Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: PHARMACARE LIMITED, Healthcare Park, Woodlands Drive, Woodmead 2191
LORIEN is contraindicated in:
Monoamine oxidase inhibitors:
There have been reports of serious and 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 fluoxetine, as in LORIEN, in combination with a monoamine oxidase inhibitor (MAOI) and in patients who have recently discontinued fluoxetine, as in LORIEN and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome (see section 4.4).
Therefore, LORIEN should not be used in combination with a MAOI, or within 14 days of discontinuing therapy with a MAOI. Since LORIEN and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping fluoxetine hydrochloride as in LORIEN before starting a MAOI.
If LORIEN has been prescribed chronically and/or at a high dose, a longer interval before starting a MAOI 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 fluoxetine, as in LORIEN and a MAOI in temporal proximity (see section 4.4).
There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations in vital signs and mental status changes that include confusion, irritability, extreme agitation progressing to delirium and coma) in patients receiving LORIEN in combination with a monoamine oxidase inhibitor (MAOI) and in patients who have recently discontinued LORIEN and are then started on a MAOI.
Some presented with features resembling serotonin syndrome (which may be confounded with (or diagnosed as) neuroleptic malignant syndrome).
Therefore, LORIEN should not be used in combination with a MAOI, or within 14 days of discontinuing therapy with a MAOI. Since LORIEN and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping LORIEN before starting a MAOI (see section 4.3).
Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events).
Patient 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. A causal role, however, for antidepressant medicine in inducing such behaviour has not been established. Patients being treated with LORIEN should, nevertheless, 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. As improvement may not occur during the first two or more weeks of treatment, patients should be closely monitored during this period. Due to the risk of suicide in major depressive episodes, close supervision of high risk patients should accompany LORIEN therapy. Medical practitioners should encourage patients to report any distressing thoughts or feelings at any time.
Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and non-psychiatric disorders, the same precautions observed when treating patients with major depressive disorders should be observed when treating patients with other psychiatric and non-psychiatric disorders.
Because of well-established co-morbidity between obsessive-compulsive disorder and depression, the same precautions observed when treating patients with depression should be observed when treating patients with obsessive-compulsive disorder.
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 suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing LORIEN, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
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.
A meta-analysis of placebo-controlled clinical trials of antidepressant medicines such as fluoxetine, as in LORIEN, in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old. Close supervision of patients and in particular those at high risk should accompany medicine therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Serotonin syndrome, which may be confused with neuroleptic malignant syndrome, may occur with the use of LORIEN, particularly when given in combination with other serotonergic (among others, L-tryptophan), neuroleptic medicines and buprenorphine/opioids may result in serotonin syndrome, a potentially life threatening condition (see section 4.5).
This syndrome is characterised by the clustering of clinical features of changes in mental state (confusion, irritability disorientation, extreme agitation, progressing to delirium and coma) and neuromuscular activity (myoclonus, hyper-reflexia, tremor, rigidity, incoordination), in combination with auto-immune dysfunction (especially fever, sweating, diarrhoea), autonomic instability with possible rapid fluctuations of vital signs and/or gastrointestinal symptoms. As this syndrome may result in potentially life-threatening conditions, treatment with LORIEN should be discontinued if such events occur and supportive symptomatic treatment should be initiated.
Serotonin syndrome has been seen in temporal association with the use of MAOI and with other serotonergic medicines but may occur in the absence of any concomitant medicines. LORIEN should be stopped immediately as serious morbidity and death may follow the serotonin syndrome.
If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms
If the decision is made to discontinue treatment, LORIEN, should be tapered.
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials, adverse events seen on treatment discontinuation occurred in approximately 60% of patients in both the fluoxetine, as in LORIEN and placebo groups. Of these adverse events, 17% in the fluoxetine group as in LORIEN and 12% in the placebo group were severe in nature. The risk of withdrawal symptoms may be dependent on several factors, including the duration and dose of therapy with LORIEN and the rate of dose reduction.
Discontinuation of LORIEN may lead to withdrawal symptoms, including dizziness, paraesthesia, headache, insomnia, tremor, confusion, sensory disturbances, sleep disturbances (including insomnia and intense dreams), asthenia, agitation, anxiety and nausea and/or vomiting (see section 4.2).
