjunctive treatment to continued antidepressant therapy.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions was 6% for adjunctive Gemplex-treated patients and 2% for adjunctive placebo-treated patients.

Commonly Observed Adverse Reactions

The commonly observed adverse reactions associated with the use of adjunctive Gemplex in patients with major depressive disorder (incidence of 5% or greater and Gemplex incidence at least twice that for placebo) were: akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision.

Less Common Adverse Reactions in Adult Patients with Major Depressive Disorder

Table 23 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks), including only those adverse reactions that occurred in 2% or more of patients treated with adjunctive Gemplex (doses ≥2 mg/day) and for which the incidence in patients treated with adjunctive Gemplex was greater than the incidence in patients treated with adjunctive placebo in the combined dataset.

Table 23: Adverse Reactions in Short-Term, Placebo-Controlled Adjunctive Trials in Patients with Major Depressive Disorder

a Adverse reactions reported by at least 2% of patients treated with adjunctive Gemplex, except adverse reactions which had an incidence equal to or less than placebo.

*Antidepressant Therapy

Dose-Related Adverse Reactions

Schizophrenia

Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with schizophrenia comparing various fixed doses (2 mg/day, 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, and 30 mg/day) of oral Gemplex to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%).

In the study of pediatric patients (13 to 17 years of age) with schizophrenia, three common adverse reactions appeared to have a possible dose response relationship: extrapyramidal disorder (incidences were placebo, 5.0%; 10 mg, 13.0%; 30 mg, 21.6%); somnolence (incidences were placebo, 6.0%; 10 mg, 11.0%; 30 mg, 21.6%); and tremor (incidences were placebo, 2.0%; 10 mg, 2.0%; 30 mg, 11.8%).

Bipolar Mania

In the study of pediatric patients (10 to 17 years of age) with bipolar mania, four common adverse reactions had a possible dose response relationship at 4 weeks; extrapyramidal disorder (incidences were placebo, 3.1%; 10 mg, 12.2%; 30 mg, 27.3%); somnolence (incidences were placebo, 3.1%; 10 mg, 19.4%; 30 mg, 26.3%); akathisia (incidences were placebo, 2.1%; 10 mg, 8.2%; 30 mg, 11.1%); and salivary hypersecretion (incidences were placebo, 0%; 10 mg, 3.1%; 30 mg, 8.1%).

Autistic Disorder

In a study of pediatric patients (6 to 17 years of age) with autistic disorder, one common adverse reaction had a possible dose response relationship: fatigue (incidences were placebo, 0%; 5 mg, 3.8%; 10 mg, 22.0%; 15 mg, 18.5%).

Tourette’s Disorder

In a study of pediatric patients (7 to 17 years of age) with Tourette’s disorder, no common adverse reaction(s) had a dose response relationship.

Extrapyramidal Symptoms

Schizophrenia

In short-term, placebo-controlled trials in schizophrenia in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for Gemplex-treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related events for Gemplex-treated patients was 8% vs. 4% for placebo. In the short-term, placebo-controlled trial of schizophrenia in pediatric patients (13 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for Gemplex-treated patients was 25% vs. 7% for placebo; and the incidence of akathisia-related events for Gemplex-treated patients was 9% vs. 6% for placebo.

Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias). In the adult schizophrenia trials, the objectively collected data did not show a difference between Gemplex and placebo, with the exception of the Barnes Akathisia Scale ( Gemplex, 0.08; placebo, –0.05). In the pediatric (13 to 17 years) schizophrenia trial, the objectively collected data did not show a difference between Gemplex and placebo, with the exception of the Simpson Angus Rating Scale (Gemplex, 0.24; placebo, –0.29).

Similarly, in a long-term (26-week), placebo-controlled trial of schizophrenia in adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias) did not show a difference between Gemplex and placebo.

Bipolar Mania

In the short-term, placebo-controlled trials in bipolar mania in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for monotherapy Gemplex-treated patients was 16% vs. 8% for placebo and the incidence of akathisia-related events for monotherapy Gemplex-treated patients was 13% vs. 4% for placebo. In the 6-week, placebo-controlled trial in bipolar mania for adjunctive therapy with lithium or valproate, the incidence of reported EPS-related events, excluding events related to akathisia for adjunctive Gemplex-treated patients was 15% vs. 8% for adjunctive placebo and the incidence of akathisia-related events for adjunctive Gemplex-treated patients was 19% vs. 5% for adjunctive placebo. In the short-term, placebo-controlled trial in bipolar mania in pediatric (10 to 17 years) patients, the incidence of reported EPS-related events, excluding events related to akathisia, for Gemplex-treated patients was 26% vs. 5% for placebo and the incidence of akathisia-related events for Gemplex-treated patients was 10% vs. 2% for placebo.

In the adult bipolar mania trials with monotherapy Gemplex, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between Gemplex and placebo (Gemplex, 0.50; placebo, –0.01 and Gemplex, 0.21; placebo, –0.05). Changes in the Assessments of Involuntary Movement Scales were similar for the Gemplex and placebo groups. In the bipolar mania trials with Gemplex as adjunctive therapy with either lithium or valproate, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive Gemplex and adjunctive placebo (Gemplex, 0.73; placebo, 0.07 and Gemplex, 0.30; placebo, 0.11). Changes in the Assessments of Involuntary Movement Scales were similar for adjunctive Gemplex and adjunctive placebo. In the pediatric (10 to 17 years), short-term, bipolar mania trial, the Simpson Angus Rating Scale showed a significant difference between Gemplex and placebo (Gemplex, 0.90; placebo, −0.05). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the Gemplex and placebo groups.

