Tinexiflo 20 Mg Capsules

TINEXIFLO is indicated for the treatment of major depressive episodes: i.e. single episode and recurrent depression with associated anxiety. TINEXIFLO is used in the treatment of Bulimia nervosa where it has been shown to significantly decrease binge-eating and purging activity. TINEXIFLO is used in the treatment of Obsessive-compulsive disorder. The obsessions or compulsions must be experienced as intrusive, markedly distressing, time consuming or interfering significantly with the person's social or occupational functioning.

Posology
A major depressive episode
Adults and elderly: A dose of 20 mg/day is recommended, preferably in the morning.
Bulimia nervosa
A dose of 60 mg/day is recommended.
Obsessive-compulsive disorder
A dose of 20 to 60 mg/day is the recommended dose for the treatment of obsessive-compulsive disorder. The recommended dose may be increased or decreased. Doses above 80 mg/day are not recommended for any indication. Upward dose titration is advised at intervals of several weeks due to the kinetic properties of TINEXIFLO (see section 5.2).
Elderly
TINEXIFLO should be used with caution in all elderly patients, particularly if they have systemic illness or are receiving multiple medications for concomitant diseases. Dosages over 20 mg per day are not recommended (see section 5.2).
Concurrent disease
A lower or less frequent dose should be considered in patients with hepatic impairment and concurrent diseases.
Discontinuation of fluoxetine
Discontinuation of TINEXIFLO may lead to withdrawal symptoms, including dizziness, paraesthesia, headache, insomnia, tremor, confusion, sensory disturbances, agitation, anxiety and nausea (see sections 4.4 and 4.8). Abrupt discontinuation should be avoided. When stopping treatment with fluoxetine, the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see section 4.4 and section 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the medical practitioner may continue decreasing the dose, but at a more gradual rate.
Method of administration
TINEXIFLO may be administered with or without food. The capsules may be swallowed whole or be dispersed in approximately 100 ml water.

TINEXIFLO is contraindicated:
u2022 In patients with hypersensitivity to fluoxetine or to any excipients in TINEXIFLO (see section 6.1).
u2022 In children under the age of 18 years, as the safety and efficacy of TINEXIFLO has not been established.
u2022 And should not be administered to patients with severe renal failure (GFR <10 ml/min) because accumulation may occur in these patients during chronic treatment.
u2022 In concomitant use with Monoamine oxidase inhibitors (see section 4.5).
u2022 In concomitant use with Thioridazine (see section 4.5).

Patients with major depressive disorder, both adults and children, may experience worsening of their depression and/or the emergence of suicidal ideation and behaviour, whether or not they are taking antidepressant medicines. This risk may persist until significant remission occurs. The safety and efficacy of TINEXIFLO have not been established in children under the age of 18 years. In clinical trials in Major Depressive Disorder, there were increased reports of hostility and suicide-related adverse events such as suicidal ideation and self-harm. (See (see section 4.3)
Suicide
Isolated cases of suicidal ideation and suicidal behaviours have been reported during TINEXIFLO therapy or early after treatment discontinuation. Although a causal role for TINEXIFLO alone in inducing such behaviours has not been established, pooled analyses from studies of some other antidepressants in psychiatric conditions indicate a potential increased risk for suicidal ideation and suicidal behaviours in paediatric patients compared to placebo. Patients being treated with TINEXIFLO should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of therapy or at any time of dose changes, either increases or decreases. Medical Practitioners should encourage patients of all ages to report any distressing thoughts or feelings at any time.
Because of the possibility of comorbidity between major depressive disorder and other psychiatric and non-psychiatric disorders, the same precautions should be observed when treating patients with major depressive disorder when treating patients with other psychiatric and non-psychiatric disorders. The following symptoms have been reported in patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania and mania. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing TINEXIFLO in patients for whom such symptoms are severe, abrupt in onset or were not part of the patientu2019s presenting symptoms. If the decision is made to discontinue treatment, TINEXIFLO should be tapered (see section 4.2)
Serotonin syndrome
A serotonin syndrome, which may be confused with neuroleptic malignant syndrome, may occur with the use of TINEXIFLO. This syndrome is characterised by the clustering of clinical features of changes in mental state (confusion, disorientation, agitation) and neuromuscular activity (myoclonus, hyper-reflexia, tremor, rigidity, inco-ordination), in combination with auto-immune dysfunction (especially fever, sweating, diarrhoea). The serotonin syndrome has been seen in temporal association with the use of monoamine oxidase inhibitors and with other serotonergic medication, but may occur in the absence of any concomitant medication. TINEXIFLO should be stopped immediately as serious morbidity and death may follow the serotonin syndrome.
Rash and possibly allergic events
Rash, anaphylactoid events and progressive systemic events, sometimes serious and involving skin, kidney, liver or lung, have been reported in patients taking TINEXIFLO. Upon the appearance of rash or of other possibly allergic phenomena, TINEXIFLO should be discontinued.
Seizures
TINEXIFLO should be introduced cautiously in patients who have a history of seizures. TINEXIFLO should be discontinued in any patient who develops seizures. TINEXIFLO should be avoided in patients with unstable epilepsy; patients with controlled epilepsy should be carefully monitored. There have been reports of prolonged seizures in patients on TINEXIFLO receiving ECT treatment (see section 4.5)

