TRUVALIN Film-coated tablet Ref.[51197] Active ingredients: Quetiapine

Suicide/suicidal thoughts or clinical worsening

Depression 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.

Other psychiatric conditions for which TRUVALIN is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may co-morbid with major depression disorder. The same precaution observed when treating patients with major depressive disorder should therefore be observed when treating with other psychiatric disorders.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment.

Neutropenia and agranulocytosis

Severe neutropenia (<0,5 X 10⁹/L) without infection has been uncommonly reported in short-term placebo-controlled monotherapy quetiapine clinical trials. There have been reports of agranulocytosis (severe neutropenia with infection) among all patients treated with TRUVALIN during clinical trials (rare) as well as post-marketing reports (including fatal cases). Most of these cases of severe neutropenia have occurred within the first two months of starting therapy with quetiapine. There was no apparent dose relationship. Possible risk factors for neutropenia include pre-existing low white cell count (WBC) and history of drug induced neutropenia.

There have been cases of agranulocytosis in patients without pre-existing risk factors. Neutropenia should be considered in patients presenting with infection, particularly in the absence of obvious predisposing factor(s), or in patients with unexplained fever, and should be managed as clinically appropriate.

TRUVALIN should be discontinued in patients with a neutrophil count <1,0 X 10⁹/L. These patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1,5 X 10⁹/L) (see section 4.8).

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including TRUVALIN.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics such as TRUVALIN 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 atypical antipsychotics such as TRUVALIN should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness.

Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics such as TRUVALIN should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic such as TRUVALIN was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect medicine.

Lipids

Increases in triglycerides and cholesterol and decreases in HDL have been observed with TRUVALIN (see section 4.8). Lipid changes should be managed as clinically appropriate.

Metabolic factors

In some patients, a worsening of more than one of the metabolic factors of weight, blood glucose and lipids was observed in clinical studies. Changes in these parameters should be managed as clinically appropriate.

Pancreatitis

Pancreatitis has been reported in clinical trials and during the post marketing experience. Among the 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 (see section 4.4 Lipids), gallstones and alcohol consumption.

Concomitant illness

TRUVALIN should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. TRUVALIN may induce orthostatic hypotension, especially during the initial dose-titration period; this is more common in elderly patients than in younger patients.

In patients who have a history of or are at risk for sleep apnoea and are receiving concomitant central nervous system (CNS) depressants, TRUVALIN should be used with caution.

Dysphagia

Dysphagia (see section 4.8) and aspiration have been reported with TRUVALIN. TRUVALIN should be used with caution in patients at risk for aspiration pneumonia.

Constipation and intestinal obstruction

Constipation represents a risk factor for intestinal obstruction. Constipation and intestinal obstruction have been reported with TRUVALIN (see section 4.8). This includes fatal reports in patients who are at higher risk of intestinal obstruction, including those that are receiving multiple concomitant medications that decrease intestinal motility and/or may not report symptoms of constipation. Patients with intestinal obstruction/ileus should be managed with close monitoring and urgent care.

Seizures

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

Tardive dyskinesia and Extrapyramidal Symptoms (EPS)

There is a potential for TRUVALIN to cause tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, discontinuation of TRUVALIN should be considered.

In placebo-controlled clinical trials of adult patients with schizophrenia and bipolar mania, the incidence of extrapyramidal symptoms was no different from that of placebo across the recommended therapeutic dose range. This predicts that TRUVALIN has less potential than typical antipsychotic agents to induce tardive dyskinesia in schizophrenia and bipolar mania patients. In short-term placebo-controlled clinical trials for bipolar depression, the incidence of EPS was higher in TRUVALIN treated patients than in placebo treated patients (see section 4.8).

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome has been associated with TRUVALIN treatment. Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, TRUVALIN should be discontinued and appropriate medical treatment given.

QT prolongation

In clinical trials, TRUVALIN was not associated with a persistent increase in QTc intervals. However, caution should be exercised when TRUVALIN is prescribed with medicines known to prolong the QTc interval, especially in the elderly.

Cardiomyopathy and Myocarditis

Cardiomyopathy and myocarditis have been reported in clinical trials and during the post-marketing experience. Treatment with TRUVALIN should be reassessed in patients with suspected cardiomyopathy or myocarditis.

