Summary of Product Characteristics (SmPC) - Atomoxetine Glenmark 80 mg hard capsules
1 NAME OF THE MEDICINAL PRODUCT
Atomoxetine Glenmark 80 mg hard capsules.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Atomoxetine Glenmark 80 mg hard capsules
Each hard capsule contains 80 mg atomoxetine as atomoxetine hydrochloride.
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Capsule, hard
Atomoxetine Glenmark 80 mg hard capsules
Hard gelatin capsule of size No 2 (length of 17.6±0.4 mm), opaque brown cap imprinted in black ink with ‘80’ and opaque white body imprinted in black ink with ‘mg’.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Atomoxetine Glenmark is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children of 6 years and older, in adolescents and in adults as part of a comprehensive treatment programme. Treatment must be initiated by a specialist in the treatment of ADHD, such as a paediatrician, child/adolescent psychiatrist, or psychiatrist. Diagnosis should be made according to current DSM criteria or the guidelines in ICD.
In adults, the presence of symptoms of ADHD that were pre-existing in childhood should be confirmed. Third-party corroboration is desirable and Atomoxetine Glenmark should not be initiated when the verification of childhood ADHD symptoms is uncertain. Diagnosis cannot be made solely on the presence of one or more symptoms of ADHD. Based on clinical judgment, patients should have ADHD of at least moderate severity as indicated by at least moderate functional impairment in 2 or more settings (for example, social, academic, and/or occupational functioning), affecting several aspects of an individual’s life.
Additional information for the safe use of this product:
A comprehensive treatment programme typically includes psychological, educational and social measures and is aimed at stabilising patients with a behavioural syndrome characterised by symptoms which may include chronic history of short attention span, distractibility, emotional lability, impulsivity, moderate to severe hyperactivity, minor neurological signs and abnormal EEG. Learning may or may not be impaired.
Pharmacological treatment is not indicated in all patients with this syndrome and the decision to use the drug must be based on a very thorough assessment of the severity of the patient’s symptoms and impairment in relation to the patient’s age and the persistence of symptoms.
4.2 Posology and method of administration
Posology
Atomoxetine Glenmark can be administered as a single daily dose in the morning. Patients who do not achieve a satisfactory clinical response (tolerability [e.g. nausea or somnolence] or efficacy) when taking Atomoxetine Glenmark as a single daily dose might benefit from taking it as twice daily evenly divided doses in the morning and late afternoon or early evening.
Paediatric population:
Dosing of paediatric population up to 70 kg Body Weight:
Atomoxetine Glenmark should be initiated at a total daily dose of approximately 0.5 mg/kg. The initial dose should be maintained for a minimum of 7 days prior to upward dose titration according to clinical response and tolerability. The recommended maintenance dose is approximately 1.2 mg/kg/day (depending on the patient’s weight and available dosage strengths of atomoxetine). No additional benefit has been demonstrated for doses higher than 1.2 mg/kg/day. The safety of single doses over 1.8 mg/kg/day and total daily doses above 1.8 mg/kg have not been systematically evaluated. In some cases it might be appropriate to continue treatment into adulthood.
Dosing of paediatric population over 70 kg Body Weight:
Atomoxetine Glenmark should be initiated at a total daily dose of 40 mg. The initial dose should be maintained for a minimum of 7 days prior to upward dose titration according to clinical response and tolerability. The recommended maintenance dose is 80mg. No additional benefit has been demonstrated for doses higher than 80 mg. The maximum recommended total daily dose is 100 mg. The safety of single doses over 120mg and total daily doses above 150mg have not been systematically evaluated.
Adults:
Atomoxetine Glenmark should be initiated at a total daily dose of 40 mg. The initial dose should be maintained for a minimum of 7 days prior to upward dose titration according to clinical response and tolerability. The recommended maintenance daily dose is 80 mg to 100 mg. The maximum recommended total daily dose is 100 mg. The safety of single doses over 120mg and total daily doses above 150 mg have not been systematically evaluated.
Additional information for the safe use of this product:
Pre-treatment screening:
Prior to prescribing it is necessary to take an appropriate medical history and conduct a baseline evaluation of a patient's cardiovascular status, including blood pressure and heart rate (see sections 4.3 and 4.4).
Ongoing monitoring:
Cardiovascular status should be regularly monitored with blood pressure and pulse recorded after each adjustment of dose and then at least every 6 months. For paediatric patients the use of a centile chart is recommended. For adults, current reference guidelines for hypertension should be followed. (See section 4.4).
Withdrawal of Treatment:
In the study programme no distinct withdrawal symptoms have been described. In cases of significant adverse effects, atomoxetine may be stopped abruptly; otherwise the drug may be tapered off over a suitable time period.
Treatment with Atomoxetine Glenmark need not be indefinite. Re-evaluation of the need for continued therapy beyond 1 year should be performed, particularly when the patient has reached a stable and satisfactory response.