Medicines metabolised by cytochrome P450IID6 isoenzyme
Because TINEXIFLO has the potential to inhibit the cytochrome P450IID6 isoenzyme, therapy with medications that are predominantly metabolised by the P450IID6 system and that have a relatively narrow therapeutic index should be initiated at the low end of the dose range if a patient is receiving TINEXIFLO concurrently or has taken it in the previous 5 weeks. If TINEXIFLO is added to the treatment regimen of a patient already receiving such a medicine, the need for decreased dose of the original medication should be considered.
Do not give TINEXIFLO together with metoprolol when it is used in cardiac failure. The risk of metoprolol adverse events, including excessive bradycardia, may be increased, because of an inhibition of its metabolism by fluoxetine (see section 4.4).
Monoamine oxidase inhibitors
There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving TINEXIFLO in combination with a monoamine oxidase inhibitor (MAOI) and in patients who have recently discontinued TINEXIFLO and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, TINEXIFLO should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI. Since TINEXIFLO and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping TINEXIFLO before starting an MAOI. If TINEXIFLO has been prescribed chronically and/or at a high dose, a longer interval should be considered. Serious and fatal cases of serotonin syndrome (which may resemble and be diagnosed as neuroleptic malignant syndrome) have been reported in patients treated with TINEXIFLO and an MAOI in temporal proximity (see section 4.4).
CNS active medicines
Caution is advised if the concomitant administration of TINEXIFLO and CNS active medicine, including lithium, is required. There have been reports of both increased and decreased lithium levels when used concomitantly with fluoxetine as in TINEXIFLO.
Serotonergic Medicines
Concomitant use of other medicines with serotonergic activity (e.g. Serotonin and Norepinephrine Reuptake Inhibitors, Selective Serotonin Reuptake Inhibitors, triptans or tramadol) may result in serotonin syndrome. (see section 4.4) There have been greater than 2-fold increases of previously stable plasma levels of other antidepressants when TINEXIFLO has been administered in combination with these medicines. Patients receiving TINEXIFLO in combination with tryptophan have been reported to experience adverse reactions, including agitation, restlessness and gastrointestinal distress. Lithium levels should be monitored. Changes in blood levels of phenytoin, carbamazepine, haloperidol, clozapine, diazepam, alprazolam, imipramine and desipramine, and in some cases clinical manifestations of toxicity, have been observed. Consideration should be given to using conservative titration schedules of the concomitant medicine and monitoring of clinical status.
Pimozide
Patients taking pimozide should not take TINEXIFLO concomitantly. Pimozide can prolong the QT interval. Fluoxetine as in TINEXIFLO can increase the level of pimozide through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval. Clinical studies of pimozide with other antidepressants demonstrate an increase in interaction or QT prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for interactions or QT prolongation warrants restricting the concurrent use of pimozide and TINEXIFLO.
Thioridazine
Thioridazine should not be administered with TINEXIFLO or within a minimum of 5 weeks after TINEXIFLO has been discontinued. Thioridazine administration produces a dose related prolongation of the QTc interval which is associated with serious ventricular dysrythmias, such as torsades de pointes - type dysrythmias and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism.
Tricyclic Antidepressants (TCAs)
In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after TINEXIFLO is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when TINEXIFLO is co-administered or has been recently discontinued (see section 4.4 and 5.1)
Benzodiazepines
The half-life of concurrently administered diazepam may be prolonged in some patients. Co-administration of alprazolam and fluoxetine as in TINEXIFLO has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.
Antipsychotics
Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine as in TINEXIFLO.
Anticoagulants
Altered anticoagulant effects (laboratory values and/or clinical signs and symptoms), with no consistent pattern, but including increased bleeding, have been reported uncommonly when fluoxetine as in TINEXIFLO is co-administered with warfarin. As is prudent in concomitant use of warfarin with many other medicines, patients receiving warfarin therapy should receive careful coagulation monitoring when TINEXIFLO is initiated or stopped.