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Acute Generalised Exanthematous Pustulosis (AGEP), Erythema multiforme (EM) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) are potentially life-threatening adverse drug reactions that have been reported during TRUVALIN exposure. SCARs commonly present with one or more of the following symptoms: extensive cutaneous rash which may be pruritic or associated with pustules, exfoliative dermatitis, fever, lymphadenopathy and possible eosinophilia or neutrophilia. Discontinue TRUVALIN if severe cutaneous adverse reactions occur.

Withdrawal

Acute withdrawal symptoms such as insomnia, nausea, and vomiting have been described after abrupt cessation of antipsychotic medicines, including TRUVALIN. Gradual withdrawal over a period of at least 1-2 weeks is advisable.

Misuse and abuse

Cases of misuse and abuse have been reported. Caution may be needed when prescribing quetiapine to patients with a history of alcohol or drug abuse.

Elderly patients with dementia

Before prescribing, medical practitioners are advised to carefully assess the risks and benefits of the use of atypical antipsychotics in elderly patients with dementia.

TRUVALIN is not approved for the treatment of dementia-related psychosis. In a meta-analysis of atypical antipsychotic medicines, it has been reported that elderly patients with dementia-related psychosis are at an increased risk of death compared to placebo. In two 10-week placebo-controlled quetiapine studies in the same patient population (n=710; mean age: 83 years; range: 56-99 years) the incidence of mortality in quetiapine treated patients was 5,5% versus 3,2% in the placebo group.

Anti-cholinergic (muscarinic) effects

Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to ADRs reflecting anti-cholinergic effects when TRUVALIN is used at recommended doses, when used concomitantly with other medications having anticholinergic effects, and in the setting of overdose. TRUVALIN should be used with caution in patients receiving medications having anti-cholinergic (muscarinic) effects. TRUVALIN 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 (see sections 4.5, 4.8, 5.1, and 4.9).

Lactose

TRUVALIN contains lactose. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, or glucose-galactose malabsorption should not take TRUVALIN.

Given the primary central nervous system effects of TRUVALIN, TRUVALIN should be used with caution in combination with other centrally acting medicines and alcohol.

Caution should be exercised when TRUVALIN is used concomitantly with medicines known to cause electrolyte imbalance or to increase QT interval (see section 4.4).

Caution should be exercised treating patients receiving other medications having anti-cholinergic (muscarinic) effects (see section 4.4).

The pharmacokinetics of lithium were not altered when co-administered with TRUVALIN.

The pharmacokinetics of sodium valproate and TRUVALIN were not altered to a clinically relevant extent when co-administered.

The pharmacokinetics of TRUVALIN were not significantly altered following co-administration with the antipsychotics, risperidone or haloperidol. However, co-administration of TRUVALIN and thioridazine caused increases in clearance of TRUVALIN.

TRUVALIN did not induce the hepatic enzyme systems involved in the metabolism of antipyrine. In a multiple dose trial in patients to assess the pharmacokinetics of TRUVALIN given before and during treatment with carbamazepine (a known hepatic enzyme inducer), co-administration of carbamazepine significantly increased the clearance of TRUVALIN. This increase in clearance reduced systemic TRUVALIN exposure (as measured by AUC) to an average of 13% of the exposure during administration of TRUVALIN alone; although a greater effect was seen in some patients. As a consequence of this interaction, lower plasma concentrations can occur and hence, in each patient, consideration for a higher dose of TRUVALIN, depending on clinical response, should be considered. It should be noted that the recommended maximum daily dose of TRUVALIN is 750 mg/day, for the treatment of schizophrenia, and 800 mg/day for the treatment of manic episodes associated with bipolar disorder.

Continued treatment at higher doses should only be considered as a result of careful consideration of the benefit risk assessment for an individual patient. Co-administration of TRUVALIN and with another microsomal enzyme inducer, phenytoin, also caused increases in the clearance of TRUVALIN. Increased doses of TRUVALIN may be required to maintain control of psychotic symptoms in patients co-administered TRUVALIN and phenytoin and other hepatic enzyme inducers (e.g. barbiturates, rifampicin etc). The dose of TRUVALIN may need to be reduced if phenytoin, carbamazepine or other hepatic enzyme inducers are withdrawn and replaced with a non-inducer (e.g. sodium valproate).

CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of TRUVALIN. The pharmacokinetics of TRUVALIN were not altered following co-administration with cimetidine or fluoxetine, both of which are known P450 enzyme inhibitors. The pharmacokinetics of TRUVALIN were not significantly altered following co-administration with the antidepressants imipramine (a known CYP2D6 inhibitor) or fluoxetine (a known CYP3A4 and CYP2D6 inhibitor). In a multiple-dose trial in healthy volunteers to assess the pharmacokinetics of TRUVALIN given before and during treatment with ketoconazole, co-administration of ketoconazole resulted in an increase in mean C_max and AUC of TRUVALIN of 235% and 522%, respectively, with a corresponding decrease in mean oral clearance of 84%. The mean half-life of TRUVALIN increased from 2,6-6,8 hours, but the mean tmax was unchanged. Due to the potential for an interaction of similar magnitude in a clinical setting, the dosage of TRUVALIN should be reduced during concomitant use of TRUVALIN and potent CYP3A4 inhibitors (such as azole antifungals, macrolide antibiotics and protease inhibitors).

There have been reports of false positive results in enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken TRUVALIN. Confirmation of questionable immunoassay screening results by an appropriate chromatographic technique is recommended.

Pregnancy

TRUVALIN is contraindicated during pregnancy and lactation, as safety has not been demonstrated. Following some pregnancies in which quetiapine was used, neonatal withdrawal symptoms have been reported.

Breastfeeding

There have been published reports of quetiapine excretion into human breast milk, however the degree of excretion was not consistent.

TRUVALIN may cause somnolence which may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery, until individual susceptibility is known.

a. Summary of the safety profile

The most commonly reported adverse drug reactions (ADRs) with TRUVALIN (≥10%) 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.