Generally, these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2 to 3 months or more). It is therefore advised that LORIEN should be gradually tapered when discontinuing treatment over a period of at least one to two weeks, according to the patient’s needs (see section 4.2).
Discontinue LORIEN in patients who develop a rash, anaphylactoid events and progressive systemic effects, involving the skin, lungs, kidneys or liver, have occurred in such patients.
Seizures are a potential risk with antidepressant medicines. Therefore, as with other antidepressants, LORIEN should be introduced cautiously in patients who have a history of seizures.
LORIEN should be discontinued in any patient who develops seizures or where there is an increase in seizure frequency.
LORIEN 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 LORIEN receiving ECT treatment.
Antidepressants, such as LORIEN, should be used with caution in patients with a history of mania/hypomania. As with all antidepressants, LORIEN should be discontinued in any patient entering a manic phase.
Fluoxetine, as in LORIEN is extensively metabolised by the liver and excreted by the kidneys. A lower dose e.g. alternate day dosing is recommended in patients with significant hepatic dysfunction or mild to moderate renal failure (GFR 10 to 50 ml/min).
When given fluoxetine, as in LORIEN 20 mg daily for 2 months, patients with severe renal failure (GFR <10 ml/min) requiring dialysis showed no difference in plasma levels of fluoxetine or norfluoxetine compared to controls with normal renal function.
LORIEN, a potent inhibitor of CYP2D6, may lead to reduced concentrations of endoxifen, one of the most important active metabolites of tamoxifen. Therefore, LORIEN should, whenever possible, be avoided during tamoxifen treatment (see section 4.5).
Clinical experience in acute cardiac disease is limited, therefore caution is advisable.
Cases of QT interval prolongation and ventricular dysrhythmia including torsade de pointes have been reported with the use of LORIEN (see sections 4.5, 4.8 and 4.9).
LORIEN should be used with caution in patients with conditions such as congenital long QT syndrome, a family history of QT prolongation or other clinical conditions that predispose to dysrhythmias (e.g., hypokalaemia, hypomagnesemia, bradycardia, acute myocardial infarction or uncompensated heart failure) or increased exposure to LORIEN (e.g., hepatic impairment) or concomitant use with medicines known to induce QT prolongation and/or torsade de points (see section 4.5).
If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started. If signs of cardiac dysrhythmia occur during treatment with LORIEN, the treatment should be withdrawn, and an ECG should be performed.
LORIEN may cause loss of weight usually proportional to baseline body weight, which could be undesirable in underweight depressed patients.
In patients with diabetes, LORIEN may alter glycaemic control. Hypoglycaemia has occurred during therapy with LORIEN and hyperglycaemia has developed following discontinuation. Insulin and/or oral hypoglycaemic dosage may need to be adjusted.
The use of fluoxetine, as in LORIEN has been associated with the development of akathisia, characterised 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.
SSRIs/SNRIs such as LORIEN may increase the risk of postpartum haemorrhage (see sections 4.6 and 4.8).
There have been reports of cutaneous bleeding abnormalities, such as ecchymosis and purpura with SSRIs including LORIEN. Ecchymosis has been reported as an infrequent event during treatment with LORIEN. Other haemorrhagic manifestations (e.g., gynaecological haemorrhages, gastrointestinal bleedings and other cutaneous or mucous bleedings) have been reported.
There have been reports of altered platelet function and/or abnormal results from laboratory studies in patients taking LORIEN. While there have been reports of abnormal bleeding in several patients taking LORIEN, it is unclear whether LORIEN had a causative role.
Caution is advised in patients taking SSRIs such as LORIEN, particularly in concomitant use with oral anticoagulants, medicines known to affect platelet function (e.g., atypical antipsychotics, such as clozapine, phenothiazines, most TCAs, aspirin, NSAIDs), or other medicines that may increase risk of bleeding, as well as in patients with a history of bleeding disorders (see section 4.5).
Mydriasis has been reported in association with the use of LORIEN, therefore, caution should be used when prescribing LORIEN in patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma.
