Geodon Im 20mg/ml Powder for solution for injection.

GEODON intramuscular (IM) is indicated for the treatment of acute agitation in schizophrenic patients for whom treatment with GEODON IM is appropriate and who need intramuscular antipsychotic medication for rapid control of the agitation.

Treatment with the intramuscular formulation should only be used in patients where treatment with an oral formulation is considered to be inappropriate.

Posology

Adults

The recommended dose is 10 mg u2013 20 mg administered as required up to a maximum dose of 40 mg per day. Doses of 10 mg may be administered every 2 hours. Some patients may require an initial dose of 20 mg, which can be followed by a further dose of 10 mg after 4 hours. Thereafter, doses of 10 mg may be given every 2 hours up to a maximum daily dose of 40 mg. Intramuscular administration of GEODON IM for more than 3 consecutive days has not been studied. If long-term therapy is indicated, oral GEODON capsules, up to 80 mg twice daily, should replace the intramuscular administration as soon as possible.

Special populations

Elderly population

Safety and effectiveness in the elderly (65 years and over) have not been established. Treatment with intramuscular injection is not recommended to these patients (see section 4.4).

Renal impairment

GEODON IM injection should be administered with caution in patients with impaired renal function (see section 5.2).

Hepatic impairment

In patients with mild to moderate hepatic insufficiency, lower doses should be considered. There is a lack of experience in patients with severe hepatic insufficiency and GEODON IM should be used with caution in this group (see section 5.2).

Smokers

No dosage adjustment is required in patients who smoke (see section 5.2).

Paediatric population

Safety and efficacy in children under 18 years have not been established.

Method of administration

For intramuscular use only. Intravenous administration must be avoided. For instructions for reconstitution, see section 6.6.

GEODON IM is contraindicated in patients with:

• Known hypersensitivity to ziprasidone or any of the excipients.
• Known QT interval prolongation including congenital long QT syndrome.
• Recent myocardial infarction.
• Uncompensated heart failure.
• Cardiac dysrhythmias treated with Class IA and III anti-dysrhythmic medicines (see sections 4.4).
• Pharmacokinetic/pharmacodynamic studies between GEODON IM and other medicines that prolong the QT interval have not been performed. An additive effect of GEODON IM and other medicines that prolong the QT interval cannot be excluded. Therefore, GEODON IM should not be given with dofetilide, sotalol, quinidine, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus. GEODON IM is also contraindicated with medicines that have demonstrated QT prolongation as one of their pharmacodynamic effects (see section 4.4).
• Pregnancy and lactation, as teratogenicity has been demonstrated in animal studies (see section 4.6).
• The safety and efficacy of GEODON IM injection has not been evaluated in children under the age of 18 years.

QT interval

GEODON IM use should be avoided in combination with other medicines that are known to prolong the QT c interval (see section 4.3 and section 4.5). Additionally, medical practitioners should be alert to the identification of other medicines that have been consistently observed to prolong the QT c interval. Such medicines should not be prescribed with GEODON IM. GEODON IM should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac dysrhythmias (see section 4.3).

A study directly comparing the QT/QT c prolonging effect of oral GEODON IM with several other medicines effective in the treatment of schizophrenia was conducted in patient volunteers. In the first phase of the trial, ECGs were obtained at the time of maximum plasma concentration when the medicine was administered alone. In the second phase of the trial, ECGs were obtained at the time of maximum plasma concentration while the medicine was co-administered with an inhibitor of the CYP4503A4 metabolism of the medicine. In the first phase of the study, the mean change in the QT c from baseline was calculated for each medicine, using a sample-based correction that removes the effect of heart rate on the QT interval. The mean increase in QT c from baseline for GEODON IM ranged from approximately 9 to 14 msec greater than for four of the comparator medicines (risperidone, olanzapine, quetiapine and haloperidol), but was approximately 14 msec less than the prolongation observed for thioridazine. In the second phase of the study, the effect of GEODON IM on QT c length was not augmented by the presence of a metabolic inhibitor (ketoconazole 200 mg twice daily).

In placebo-controlled trials, oral GEODON IM increased the mean QT c interval compared to placebo by approximately 10 msec at the highest recommended daily dose of 160 mg. Patients with low serum potassium and/or magnesium should be repleted with those electrolytes before proceeding with treatment. It is essential to periodically monitor serum electrolytes in patients for whom diuretic therapy is introduced during GEODON IM treatment. Persistently prolonged QT c intervals may also increase the risk of further prolongation and dysrhythmia, but it is not clear that routine screening ECG measures are effective in detecting such patients. Rather, GEODON IM should be avoided in patients with histories of significant cardiovascular illness e.g. QT prolongation, recent acute myocardial infarction, uncompensated heart failure or cardiac dysrhythmia (see section 4.3). GEODON IM should be discontinued in patients who are found to have persistent QT c measurements > 500 msec. For patients taking GEODON IM who experience symptoms that could indicate the occurrence of torsade de pointes e.g. dizziness, palpitations, or syncope, the medical practitioner should initiate further evaluation e.g. Holter monitoring may be useful. There have been post-marketing reports of torsade de pointes in patients with multiple confounding risk factors taking GEODON IM. A causal relationship with GEODON IM has not been established.