Special Populations
Hepatic insufficiency:
For patients with moderate hepatic insufficiency (Child-Pugh Class B), initial and target doses should be reduced to 50% of the usual dose. For patients with severe hepatic insufficiency (Child-Pugh Class C), initial dose and target doses should be reduced to 25% of usual dose. (see section 5.2)
Renal insufficiency:
Subjects with end-stage renal disease had higher systemic exposure to atomoxetine than healthy subjects (about a 65% increase), but there was no difference when exposure was corrected for mg/kg dose. Atomoxetine Glenmark can therefore be administered to ADHD patients with end stage renal disease or lesser degrees of renal insufficiency using the usual dosing regimen. Atomoxetine may exacerbate hypertension in patients with end-stage renal disease (see section 5.2).
Approximately 7% of Caucasians have a genotype corresponding to a non-functional CYP2D6 enzyme (called CYP2D6 poor metabolisers). Patients with this genotype have a several fold higher exposure to atomoxetine when compared to patients with a functional enzyme. Poor metabolisers are therefore at higher risk of adverse events (see sections 4.8 and 5.2). For patients with a known poor metaboliser genotype, a lower starting dose and slower up titration of the dose may be considered.
Elderly population:
The use of atomoxetine in patients over 65 years of age has not been systematically evaluated.
Paediatric population under six years of age:
The safety and efficacy of atomoxetine in children under 6 years of age have not been established. Therefore Atomoxetine Glenmark should not be used in children under 6 years of age. (see section 4.4)
Method of administration
For oral use. Atomoxetine Glenmark can be administered with or without food. The capsules should not be opened and the contents inside the capsules should not be removed and taken in any other way (see section 4.4).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Atomoxetine should not be used in combination with monoamine oxidase inhibitors (MAOI). Atomoxetine should not be used within a minimum of 2 weeks after discontinuing therapy with MAOI. Treatment with MAOI should not be initiated within 2 weeks after discontinuing atomoxetine.
Atomoxetine should not be used in patients with narrow angle glaucoma, as in clinical trials the use of atomoxetine was associated with an increased incidence of mydriasis.
Atomoxetine should not be used in patients with severe cardiovascular or cerebrovascular disorders (see section 4.4 Special warnings and precautions for use - Cardiovascular Effects). Severe cardiovascular disorders may include severe hypertension, heart failure, arterial occlusive disease, angina, haemodynamically significant congenital heart disease, cardiomyopathies, myocardial infarction, potentially life-threatening arrhythmias and channelopathies (disorders caused by the dysfunction of ion channels). Severe cerebrovascular disorders may include cerebral aneurysm or stroke.
Atomoxetine should not be used in patients with pheochromocytoma or a history of pheochromocytoma (see section 4.4 Special warnings and precautions for use - Cardiovascular Effects).
4.4 Special warnings and precautions for use
Suicide-related behaviour
Suicide related behaviour (suicide attempts and suicidal ideation) has been reported in patients treated with atomoxetine. In double blind clinical trials, suicide related behaviours were uncommon but more frequently observed among children and adolescents treated with atomoxetine compared to those treated with placebo, where there were no events. In adult double-blind clinical trials there was no difference in the frequency of suicide related behaviour between atomoxetine and placebo. Patients who are being treated for ADHD should be carefully monitored for the appearance or worsening of suicide related behaviour.
Sudden death and pre-existing cardiac abnormalities
Sudden death has been reported in patients with structural cardiac abnormalities who were taking atomoxetine at usual doses. Although some serious structural cardiac abnormalities alone carry an increased risk of sudden death, atomoxetine should only be used with caution in patients with known serious structural cardiac abnormalities and in consultation with a cardiac specialist.
Cardiovascular effects
Atomoxetine can affect heart rate and blood pressure.
Most patients taking atomoxetine experience a modest increase in heart rate (mean <10 bpm) and/or increase in blood pressure (mean <5 mm Hg) (see section 4.8).
However, combined data from controlled and uncontrolled ADHD clinical trials show that approximately 8-12% of children and adolescents, and 6-10% of adults experience more pronounced changes in heart rate (20 beats per minute or greater) and blood pressure (15-20 mmHg or greater). Analysis of these clinical trial data showed that approximately 15-26% of children and adolescents, and 27-32% of adults experiencing such changes in blood pressure and heart rate during atomoxetine treatment had sustained or progressive increases. Long- term sustained changes in blood pressure may potentially contribute to clinical consequences such as myocardial hypertrophy.
As a result of these findings, patients who are being considered for treatment with atomoxetine should have a careful history and physical exam to assess for the presence of cardiac disease, and should receive further specialist cardiac evaluation if initial findings suggest such history or disease.