There have been rare reports of prolonged seizures in patients on LORIEN receiving ECT treatment; therefore, caution is advisable.
SSRIs/SNRIs such as LORIEN may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of the SSRIs/SNRI.
Suicide-related behaviours (suicidal attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo.
In addition, only limited evidence is available concerning long-term effect on safety in children and adolescents, including effects on growth, sexual maturation and cognitive, emotional and behavioural developments.
In a 19-week clinical trial, decreased height and weight gain was observed in children and adolescents treated with fluoxetine, as in LORIEN. It has not been established whether there is an effect on achieving normal adult height. The possibility of a delay in puberty cannot be ruled out (see section 4.8).
Growth and pubertal development (height, weight, and TANNER staging) should therefore be monitored during and after treatment with LORIEN. If either is slowed, referral to a paediatrician should be considered.
In paediatric trials, mania and hypomania were reported (see section 4.8). Therefore, regular monitoring for the occurrence of mania/hypomania is recommended. LORIEN should be discontinued in any patient entering a manic phase. It is important that the doctor or healthcare practitioner prescribing LORIEN carefully discusses the risks and benefits of treatment with the child/young person and/or their parents.
LORIEN capsules contains lactose monohydrate.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take LORIEN capsules.
The long elimination half-lives of both fluoxetine and norfluoxetine as in LORIEN should be borne in mind (see section 5.2) when considering pharmacodynamic or pharmacokinetic medicine interactions (e.g., when switching from fluoxetine to other antidepressants).
LORIEN should not be used concomitantly with monoamine oxidase inhibitors (see section 4.3 and 4.4).).
Some cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI such as LORIEN in combination with an irreversible, non-selective monoamine oxidase inhibitor (MAOI). These cases presented with features resembling serotonin syndrome (which may be confounded with or diagnosed as neuroleptic malignant syndrome). Cyproheptadine or dantrolene may benefit patients experiencing such reactions.
Symptoms of a medicine interaction with a MAOI include hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma (see section 4.3 and 4.4).
Because of the two weeks-lasting effect of treatment with an irreversible, non-selective MAOI, LORIEN should only be started 2 weeks after discontinuation of an irreversible, non-selective MAOI. Similarly, at least 5 weeks should elapse after discontinuing LORIEN treatment before starting an irreversible, non-selective MAOI.
Metoprolol, used in cardiac failure can cause adverse events including excessive bradycardia, may be increased because of an inhibition of its metabolism by LORIEN (see section 4.3).
In formal testing, fluoxetine as in LORIEN did not raise blood alcohol levels or enhance the effects of alcohol. However, the combination of SSRI treatment such as LORIEN and alcohol is not advisable.
Pharmacokinetic interaction between CYP2D6 inhibitors such as LORIEN and tamoxifen, showing a 65 to 75 % reduction in plasma levels of one of the more active forms of the tamoxifen, i.e. endoxifen, has been reported in the literature. Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI antidepressants in some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 19 inhibitors (including LORIEN) should whenever possible be avoided (see section 4.4).
Risk of serotonin syndrome including diarrhoea, tachycardia, sweating, tremor, confusion or coma. If concomitant use of these medicines with LORIEN cannot be avoided, close clinical monitoring should be undertaken, and the concomitant medicines should be initiated at the lower recommended doses (see section 4.4).
Risk of mequitazine adverse events (such as QT prolongation) may be increased because of an inhibition of its metabolism by LORIEN.
LORIEN should be used cautiously when co-administered with buprenorphine/opioids as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4).
Concomitant use of other medicines with serotonergic activity (e.g., lithium, tramadol, triptans, tryptophan, selegiline (MAOI-B), St. John’s 1 Wort (Hypericum perforatum) may result in mild serotonin syndrome. Therefore, the concomitant use of LORIEN with these medicines should be undertaken with caution and closer, more frequent clinical monitoring (see section 4.4).
Pharmacokinetic and pharmacodynamic studies between LORIEN and other medicines that prolong the QT interval have not been performed. An additive effect of LORIEN and these medicines cannot be excluded.