Major Depressive Disorder

In the short-term, placebo-controlled trials in major depressive disorder, the incidence of reported EPS-related events, excluding events related to akathisia, for adjunctive Gemplex-treated patients was 8% vs. 5% for adjunctive placebo-treated patients; and the incidence of akathisia-related events for adjunctive Gemplex-treated patients was 25% vs. 4% for adjunctive placebo-treated patients.

In the major depressive disorder trials, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive Gemplex and adjunctive placebo (Gemplex, 0.31; placebo, 0.03 and Gemplex, 0.22; placebo, 0.02). Changes in the Assessments of Involuntary Movement Scales were similar for the adjunctive Gemplex and adjunctive placebo groups.

Autistic Disorder

In the short-term, placebo-controlled trials in autistic disorder in pediatric patients (6 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for Gemplex-treated patients was 18% vs. 2% for placebo and the incidence of akathisia-related events for Gemplex-treated patients was 3% vs. 9% for placebo.

In the pediatric (6 to 17 years) short-term autistic disorder trials, the Simpson Angus Rating Scale showed a significant difference between Gemplex and placebo (Gemplex, 0.1; placebo, –0.4). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the Gemplex and placebo groups.

Tourette’s Disorder

In the short-term, placebo-controlled trials in Tourette’s disorder in pediatric patients (6 to 18 years), the incidence of reported EPS-related events, excluding events related to akathisia, for Gemplex-treated patients was 7% vs. 6% for placebo and the incidence of akathisia-related events for Gemplex-treated patients was 4% vs. 6% for placebo.

In the pediatric (6 to 18 years) short-term Tourette’s disorder trials, changes in the Simpson Angus Rating Scale, Barnes Akathisia Scale and Assessments of Involuntary Movement Scale were not clinically meaningfully different for Gemplex and placebo.

Dystonia

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Additional Findings Observed in Clinical Trials

Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials

The adverse reactions reported in a 26-week, double-blind trial comparing oral Gemplex and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for Gemplex vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 ≤49 days), and were of limited duration (7/12 ≤10 days). Tremor infrequently led to discontinuation (<1%) of Gemplex. In addition, in a long-term (52-week), active-controlled study, the incidence of tremor was 5% (40/859) for Gemplex. A similar profile was observed in a long-term monotherapy study and a long-term adjunctive study with lithium and valproate in bipolar disorder.

Other Adverse Reactions Observed During the Premarketing Evaluation of Gemplex

The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.

Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients:

Adults -

Oral Administration

Blood and Lymphatic System Disorders:

rare - thrombocytopenia

Cardiac Disorders:

infrequent – bradycardia, palpitations, rare – atrial flutter, cardio-respiratory arrest, atrioventricular block, atrial fibrillation, angina pectoris, myocardial ischemia, myocardial infarction, cardiopulmonary failure

Eye Disorders:

infrequent – photophobia; rare - diplopia

Gastrointestinal Disorders:

infrequent - gastroesophageal reflux disease

General Disorders and Administration Site Conditions:

frequent - asthenia; infrequent – peripheral edema, chest pain; rare – face edema

Hepatobiliary Disorders:

rare - hepatitis, jaundice

Immune System Disorders:

rare-hypersensitivity

Injury, Poisoning, and Procedural Complications:

infrequent – fall; rare – heat stroke

Investigations:

frequent - weight decreased, infrequent - hepatic enzyme increased, blood glucose increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased; rare – blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased

Metabolism and Nutrition Disorders:

frequent – anorexia; infrequent - rare - hypokalemia, hyponatremia, hypoglycemia

Musculoskeletal and Connective Tissue Disorders:

infrequent - muscular weakness, muscle tightness; rare – rhabdomyolysis, mobility decreased

Nervous System Disorders:

infrequent - parkinsonism, memory impairment, cogwheel rigidity, hypokinesia, myoclonus, bradykinesia; rare – akinesia, myoclonus, coordination abnormal, speech disorder, Grand Mal convulsion; <1/10,000 patients -choreoathetosis

Psychiatric Disorders:

infrequent – aggression, loss of libido, delirium; rare – libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking

Renal and Urinary Disorders:

rare - urinary retention, nocturia

Reproductive System and Breast Disorders:

infrequent - erectile dysfunction; rare – gynaecomastia, menstruation irregular, amenorrhea, breast pain, priapism

Respiratory, Thoracic, and Mediastinal Disorders:

infrequent -nasal congestion, dyspnea

Skin and Subcutaneous Tissue Disorders:

infrequent - rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia; rare -urticaria

Vascular Disorders:

infrequent – hypotension, hypertension

Pediatric Patients -

Oral Administration

Most adverse events observed in the pooled database of 1,686 pediatric patients, aged 6 to 18 years, were also observed in the adult population. Additional adverse reactions observed in the pediatric population are listed below.

Eye Disorders

infrequent - oculogyric crisis

Gastrointestinal Disorders:

infrequent - tongue dry, tongue spasm

Investigations:

frequent - blood insulin increased

Nervous System Disorders:

infrequent - sleep talking

Renal and Urinary Disorders:

frequent – enuresis

Skin and Subcutaneous Tissue Disorders:

infrequent - hirsutism

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Gemplex. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), pathological gambling, hiccups and blood glucose fluctuation.