Rostrum XR

Uses

• Treatment of schizophrenia.
• Treatment of bipolar disorder:
• 1) For the treatment of moderate to severe manic episodes in bipolar disorder
• 2) For the treatment of major depressive episodes in bipolar disorder
• 3) For the prevention of recurrence of manic or depressed episodes in patients with bipolar disorder who previously responded to Rostrum XR Fumarate treatment.

Rostrum XR is also used to associated treatment for these conditions: Acute Depressive Episode, Bipolar 1 Disorder, Generalized Anxiety Disorder (GAD), Major Depressive Disorder (MDD), Mixed manic depressive episode, Post Traumatic Stress Disorder (PTSD), Psychosis, Schizophrenia, Acute Manic episode

How Rostrum XR works

Although the mechanism of action of quetiapine is not fully understood, several proposed mechanisms exist. In schizophrenia, its actions could occur from the antagonism of dopamine type 2 (D2) and serotonin 2A (5HT2A) receptors. In bipolar depression and major depression, quetiapine's actions may be attributed to the binding of this drug or its metabolite to the norepinephrine transporter. Additional effects of quetiapine, including somnolence, orthostatic hypotension, and anticholinergic effects, may result from the antagonism of H1 receptors, adrenergic α1 receptors, and muscarinic M1 receptors, respectively.

Dosage

Rostrum XR dosage

Adults For the treatment of schizophrenia: For the treatment of schizophrenia, Rostrum XR Fumarate should be administered twice a day. The total daily dose for the first four days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). From Day 4 onwards, the dose should be titrated to the usual effective dose of 300 to 450 mg/day. Depending on the clinical response and tolerability of the individual patient, the dose may be adjusted within the range 150 to 750 mg/day.

For the treatment of moderate to severe manic episodes in bipolar disorder: For the treatment of manic episodes associated with bipolar disorder, Rostrum XR Fumarate should be administered twice a day. The total daily dose for the first four days of therapy is 100 mg (Day 1), 200 mg (Day 2), 300 mg (Day 3) and 400 mg (Day 4). Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day. The dose may be adjusted depending on clinical response and tolerability of the individual patient, within the range of 200 to 800 mg/day. The usual effective dose is in the range of 400 to 800 mg/day.

For the treatment of major depressive episodes in bipolar disorder: Rostrum XR Fumarate should be administered once daily at bedtime. The total daily dose for the first four days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). The recommended daily dose is 300 mg. In clinical trials, no additional benefit was seen in the 600 mg group compared to the 300 mg group.

Individual patients may benefit from a 600 mg dose. Doses greater than 300 mg should be initiated by physicians experienced in treating bipolar disorder. In individual patients, in the event of tolerance concerns, clinical trials have indicated that dose reduction to a minimum of 200 mg could be considered.

For preventing recurrence in bipolar disorder: For preventing recurrence of manic, mixed or depressive episodes in bipolar disorder, patients who have responded to Rostrum XR Fumarate for acute treatment of bipolar disorder should continue therapy at the same dose. The dose may be adjusted depending on clinical response and tolerability of the individual patient, within the range of 300 to 800 mg/day administered twice daily. It is important that the lowest effective dose is used for maintenance therapy.

Elderly As with other antipsychotics, Rostrum XR Fumarate should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration may need to be slower, and the daily therapeutic dose lower, than that used in younger patients, depending on the clinical response and tolerability of the individual patient. The mean plasma clearance of quetiapine was reduced by 30-50% in elderly subjects when compared to younger patients.

Paediatric population: Rostrum XR Fumarate is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group.

Renal impairment: Dosage adjustment is not necessary in patients with renal impairment.

Hepatic impairment: Patients with known hepatic impairment should be started with 25 mg/day. The dosage should be increased daily with increments of 25 – 50 mg/day until an effective dosage, depending on the clinical response and tolerability of the individual patient.

Rostrum XR Fumarate can be administered with or without food.

Side Effects

The most commonly reported Adverse Drug Reactions (ADRs) with Rostrum XR Fumarate are somnolence, dizziness, dry mouth, withdrawal (discontinuation) symptoms, elevations in serum triglyceride levels, elevations in total cholesterol (predominantly LDL cholesterol), decreases in HDL cholesterol, weight gain, decreased haemoglobin and extrapyramidal symptoms.

Toxicity

The oral LD50 if quetiapine in rats is 2000 mg/kg.