Therefore, co-administration of LORIEN with medicines that prolong the QT interval, such as Class IA and III antidysrhythmic, antipsychotics (e.g. phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial medicines (e.g. sparfloxacin, moxifloxacin, erythromycin IV, pentamidine), anti-malaria treatment particularly halofantrine, certain antihistamines (astemizole, mizolastine), should be used with caution (see sections 4.4, 4.8 and 4.9)
Caution is advised if the concomitant administration of LORIEN and CNS active medicines, including lithium, is required. There have been reports of both increased and decreased lithium levels when used concomitantly with LORIEN. Lithium levels should be monitored.
There have been greater than 2-fold increases of previously stable plasma levels of other antidepressants when LORIEN has been administered in combination with these medicines.
Patients receiving LORIEN in combination with tryptophan have been reported to experience adverse reactions, including agitation, restlessness and gastrointestinal distress.
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.
The half-life of concurrently administered diazepam may be prolonged.
Altered anticoagulant effects (laboratory values and/or clinical signs and symptoms), with no consistent pattern, but including increased bleeding, have been reported when fluoxetine, as in LORIEN 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 LORIEN is initiated or stopped (see below on medicines affecting haemostasis).
LORIEN is bound to plasma protein and concurrent administration may alter plasma concentrations of other plasma protein bound medicines, e.g. warfarin, digoxin, or conversely, LORIEN binding may be changed by these medicines.
There are individual case reports of reduced antidepressant activity of LORIEN when used in combination with cyproheptadine.
There have been reports of prolonged seizures in patients on fluoxetine, as in LORIEN receiving ECT treatment (see section 4.4).
Hyponatremia is an undesirable effect of LORIEN. Use in combination with other medicines associated with hyponatremia (e.g. diuretics, desmopressin, carbamazepine and oxcarbazepine) may lead to an increased risk. (see section 4.8).
Seizures are an undesirable effect of LORIEN. Use in combination with other medicines which may lower the seizure threshold (for example, TCAs, other SSRIs, phenothiazines, butyrophenones, mefloquine, chloroquine, bupropion, tramadol) may lead to an increased risk (see section 4.8).
LORIEN has the potential to inhibit the cytochrome P450IID6 isoenzyme. Therapy with medicines 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 LORIEN concurrently or has taken it in the previous 5 weeks. If LORIEN is added to the treatment regimen of a patient already receiving such a medicine, the need for decreased dose of the original medicines should be considered.
LORIEN is a strong inhibitor of CYP2D6 enzyme, therefore concomitant therapy with medicines also metabolised by this enzyme system may lead to medicine interactions, notably those having a narrow therapeutic index (such as flecainide, propafenone and nebivolol) and those that are titrated, but also with atomoxetine, carbamazepine, tricyclic antidepressants and risperidone. They should be initiated at or adjusted to the low end of their dose range. This may also apply if LORIEN has been taken in the previous 5 weeks.
Medicines affecting haemostasis (oral anticoagulants, whatever their mechanism, platelets antiaggregants including aspirin and NSAIDs): risk of increased bleeding. Clinical monitoring, and more frequent monitoring of INR with oral anticoagulants, should be made dose adjustment during the fluoxetine treatment, such as LORIEN, and after its discontinuation may be suitable (see sections 4.4 and 4.8).
Safety in pregnancy has not been demonstrated.
Some epidemiological studies suggest an increased risk of cardiovascular defects associated with the use of fluoxetine as in LORIEN during the first trimester. The mechanism is unknown. Overall the data suggest that the risk of having an infant with a cardiovascular defect following maternal fluoxetine exposure is in the region of 2/100 compared with an expected rate for such defects of approximately 1/100 in the general population.
Epidemiological data have suggested that the use of SSRIs such as LORIEN in pregnancy, particular in late pregnancy, may increase the risk of persistent pulmonary hypertension in the new-born (PPHN). The observed risk was approximately 5 cases per 1 000 pregnancies. In the general population 1 to 2 cases of PPHN per 1 000 pregnancies occur.