Pregnancy
TINEXIFLO is not recommended to be used in pregnancy, due to the potential risk to the foetus. After administration of fluoxetine late in pregnancy, the following effects have been reported in neonates: irritability, tremor, hypotonia, persistent crying, and difficulty in sucking or in sleeping. These symptoms may indicate either serotonergic effects or a withdrawal syndrome. Epidemiological data have suggested that the use of SSRIs in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Abrupt discontinuation of therapy should be avoided during pregnancy (see Section 4.2).
Lactation
The safety of TINEXIFLO has not been established in breastfeeding women.
Fertility:
Animal data have shown that fluoxetine may affect sperm quality. Human case reports with some SSRIs have shown that an effect on sperm quality is reversible. Impact on human fertility has not been observed so far.

Although TINEXIFLO has been shown not to affect psychomotor performance in healthy volunteers, any psychoactive medicine may impair judgement, thinking or motor skills. Therefore, patients should be advised to avoid driving a car or operating hazardous machinery until they are certain that their performance is not affected.

a. Summary of the safety profile
The most commonly reported adverse reaction are chest pain, chills, haemorrhage, hypertension and palpitations. Adverse reactions affecting the digestive system include increased appetite, nausea and vomiting. Weight gain is also a commonly reported adverse reaction. Common adverse reaction affecting the nervous system include agitation, amnesia, confusion, emotional lability and sleep disorder. Ear pain, taste perversion and tinnitus were common reported adverse reaction affecting the senses. Increase in urinary frequency has also been reported.
b. Tabulated list of adverse reactions
System organ class
Frequent (u22651/100 to <1/10)
Less frequent (u22651/1000 to <1/100)
Blood and lymphatic system disorders
Anaemia, ecchymosis, Blood dyscrasia, hypochromic anaemia, leucopenia, lymphoedema, lymphocytosis, petechia,
Endocrine System
Hypothyroidism, Diabetic acidosis, diabetes mellitus
Metabolism and nutrition disorders
Weight gain
Dehydration, generalised oedema, gout, hypercholesterolaemia, hyperlipidaemia, hypokalaemia, peripheral oedema, Alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalaemia, hyperuricaemia, hypocalcaemia, iron deficiency anaemia, ALT increased
Nervous System Disorders
Agitation, amnesia, confusion, emotional lability, sleep disorder
Abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalisation, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder 2, psychosis, vertigo, Abnormal electroencephalogram, antisocial reaction, circumoral paraesthaesia, coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperaesthesia, neuritis, paralysis, reflexes decreased, reflexes increased, stupor
Eye Disorders
Conjunctivitis, dry eyes, mydriasis, photophobia, Blepharitis, diplopia, exophthalmos, eye haemorrhage, glaucoma, iritis, scleritis, strabismus, visual field defect
Ear and labyrinth disorders
Ear pain, tinnitus
Deafness, hyperacusis, parosmia
Cardiac Disorders
Haemorrhage, hypertension, palpitation
Angina pectoris, dysrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, tachycardia, vascular headache, Atrial fibrillation, bradycardia, cerebral embolism, cerebral ischaemia, cerebrovascular accident, extrasystoles, heart arrest, heart block, pallor, peripheral vascular disorder,
Respiratory, thoracic and mediastinal disorders