b. Tabulated summary of adverse reactions

^a See section 4.4 Special warnings and precautions for use
^b Somnolence may occur, usually during the first 2 weeks of treatment and generally resolves with the continued administration of TRUVALIN.
^c Based on ≥7% increase in body weight from baseline. Occurs predominantly during the early weeks of treatment.
^d Asymptomatic elevations (shift from normal to ≥3X ULN at any time) in serum transaminase (ALT, AST) or gamma-GT-levels have been observed in patients administered TRUVALIN. These elevations were usually reversible on continued TRUVALIN treatment.
^e TRUVALIN may induce orthostatic hypotension, associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period.
^f Manifestations of hypersensitivity may include angioedema, anaphylaxis and urticaria/rash
^g In all short-term placebo-controlled monotherapy trials among patients with a baseline neutrophil count ≥1,5 X 10⁹/L, the incidence of at least one occurrence of neutrophil count <1,5 X 10⁹/L, was 1,9% in patients treated with quetiapine compared to 1,5% in placebo-treated patients. The incidence >0,5 - <1,0 × 10⁹/L was 0,2% in patients treated with quetiapine and 0,2% in placebo-treated patients. In clinical trials conducted prior to a protocol amendment for discontinuation of patients with treatment- emergent neutrophil count <1,0 × 10⁹/L, among patients with a baseline neutrophil count ≥1,5 X 10⁹/L, the incidence of at least one occurrence of neutrophil count <0,5 X 10⁹/L was 0,21% in patients treated with quetiapine and 0% in placebo treated patients.
^h Fasting blood glucose ≥126 mg/dL or a non-fasting blood glucose ≥200 mg/dL on at least one occasion.
ⁱ An increase in the rate of dysphagia with quetiapine vs. placebo was only observed in the clinical trials in bipolar depression.
^j In acute placebo-controlled, monotherapy clinical trials, which evaluated discontinuation symptoms, the aggregated incidence of discontinuation symptoms after abrupt cessation was 12,1% for quetiapine and 6,7% for placebo. The aggregated incidence of the individual adverse events (e.g., insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability) did not exceed 5,3% in any treatment group and usually resolved after 1 week post-discontinuation.
^k Triglycerides ≥200 mg/dL (patients ≥18 years of age) or ≥150 mg/dL (patients <18 years of age) on at least one occasion.
^l Cholesterol ≥240 mg/dL (patients ≥18 years of age) or ≥200 mg/dL (patients <18 years of age) on at least one occasion.
^m Based on clinical trial adverse event reports of blood creatine phosphokinase increase not associated with neuroleptic malignant syndrome.
ⁿ Platelets ≤100 × 10⁹/L on at least one occasion.
o Prolactin levels (patients ≥18 years of age): >20 μg/L males; >30 μg/L females at any time.
^p See text below in sub-heading "c. Description of selected adverse reactions"
^q May lead to falls.
^r HDL cholesterol: <40 mg/dL males; <50 mg/dL females at any time.
^s Decreased haemoglobin to ≤13 g/dL males, ≤12 g/dL females on at least one occasion occurred in 11% of quetiapine patients in all trials including open label extensions. In short term placebo-controlled trials, decreased haemoglobin to ≤13 g/dL males, ≤12 g/dL females on at least one occasion occurred in 8,3% of quetiapine patients compared to 6,2% of placebo patients.
^t These reports often occurred in the setting of tachycardia, dizziness, orthostatic hypotension, and/or underlying cardiac/respiratory disease.
^u Based on shifts from normal baseline to potentially clinically important value at any time postbaseline in all trials. Shifts in total T4, free T4, total T3 and free T3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is >5 mIU/L at any time.
^v Based upon the increased rate of vomiting in elderly patients (≥65 years of age).
^w Based on shifts from normal baseline to potentially clinically important value at any time postbaseline in all trials. Shifts in eosinophils are defined as ≥1 × 10⁹ cells/L at any time.
^x Based on shifts from normal baseline to potentially clinically important value at any time postbaseline in all trials. Shifts in WBCs are defined as ≤3 X 10⁹ cells/L at any time.
^y May occur at or near initiation of treatment and be associated with hypotension and/or syncope. Frequency based on adverse event reports of bradycardia and related events in all clinical trials with quetiapine.
^z Based on the frequency of patients during all quetiapine clinical trials with severe neutropenia (<0.5 × 10⁹/L) and infection.
^aa See section 4.6 Pregnancy and lactation.
^ab During post-marketing experience, resolution of leucopenia and/or neutropenia usually followed cessation of therapy with TRUVALIN. Possible risk factors for leucopenia and/or neutropenia include pre-existing low white cell count and history of medicine induced leucopenia and/or neutropenia. Other adverse events reported since market introduction, which weretemporally related to quetiapine therapy, but not necessarily causally related, include agranulocytosis.

c. Description of selected adverse reactions

TRUVALIN treatment was associated with dose-related decreases in thyroid hormone levels. In short term placebo-controlled clinical trials, the incidence of potentially clinically significant shifts in thyroid hormone levels were total T4: 3,4% for quetiapine versus 0,6% for placebo; free T4: 0,7% for quetiapine versus 0,1% for placebo; total T3: 0,54% for quetiapine versus 0,0% for placebo and free T3: 0,2% for quetiapine versus 0,0% for placebo. The incidence of shifts in TSH was 3,2% for quetiapine versus 2,7% for placebo. In short term placebo-controlled monotherapy trials, the incidence of reciprocal, potentially clinically significant shifts in T3 and TSH was 0,0% for both quetiapine and placebo and 0,1% for quetiapine versus 0,0% for placebo for shifts in T4 and TSH. These changes in thyroid hormone levels are generally not associated with clinically symptomatic hypothyroidism. The reduction in total and free T4 was maximal within the first six weeks of TRUVALIN treatment, with no further reduction during long-term treatment. There was no evidence of clinically significant changes in TSH concentration over time. In nearly all cases, cessation of TRUVALIN treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment. In eight patients, where TBG was measured levels of TBG were unchanged.

Extrapyramidal symptoms (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity and tremor) occur at an incidence similar to placebo and are not dose related.

TRUVALIN may cause prolongation of the QTc interval (see section 4.4).

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 “6.04 Adverse Drug Reaction Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8

Not applicable.