If LORIEN is used during pregnancy, caution should be exercised, especially during late pregnancy or just prior to the onset of labour, since some other effects have been reported in neonates: irritability, tremor, hypotonia, persistent crying, difficulty in sucking or in sleeping. These symptoms may indicate either serotonergic effects or a withdrawal syndrome. The time to occur and the duration of these symptoms may be related to the long half-life of LORIEN (4 to 6 days) and its active metabolite, norfluoxetine (4 to 16 days).
There is data of an increased risk (less than 2-fold) of postpartum haemorrhage following exposure to an SSRI or SNRI within the month prior to birth. Although no studies have investigated an association between fluoxetine, as in LORIEN, treatment and postpartum haemorrhage, there is a potential risk, considering the related mechanism of action (see section 4.4).
The safety of LORIEN has not been established in breastfeeding women. LORIEN is excreted in human milk. Adverse events have been reported in breastfeeding infants.
If treatment with LORIEN is considered necessary, discontinuation of breastfeeding should be considered. However, if breastfeeding is continued, the lowest effective dose of LORIEN should be prescribed.
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.
LORIEN has a moderate influence on the ability to drive and use machinery. Since adverse reactions such as convulsions, headaches and visual disturbances have been reported in patients receiving LORIEN, patients should not drive, use machinery or perform any tasks that require concentration, until they are certain that LORIEN does not adversely affect their ability to do so safely (see section 4.8).
The most commonly reported adverse reactions in patients treated with LORIEN were headache, nausea, insomnia, fatigue and diarrhoea. Undesirable effects may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy.
The adverse reactions observed with fluoxetine treatment, as in LORIEN, in adult and paediatric populations are listed in the table below. Some of these adverse reactions are common with other SSRIs.
| System organ class | Frequent | Less frequent | Frequency unknown (cannot be estimated from the available data) |
|---|---|---|---|
| Blood and the lymphatic system disorders | Anaemia, blood dyscrasias, hypochromic anaemia, leucopenia, lymphoedema, lymphocytosis, petechia, purpura, thrombocythaemia, thrombocytopenia, l neutropenia | Aplastic anaemia, eosinophilic pneumonia, pancytopenia, immune related haemolytic anaemia, thrombocytopenic purpura | |
| Immune system disorders | Anaphylactic reaction, serum sickness | ||
| Endocrine disorders | Hypothyroidism, diabetic acidosis, diabetes mellitus, inappropriate antidiuretic hormone secretion | ||
| Metabolism and nutrition disorders | Weight gain, increased appetite, decreased appetite1 | Alcohol intolerance, anorexia, dehydration, gout, hyperkalaemia, hyperuricaemia, hypokalaemia, iron deficiency anaemia, weight loss, hypocalcaemia | Hyponatraemia |
| Psychiatric disorders | Amnesia, emotional lability, insomnia2, anxiety, decreased libido3, sleep disorder, abnormal dreams4,restlessness, tension | Antisocial reaction, delusions, apathy, hostility, hypomania, increased libido, mania, paranoid reaction, personality disorder, psychosis, stupor, depersonalisation, elevated mood, euphoric mood, abnormal thinking, abnormal orgasm5, bruxism, hallucinations, agitation, panic attacks, confusion, dysphemia, aggression, suicidal thoughts and behaviour6 | Violent Behaviour |
| Nervous system disorders | Headache, nervousness, drowsiness, tremor, disturbance in attention, dizziness, dysgeusia, lethargy, somnolence7 | Abnormal electroencephalogram, abnormal gait, acute brain syndrome, akathisia, ataxia, bucco glossal syndrome, circumoral paraesthesia, CNS depression, coma, dizziness, dysarthria, dystonia, extrapyramidal syndrome, fatigue, foot drop, hyperaesthesia, hyperkinesia, hypertonia, hypoaesthesia, incoordination, mania, myoclonus, neuralgia, neuritis, neuropathy, neurosis, paralysis, decreased reflexes, increased reflexes, vertigo, memory impairment, balance disorder, convulsion, serotonin syndrome, migraine, taste loss / ageusia, parosmia, psychomotor hyperactivity | Dyskinesia, seizures, movement disorders, cerebral embolism |