Overdose information

Some signs and symptoms of a quetiapine overdose include sedation, drowsiness, tachycardia, and hypotension. Clinical trials demonstrate that overdoses of up to 30 grams of quetiapine did not result in death. A lethal outcome was reported in a clinical trial after an overdose of 13.6 grams of quetiapine. In the case of an acute overdose, ensure to maintain an airway and provide adequate ventilation and oxygenation. Gastric lavage following intubation (if necessary) along with activated charcoal and a laxative may be considered. The possibility of obtundation, seizure or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiac monitoring should also take place.

A note on QT-interval prolongation in an overdose

Postmarketing reports reveal increases in the cardiac QT interval in cases of quetiapine overdose, concomitant illness, and in those taking drugs that increase QT interval or affect electrolyte levels. Note that disopyramide, procainamide, and quinidine may exert additive QT-prolonging effects when administered in patients who have overdosed with quetiapine, and should be avoided.

Precaution

Neuroleptic malignant syndrome, tardive dyskinesia. Hypotension and syncope, especially during the initial dose titration period. Conduct eye examinations prior to or shortly after starting Rostrum XR Fumarate and at 6-month intervals thereafter; discontinue the drug if clinically significant lens changes are observed. History of seizures. Hypothyroidism. Hyperprolactinemia. Antiemetic effect. Suicide. Use with great caution in moderate or severe hepatic impairments. Renal impairment, cardiovascular disease. Disruption of body temperature regulation. Hyperglycemia. Lactation (avoid breast-feeding).

Interaction

Caution should be exercised when Rostrum XR Fumarate is used concomitantly with medicines known to cause electrolyte imbalance or to increase QT interval. Co-administration of Rostrum XR Fumarate and thioridazine or carbamazepine caused increases in the clearance of Rostrum XR Fumarate . Co-administration of Rostrum XR Fumarate with another microsomal enzyme inducer, phenytoin, also caused increases in the clearance of Rostrum XR Fumarate.

Food Interaction

• Avoid alcohol.
• Take with or without food. If taken with food, take with a light meal.

Rostrum XR Alcohol interaction

[Minor] Rostrum XR has been reported to potentiate the cognitive and motor effects of alcohol.

The mechanism of the interaction is not known.

Alcohol should be avoided by patients who are receiving quetiapine.

Rostrum XR Cholesterol interaction

[Moderate] Atypical antipsychotic drugs have been associated with undesirable alterations in lipid levels.

While all agents in the class have been shown to produce some changes, each drug has its own specific risk profile.

Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment.

[Moderate] According to the manufacturer, patients treated with quetiapine in 3- to 6-week placebo-controlled trials had increases in cholesterol and triglyceride of 11% and 17%, respectively, compared to slight decreases in the placebo group.

Patients with preexisting hyperlipidemia may require closer monitoring during quetiapine therapy, and adjustments made accordingly in their lipid-lowering regimen.

Rostrum XR Hypertension interaction

[Moderate] The use of quetiapine may be associated with in increase systolic and diastolic blood pressure in children and adolescents.

During the 26 week open-label clinical trial, one child with a reported history of hypertension experienced a hypertensive crisis.

Blood pressure in children and adolescents should be measured at the beginning of, and periodically during treatment with quetiapine.

Rostrum XR Drug Interaction

Major: escitalopramModerate: aripiprazole, duloxetine, lithium, pregabalin, metoprolol, metoprolol, albuterol, lisdexamfetamine, alprazolam, sertralineUnknown: amphetamine / dextroamphetamine, aspirin, omega-3 polyunsaturated fatty acids, lamotrigine, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

Rostrum XR Disease Interaction

Major: dementia, QT Prolongation, acute alcohol intoxication, CNS depression, NMS, tardive dyskinesiaModerate: depression, aspiration, seizure, hematologic abnormalities, hyperglycemia/diabetes, hypotension, lipid alterations, priapism, weight gain, hyperprolactinemia, liver disease, parkinsonism, ALT elevations, cataracts, hyperlipidemia, hypothyroidism, increase systolic and diastolic blood pressure

Volume of Distribution

Rostrum XR distributes throughout body tissues. The apparent volume of distribution of this drug is about 10±4 L/kg.