Asthma, epistaxis, hiccup, hyperventilation, Apnoea, atelectasis, cough decreased, emphysema, haemoptysis, hypoventilation, hypoxia, larynx oedema, lung oedema, pneumothorax, stridor
Gastrointestinal disorders
Increased appetite, nausea and vomiting
Aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, oesophagitis, gastritis, gastroenteritis, glossitis, gum haemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, melena, mouth ulceration, nausea/ vomiting/diarrhoea, stomach ulcer, stomatitis, thirst, Biliary pain, bloody diarrhoea, cholecystitis, duodenal ulcer, enteritis, oesophageal ulcer, faecal incontinence, gastrointestinal haemorrhage, hematemesis, haemorrhage of colon, hepatitis, intestinal obstruction, liver fatty deposit,
Skin and subcutaneous tissue disorders
Acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discolouration, skin ulcer, vesiculobullous rash, Furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhoea
Musculoskeletal and connective tissue disorders
Arthritis, bone pain, bursitis, leg cramps, tenosynovitis, Arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis
Renal and urinary disorders
Urinary frequency increased
Abortion, albuminuria, amenorrhoea, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation, fibrocystic breast, haematuria, leucorrhoea, menorrhagia, metrorrhagia, nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal haemorrhage, Breast engorgement, glycosuria, hypomenorrhoea, kidney pain, oliguria,
General disorders and administrative site conditions
Chest pain, chills
Chills and fever, face oedema, intentional overdose, malaise, pelvic pain, suicide attempt, Acute abdominal syndrome, hypothermia, intentional injury, neuroleptic malignant syndrome, photosensitivity reaction
c. Description of selected adverse reactions
Suicide/suicidal thoughts or clinical worsening: Cases of suicidal ideation and suicidal behaviour have been reported during fluoxetine therapy or early after treatment discontinuation (see section 4.4). In paediatric clinical trials suicide-related behaviours (suicide attempt and suicidal thoughts), hostility, and self-harm have been reported.
Seizures
There have been reports of prolonged seizures in patients on TINEXIFLO receiving ECT treatment (see section 4.5)
Withdrawal symptoms seen on discontinuation of SSRI treatment
Discontinuation of fluoxetine as in TINEXIFLO (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), asthenia, agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions. It is therefore advised that when TINEXIFLO treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see section 4.2).
Clinical experience in acute cardiac disease is limited, therefore caution is advisable (See section 4.5)
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u20186.04 Adverse Drug Reactions Reporting Formu2019. Found under SAHPRAu2019s publications: https://www/sahpra.org.za/Publications/Index/8

Symptoms
Symptoms of overdose included nausea, vomiting, seizures, cardiovascular dysfunction ranging from asymptomatic dysrhythmias to cardiac arrest, pulmonary dysfunction and signs of altered CNS status ranging from excitation to coma.
Treatment
Cardiac and vital signs monitoring is recommended along with general symptomatic and supportive measures. There are no specific antidotes for TINEXIFLO. Due to the large volume of distribution of TINEXIFLO, forced diuresis, dialysis, haemoperfusion and exchange transfusion are unlikely to be of benefit. In managing overdosage, the possibility of multiple drug involvement should be considered.