| Eye disorders | Vision blurred | Blepharitis, conjunctivitis, diplopia, dry eyes, exopthalmos, eye haemorrhage, iritis, mydriasis, photophobias, scleritis, strabismus, visual disturbances, visual field defect, glaucoma | |
| Ear and labyrinth disorders | Ear pain, tinnitus | Deafness, hyperacusis | |
| Cardiac disorders | Hypertension, palpitations, electrocardio-gram QT prolonged QTcF ≥450 msec)8 | Angina pectoris, dysrhythmia, atrial fibrillation, bradycardia, cerebral ischaemia, cerebrovascular accident, congestive heart failure, extrasystoles, heart arrest, heart block, myocardial infarct, postural syncope, tachycardia, ventricular dysrhythmia including torsade de pointes, ventricular extrasystoles, ventricular fibrillation | |
| Vascular disorders | Haemorrhage, flushing9 | Pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, hypotension, vasculitis, vasodilation | |
| Respiratory, thoracic and mediastinal disorders | Yawning | Apnoea, dyspnoea, asthma, atelectasis, decreased cough, emphysema, epistaxis, haemoptysis, hiccup, hyperventilation, hypoventilation, hypoxia, larynx oedema, lung oedema, pneumothorax, stridor, pharyngitis, pulmonary events (inflammatory processes of varying histopathology and/or fibrosis)10 | |
| Gastrointestinal disorders | Nausea, vomiting, diarrhoea, dyspepsia, dry mouth | Aphthous stomatitis, biliary pain, bloody diarrhoea, cholecystitis, cholelithiasis, colitis, duodenal ulcer, dysphagia, enteritis, eructation, oesophageal ulcer, oesophagitis, faecal incontinence, gastritis, gastroenteritis, gastrointestinal haemorrhage11, glossitis, gum haemorrhage, haematemesis, haemorrhage of colon, hepatitis, hyperchlorhydria, increased salivation, intestinal obstruction, melaena, mouth ulceration, pancreatitis, peptic ulcer, rectal haemorrhage, salivary gland enlargement, stomach ulcer haemorrhage, thirst, tongue oedema, melena. | |
| Hepatobiliary disorders | Liver function tests abnormal (increased alkaline phosphatase, increased ALT), liver fatty deposit, idiosyncratic hepatitis | ||
| Skin and subcutaneous tissue disorders | Excessive sweating, rash12, urticaria, pruritus, hyperhidrosis | Acne, alopecia, contact dermatitis, eczema, furunculosis, herpes zoster, hirsutism, maculopapular rash, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhoea, skin discolouration, skin ulcer, vesiculobullous rash, increased tendency to bruise, cold sweat, ecchymosis, photosensitivity reaction, purpura, erythema multiforme, Stevens-Johnson syndrome, Toxic Epidermal Necrolysis (Lyell Syndrome), angioedema | |
| Musculoskeletal and connective tissue disorders | Arthritis, arthrosis, bone pain, bursitis, chondrodystrophy, leg cramps, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, tenosynovitis, arthralgia | Muscle twitching, myalgia | |
| Renal and urinary disorders | Frequent urination13 | Albuminuria, increased blood urea nitrogen, cystitis, dysuria, haematuria, nocturia, polyuria, urinary incontinence, urinary urgency, glycosuria, kidney pain, oliguria, uterine haemorrhage, enlarged uterine fibroids, micturition disorder, urinary incontinence, urinary retention, urinary urgency | |
| Reproductive system and breast disorders | Sexual dysfunction (delayed or inhibited orgasm), gynaecological bleeding14, erectile dysfunction, ejaculation disorder15 | Abortion, amenorrhoea, breast enlargement, breast engorgement, breast pain, female lactation, fibrocystic breast, hypomenorrhoea, leucorrhoea, menorrhagia, metrorrhagia, priapism, vaginal haemorrhage, galactorrhoea, hyperprolactinaemia | postpartum haemorrhage* |
| General disorders and administrative site conditions | Chest pain, chills, fatigue16, feeling jittery | Asthenia, fever, generalised oedema, facial oedema, malaise, pelvic pain, peripheral oedema, acute abdominal syndrome, hypothermia, intentional injury, neuroleptic malignant syndrome, photosensitivity reaction, feeling abnormal, feeling hot, mucosal haemorrhage, intentional overdose | |
| Investigations | Increased creatine phosphokinase, hypercholesterolaemia, hyperlipidaemia, transaminases increased, gamma-glutamyl transferase increased |
1 Includes anorexia
2 Includes early morning awakening, initial insomnia, middle insomnia
3 Includes loss of libido
4 Includes nightmares
5 Includes anorgasmia
6 Includes completed suicide, depression suicidal, intentional self-injury, self-injurious ideation, suicidal behaviour, suicidal ideation, suicide attempt, morbid thoughts, self-injurious behaviour. These symptoms may be due to underlying disease.