Elderly (> 65 years)

Elderly patients have not been included in clinical trials in sufficient numbers. Thus, no recommendations as regards dosing could be given and intramuscular treatment in these patients is not recommended.

Neuroleptic malignant syndrome (NMS)

Neuroleptic malignant syndrome (NMS), a potentially fatal complex has been reported in association with GEODON IM. The management of NMS should include immediate discontinuation of all antipsychotic medication, including GEODON IM.

Severe cutaneous adverse reactions

Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with GEODON IM exposure. DRESS consists of a combination of three or more of the following: cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, lymphadenopathy and one or more systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis. Other severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported with GEODON IM exposure. Severe cutaneous adverse reactions are sometimes fatal. Discontinue GEODON IM if severe cutaneous adverse reactions occur.

Cardiovascular disease

Safety and effectiveness in patients with cardiovascular disease have not been established (see section 4.3).

Blood pressure

Dizziness, tachycardia and postural hypotension are not unusual in patients following intramuscular administration of GEODON IM. Single cases of hypertension have also been reported. Caution should be exercised, particularly in ambulatory patients.

Tardive dyskinesia

Although in clinical trials the incidence of treatment emergent tardive dyskinesia was comparable in patients receiving GEODON IM and placebo, the risk of tardive dyskinesia may increase with long-term exposure. Therefore, if signs or symptoms of tardive dyskinesia appear in a patient on GEODON IM, a dose reduction or medicine discontinuation should be considered. These symptoms can temporarily deteriorate or even arise after discontinuation of treatment.

Falls

GEODON IM may cause somnolence, dizziness, postural hypotension, gait disturbance, which may lead to falls. Caution should be taken when treating patients at higher risk, and a lower starting dose should be considered (e.g. elderly or debilitated patients) (see section 4.2).

Seizures

Caution is recommended when treating patients with a history of seizures.

Increased mortality in elderly patients with dementia-related psychosis

Elderly patients with dementia-related psychosis have been shown to be at an increased risk of death and/or potentially, cerebrovascular adverse events compared with placebo when treated with some atypical antipsychotic medicines. GEODON IM is not approved for the treatment of elderly patients with dementia-related psychosis.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicines. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with GEODON IM and preventive measures undertaken.

Priapism

Cases of priapism have been reported with antipsychotic use, including GEODON IM. This adverse reaction, as with other psychotropic medicines, did not appear to be dose-dependent and did not correlate with the duration of treatment.

Post-marketing reports of mortality

Fatalities with the use of GEODON IM, generally in patients with multiple confounding risk factors, have been reported. Although a causal relationship has not been established, GEODON IM should be used with caution.

Suicide

Close supervision of high-risk patients for suicide should accompany medicine therapy.

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar non-ketotic coma or death, has been reported in patients treated with GEODON IM. Patients with an established diagnosis of diabetes mellitus who are started on GEODON IM should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with GEODON IM should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycaemia during treatment with GEODON IM should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when GEODON IM was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect medicine.

GEODON IM contains sodium GEODON IM contains less than 1 mmol sodium (23 mg) per mL of reconstituted solution for injection. Patients on low sodium diets can be informed that this medicine is essentially u2018sodium freeu2019.

Class IA and III anti-dysrhythmics u2013 see section 4.3 and section 4.4.

Concomitant use with other medicines that prolong QT interval u2013 see section 4.4.

CNS medicines/alcohol

Given the primary CNS effects of GEODON IM, caution should be used when it is taken in combination with other centrally acting medicines, including alcohol and medicines acting on the dopaminergic and serotonergic systems.

Effect of GEODON IM on other medicines

All interaction studies have been conducted with oral GEODON. An in vivo study with dextromethorphan showed no marked inhibition with CYP2D6 at plasma concentrations 50 % lower than those obtained after 40 mg GEODON twice daily. In vitro data indicated that GEODON may be a modest inhibitor of CYP2D6 and CYP3A4. However, it is unlikely that GEODON will affect the pharmacokinetics of medicines metabolised by these cytochrome P450 isoforms to a clinically relevant extent.

Oral contraceptives u2013 GEODON administration resulted in no significant change to the pharmacokinetics of estrogen (ethinyl estradiol, a CYP3A4 substrate) or progesterone components.

Lithium u2013 Co-administration of GEODON had no effect on the pharmacokinetics of lithium.

Effects of other medicines on GEODON IM

The CYP3A4 inhibitor ketoconazole (400 mg/day) increased the serum concentrations of GEODON by < 40 %. The serum concentrations of S-methyl-dihydroziprasidone and ziprasidone sulphoxide, at the expected T max of GEODON, were increased by 55 % and 8 % respectively. No additional QT c prolongation was observed. Changes in pharmacokinetics due to co-administration of potent CYP3A4 inhibitors are unlikely to be of clinical importance.

Carbamazepine therapy, 200 mg twice daily for 21 days, resulted in a decrease of approximately 35 % in the exposure to GEODON.