Elimination Route

Rostrum XR is rapidly and well absorbed after administration of an oral dose. Steady-state is achieved within 48 hours Peak plasma concentrations are achieved within 1.5 hours. The bioavailability of a tablet is 100%. The steady-state Cmax of quetiapine in Han Chinese patients with schizophrenia after a 300 mg oral dose of the extended released formulation was approximately 467 ng/mL and the AUC at steady-state was 5094 ng·h/mL. Absorption of quetiapine is affected by food, with Cmax increased by 25% and AUC increased by 15%.

Half Life

The average terminal half-life of quetiapine is about 6-7 hours.

Clearance

The clearance of quetiapine healthy volunteers in the fasted state during a clinical study was 101.04±39.11 L/h. Elderly patients may require lower doses of quetiapine, as clearance in these patients may be reduced by up to 50%. Those with liver dysfunction may also require lower doses.

Elimination Route

After an oral dose of radiolabeled quetiapine, less than 1% of unchanged drug was detected in the urine, suggesting that quetiapine is heavily metabolized. About 73% of a dose was detected in the urine, and about 20% in the feces.

Pregnancy & Breastfeeding use

First trimester: Rostrum XR Fumarate should only be used during pregnancy if the benefits justify the potential risks.

Third trimester: Neonates exposed to antipsychotics (including Rostrum XR Fumarate) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully. Breast-feeding: Due to lack of robust data, a decision must be made whether to discontinue breast-feeding or to discontinue Rostrum XR Fumarate therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Contraindication

Known hypersensitivity to this medication or any of its ingredients.

Special warnings and precautions for use: As Rostrum XR has several indications, the safety profile should be considered with respect to the individual patient’s diagnosis and the dose being administered.

Paediatric population: Rostrum XR is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group.

Suicide/suicidal thoughts or clinical worsening: Depression in bipolar disorder is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Metabolic Risk: Given the observed risk for worsening of their metabolic profile, including changes in weight, blood glucose and lipids, which was seen in clinical studies, patients’ metabolic parameters should be assessed at the time of treatment initiation and changes in these parameters should be regularly controlled for during the course of treatment. Worsening in these parameters should be managed as clinically appropriate.

Extrapyramidal symptoms: The use of quetiapine has been associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Tardive dyskinesia: If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of quetiapine should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment.

Somnolence and dizziness: Patients experiencing somnolence of severe intensity may require more frequent contact for a minimum of 2 weeks from onset of somnolence, or until symptoms improve and treatment discontinuation may need to be considered.

Orthostatic hypotension: Rostrum XR treatment has been associated with orthostatic hypotension and related dizziness which, like somnolence has onset usually during the initial dose-titration period. Rostrum XR should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. Dose reduction or more gradual titration should be considered if orthostatic hypotension occurs, especially in patients with underlying cardiovascular disease.

Sleep apnoea syndrome: In patients receiving concomitant central nervous system depressants and who have a history of or are at risk for sleep apnoea, such as those who are overweight/obese or are male, quetiapine should be used with caution.

Seizures: As with other antipsychotics, caution is recommended when treating patients with a history of seizures.

Neuroleptic malignant syndrome: In such an event, quetiapine should be discontinued and appropriate medical treatment given.

Anti-cholinergic (muscarinic) effects: Nor quetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. Rostrum XR should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, intestinal obstruction or related conditions, increased intraocular pressure or narrow angle glaucoma.

Interactions: Concomitant use of quetiapine with a strong hepatic enzyme inducer such as carbamazepine or phenytoin substantially decreases quetiapine plasma concentrations, which could affect the efficacy of quetiapine therapy. It is important that any change in the inducer is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate).

Weight: Weight gain has been reported in patients who have been treated with quetiapine, and should be monitored and managed as clinically appropriate as in accordance with utilized antipsychotic guidelines.

Hyperglycaemia: Patients treated with any antipsychotic agent including quetiapine, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly. Lipids: Increases in triglycerides, LDL and total cholesterol, and decreases in HDL cholesterol have been observed in clinical trials with quetiapine. Lipid changes should be managed as clinically appropriate. Cardiomyopathy and myocarditis: Treatment with quetiapine should be reassessed in patients with suspected cardiomyopathy or myocarditis.

Withdrawal: Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhoea, vomiting, dizziness and irritability have been described after abrupt cessation of quetiapine. Gradual withdrawal over a period of at least one to two weeks is advisable.

Elderly patients with dementia-related psychosis: Rostrum XR is not approved for the treatment of dementia-related psychosis.