7 Includes hypersomnia, sedation
8 Based on ECG measurements from clinical trials
9 Includes hot flush
10 Includes atelectasis, interstitial lung disease, pneumonitis
11 Includes most frequently gingival bleeding, haematemesis, haematochezia, rectal haemorrhage, diarrhoea haemorrhagic, melaena, and gastric ulcer haemorrhage
12 Includes erythema, exfoliative rash, heat rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash macular-papular, rash morbilliform, rash papular, rash pruritic, rash vesicular, umbilical erythema rash
13 Includes pollakiuria
14 Includes cervix haemorrhage, uterine dysfunction, uterine bleeding, genital haemorrhage, menometrorhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal haemorrhage, uterine haemorrhage, vaginal haemorrhage
15 Includes ejaculation failure, ejaculation dysfunction, premature ejaculation, ejaculation delayed, retrograde ejaculation
16 Includes asthenia
* This event has been reported for the therapeutic class of SSRIs/SNRIs (see sections 4.4 and 4.6).
Hyponatraemia (including serum sodium lower than 110 mmol/l) has been reported. The hyponatraemia may be reversible when LORIEN is discontinued. Although these cases were complex with varying possible aetiologies, some were possibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). More often these occurrences have been in older patients and in patients taking diuretics or who were otherwise volume depleted.
Dyskinesia (including, for example a case of buccallingual-masticatory syndrome, which resolved following medicine discontinuation), seizures (see section 4.4). Movement disorders developing in patients with risk factors (including medicines associated with such events) and worsening of pre-existing movement disorders.
There have been reports of extrapyramidal symptoms associated with the use of LORIEN and of aggravation of Parkinson’s disease in patients taking LORIEN. Therefore, LORIEN should be used with care in patients with extrapyramidal disorders.
Glaucoma has been reported with the use of LORIEN, the symptoms usually subsided within 2 days of medicine withdrawal. Intra-ocular pressure following LORIEN administration was recorded in some patients.
Dyspnoea. Pulmonary events (including inflammatory processes of varying histopathology and/or fibrosis) have been reported. Dyspnoea may be the only preceding symptom.
Serious systemic events, possibly related to vasculitis, have developed in patients with rash and death has been reported.
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs, such as LORIEN and TCAs. The mechanism leading to the risk is unknown. Withdrawal symptoms seen on discontinuation of LORIEN treatments:
Discontinuation of LORIEN commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), confusion asthenia, agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions. Generally, these events are mild to moderate and are self-limiting, however, in some patients they may be severe and/or prolonged (see section 4.4). It is therefore advised that when LORIEN is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).
In paediatric clinical trials, suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (the events reported were: anger, irritability, aggression, agitation, activation syndrome), manic reactions, including mania and hypomania (no prior episodes reported in these patients) and epistaxis, were commonly reported and were more frequently observed among children and adolescents treated with antidepressants compared to those treated with placebo.
Isolated cases of growth retardation have also been reported from clinical use. In paediatric clinical trials, fluoxetine treatment as in LORIEN was also associated with a decrease in alkaline phosphatase levels.
Isolated cases of adverse events potentially indicating delayed sexual maturation or sexual dysfunction have been reported from paediatric clinical use (see section 5.3).
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to: SAHPRA: https://www.sahpra.org.za/health-products-vigilance/
Aspen Pharmacare:
E-mail: Drugsafety@aspenpharma.com
Tel: 0800 118 088
Not applicable.
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