Antacid u2013 multiple doses of aluminium and magnesium containing antacid or cimetidine did not affect the pharmacokinetics of GEODON.

Serotonergic medicines

In isolated cases, there have been reports of serotonin syndrome temporally associated with the therapeutic use of GEODON in combination with other serotonergic medicines such as SSRIs (see section 4.8). The features of serotonin syndrome can include confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea.

Protein binding

GEODON extensively binds to plasma proteins. The in vitro plasma protein binding of GEODON was not altered by warfarin or propranolol, two highly protein-bound medicines, nor did GEODON alter the binding of these medicines in human plasma. Thus, the potential for medicine interactions with GEODON due to displacement is unlikely.

Pregnancy

GEODON IM is not recommended in pregnancy and lactation (see section 4.3). Safety in pregnancy and lactation has not been demonstrated u2013 teratogenicity was demonstrated in animal studies (see section 4.3).

Women of childbearing potential

Women of childbearing potential receiving GEODON IM should use an appropriate method of contraception.

Breastfeeding

There are no adequate and well-controlled studies in lactating women. A single case report found that GEODON IM was detectable in breast milk. Patients should be advised not to breastfeed an infant if they are receiving GEODON IM.

Administration of GEODON IM results in somnolence. Patients should be instructed not to drive or operate machines until this effect has resolved.

Summary of the safety profile

The table below contains adverse events with possible, probable or unknown relationship to GEODON IM in flexible dose phase 2/3 trials. The most common reactions were nausea, sedation, dizziness, injection site pain, headache and somnolence.

Tabulated summary of adverse reactions

All adverse reactions are listed by class and frequency: Very common (u2265 1/10); common (u2265 1/100 to <1/10); uncommon (u2265 1/1 000 to <1/100); rare ( u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data). Some of the symptoms reported as adverse reactions may be associated symptoms of underlying disease.

System organ class Frequency Adverse reaction

Immune system disorders Not known Anaphylactic reaction

Metabolism and nutrition disorders Uncommon Decreased appetite

Psychiatric disorders Common Agitation

Uncommon Psychotic disorder, antisocial behaviour, tic, personality disorder, psychosis

Nervous system disorders Common Extrapyramidal disorder, akathisia, tremor, somnolence, headache, dizziness, sedation

Uncommon Dyskinesia, parkinsonism, cogwheel rigidity, dysarthria, dyspraxia, postural dizziness, aphasia

Ear and labyrinth disorders Uncommon Vertigo

Cardiac disorders Uncommon Bradycardia

Vascular disorders Common Hypertension

Uncommon Flushing

Respiratory, thoracic and mediastinal disorders Uncommon Laryngospasm

Gastrointestinal disorders Common Nausea, constipation, dry mouth

Uncommon Diarrhoea, loose stools

Skin and subcutaneous tissue disorders Uncommon Hyperhidrosis

Musculoskeletal and connective tissue disorders Common Muscle rigidity

Renal and urinary disorders Rare Dysuria

General disorders and administration site conditions Common Asthenia, injection site pain, injection site burning, fatigue

Uncommon Medicine withdrawal syndrome, influenza like illness, injection site discomfort, injection site irritation

Investigations Uncommon Decreased blood pressure, increased hepatic enzyme

In short-term and long-term GEODON IM clinical trials, the incidence of seizures and hypotension was uncommon, occurring in less than 1 % of GEODON IM-treated patients. In long-term maintenance treatment in clinical trials, prolactin levels in patients treated with GEODON IM were sometimes elevated, but, in most patients, returned to normal ranges without cessation of treatment. In addition, potential clinical manifestation (e.g. gynaecomastia and breast enlargement) was rare.

Post-marketing experience

The following adverse events have been reported during post-marketing experience:

System organ class Adverse reaction

Immune system disorders Hypersensitivity

Psychiatric disorders Insomnia, mania, hypomania

Nervous system disorders Dystonia, syncope, neuroleptic malignant syndrome, serotonin syndrome, tardive dyskinesia, facial droop

Cardiac disorders Tachycardia, torsade de pointes

Vascular disorders Hypotension, orthostatic hypotension, venous embolism

Gastrointestinal disorders Vomiting, dysphagia, tongue oedema

Skin and subcutaneous tissue disorders Allergic reaction, rash, drug reaction with eosinophilia and systemic symptoms (DRESS), angioedema

Renal and urinary disorders Urinary incontinence, enuresis

Reproductive system and breast disorders Priapism, galactorrhoea

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Experience with GEODON IM overdosage is limited. With oral dosing, the largest confirmed single ingestion is 12 800 mg. In this case, extrapyramidal symptoms and a QT c interval of 446 msec (with no cardiac sequelae) were reported. In overdose cases in general, the most commonly reported symptoms are extrapyramidal symptoms, somnolence, tremor and anxiety. In cases of acute overdosage, establish and maintain an airway and ensure adequate ventilation and oxygenation. The possibility of obtundation, seizures or dystonic reaction of the head and neck following overdosage may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible dysrhythmias. There is no specific antidote to GEODON IM.