QT Prolongation: In post-marketing, QT prolongation was reported with quetiapine at the therapeutic doses and in overdose. As with other antipsychotics, caution should be exercised when quetiapine is prescribed in patients with cardiovascular disease or family history of QT prolongation. Also caution should be exercised when quetiapine is prescribed either with medicines known to increase QT interval or with concomitant neuroleptics, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia.

Dysphagia: Dysphagia has been reported with quetiapine. Rostrum XR should be used with caution in patients at risk for aspiration pneumonia.

Constipation and intestinal obstruction: Constipation represents a risk factor for intestinal obstruction. Patients with intestinal obstruction/ileus should be managed with close monitoring and urgent care.

Venous thromboembolism (VTE): Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. 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 quetiapine and preventive measures undertaken.

Pancreatitis: Pancreatitis has been reported in clinical trials and during post marketing experience. Among post marketing reports, while not all cases were confounded by risk factors, many patients had factors which are known to be associated with pancreatitis such as increased triglycerides , gallstones, and alcohol consumption.

Additional information: Rostrum XR Fumarate data in combination with divalproex or lithium in acute moderate to severe manic episodes is limited; however, combination therapy was well tolerated. The data showed an additive effect at week 3.

Lactose: Rostrum XR Fumarate Fumarate contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interaction with other medicinal products and other forms of interaction: Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the cytochrome P450 mediated metabolism of Rostrum XR Fumarate . On the basis of this, concomitant use of Rostrum XR Fumaratewith CYP3A4 inhibitors is contraindicated. It is also not recommended to consume grapefruit juice while on Rostrum XR Fumarate therapy. In a multiple dose trial in patients to assess the pharmacokinetics of Rostrum XR Fumarate given before and during treatment with carbamazepine (a known hepatic enzyme inducer), co-administration of carbamazepine significantly increased the clearance of Rostrum XR Fumarate . Co-administration of Rostrum XR Fumarate and phenytoin (another microsomal enzyme inducer) caused a greatly increased clearance of quetiapine by approx. 450%. It is important that any change in the inducer is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate). Concomitant use of quetiapine and thioridazine caused an increased clearance of Rostrum XR Fumarate with approx. 70%. The pharmacokinetics of lithium were not altered when co-administered with Rostrum XR Fumarate . The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent when co-administered. A retrospective study of children and adolescents who received valproate, Rostrum XR Fumarate or both, found a higher incidence of leucopenia and neutropenia in the combination group versus the monotherapy groups. Caution should be exercised when Rostrum XR Fumarate is used concomitantly with medicinal products known to cause electrolyte imbalance or to increase QT interval.

Special Warning

Pediatric use: Rostrum XR Fumarate is not indicated for use in children and adolescents below 18 years of age.

Elderly: As with other antipsychotics, Rostrum XR Fumarate should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration may need to be slower, and the daily therapeutic dose lower, than that used in younger patients, depending on the clinical response and tolerability of the individual patient. The mean plasma clearance of Rostrum XR Fumarate was reduced by 30% to 50% in elderly subjects when compared with younger patients.

Acute Overdose

Symptoms: In general, reported signs and symptoms were those resulting from an exaggeration of the active substance’s known pharmacological eects, i.e., drowsiness and sedation, tachycardia and hypotension. Overdose could lead to QT-prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium, and/or agitation, coma and death. Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose.

Management of overdose: In cases of severe signs, the possibility of multiple drug involvement should be considered, and intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system. Based on public literature, patients with delerium and agitation and a clear anticholinergic syndrome may be treated with physostigmine, 1-2 mg (under continuous ECG monitoring). This is not recommended as standard treatment, because of potential negative effect of physostigmine on cardiac conductance. Physostigmine may be used if there are no ECG aberrations. Do not use physostigmine in case of dysrhythmias, any degree of heart block or QRS-widening. Whilst the prevention of absorption in overdose has not been investigated, gastric lavage can be indicated in severe poisonings and if possible to perform within one hour of ingestion. The administration of activated charcoal should be considered. In cases of quetiapine overdose refractory hypotension should be treated with appropriate measures such as intravenous uids and/or sympathomimetic agents. Epinephrine and dopamine should be avoided, since beta stimulation may worsen hypotension in the setting of quetiapine-induced alpha blockade. Close medical supervision and monitoring should be continued until the patient recovers.

Storage Condition

Keep this medicine out of the sight and reach of children. • Do not use this medicine after the expiry date which is stated on the blister pack and the carton. The expiry date refers to the last day of that month. • Store in a cool and dry place away from light.

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