It is recommended that heart rate and blood pressure be measured and recorded before treatment is started and, during treatment, after each adjustment of dose and then at least every 6 months to detect possible clinically important increases. For paediatric patients the use of a centile chart is recommended. For adults, current reference guidelines for hypertension should be followed.
Atomoxetine should not be used in patients with severe cardiovascular or cerebrovascular disorders (see section 4.3 Contraindications – Severe Cardiovascular and Cerebrovascular Disorders).
Atomoxetine should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure and heart rate, such as patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease.
Patients who develop symptoms such as palpitations, exertional chest pain, unexplained syncope, dyspnoea or other symptoms suggestive of cardiac disease during atomoxetine treatment should undergo a prompt specialist cardiac evaluation.
In addition, atomoxetine should be used with caution in patients with congenital or acquired long QT or a family history of QT prolongation (see sections 4.5 and 4.8).
As orthostatic hypotension has also been reported, atomoxetine should be used with caution in any condition that may predispose patients to hypotension or conditions associated with abrupt heart rate or blood pressure changes.
Cerebrovascular effects
Patients with additional risk factors for cerebrovascular conditions (such as a history of cardiovascular disease, concomitant medications that elevate blood pressure) should be assessed at every visit for neurological signs and symptoms after initiating treatment with atomoxetine.
Hepatic effects
Very rarely, spontaneous reports of liver injury, manifested by elevated hepatic enzymes and bilirubin with jaundice, have been reported. Also very rarely, severe liver injury, including acute liver failure, have been reported. Atomoxetine Glenmark should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted.
Psychotic or manic symptoms
Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, mania or agitation in patients without a prior history of psychotic illness or mania can be caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered. The possibility that Atomoxetine Glenmark will cause the exacerbation of pre-existing psychotic or manic symptoms cannot be excluded.
Aggressive behaviour, hostility or emotional lability
Hostility (predominantly aggression, oppositional behaviour and anger) was more frequently observed in clinical trials among children, adolescents and adults treated with atomoxetine compared to those treated with placebo. Emotional lability was more frequently observed in clinical trials among children treated with atomoxetine compared to those treated with placebo. Patients should be closely monitored for the appearance or worsening of aggressive behaviour, hostility or emotional lability.
Possible allergic events
Although uncommon, allergic reactions, including anaphylactic reactions, rash, angioneurotic oedema, and urticaria, have been reported in patients taking atomoxetine.
Seizures
Seizures are a potential risk with atomoxetine. Atomoxetine should be introduced with caution in patients with a history of seizure. Discontinuation of atomoxetine should be considered in any patient developing a seizure or if there is an increase in seizure frequency where no other cause is identified.
Growth and development
Growth and development should be monitored in children and adolescents during treatment with atomoxetine. Patients requiring long-term therapy should be monitored and consideration should be given to dose reduction or interrupting therapy in children and adolescents who are not growing or gaining weight satisfactorily.
Clinical data do not suggest a deleterious effect of atomoxetine on cognition or sexual maturation, however the amount of available long-term data is limited. Therefore, patients requiring long-term therapy should be carefully monitored.
New-onset or worsening of Comorbid Depression, Anxiety and Tics In a controlled study of paediatric patients with ADHD and co morbid chronic motor tics or Tourette’s Disorder, atomoxetine-treated patients did not experience worsening of tics compared to placebo-treated patients. In a controlled study of adolescent patients with ADHD and co morbid Major Depressive Disorder, atomoxetine-treated patients did not experience worsening of depression compared to placebo-treated patients. In two controlled studies (one in paediatric patients and one in adult patients) of patients with ADHD and co-morbid anxiety disorders, atomoxetine-treated patients did not experience worsening of anxiety compared to placebo-treated patients.
There have been rare postmarketing reports of anxiety and depression or depressed mood and very rare reports of tics in patients taking atomoxetine (see section 4.8).
Patients who are being treated for ADHD with atomoxetine should be monitored for the appearance or worsening of anxiety symptoms, depressed mood and depression or tics.
Paediatric population under six years of age
Atomoxetine should not be used in patients less than six years of age as efficacy and safety have not been established in this age group.
Other therapeutic use
Atomoxetine is not indicated for the treatment of major depressive episodes and/or anxiety as the results of clinical trials in adults in these conditions, where ADHD is not present, did not show an effect compared to placebo (see section 5.1).
4.5 Interaction with other medicinal products and other forms of interaction
Effects of other drugs on atomoxetine:
MAOIs: Atomoxetine should not be used with MAOIs (see section 4.3).
CYP2D6 inhibitors (SSRIs (e.g. fluoxetine, paroxetine), quinidine, terbinafine): In patients receiving these drugs, atomoxetine exposure may be 6-to 8-fold increased and Css max 3 to 4 times higher, because it is metabolised by the CYP2D6 pathway. Slower titration and final lower dosage of atomoxetine may be necessary in patients who are already taking CYP2D6 inhibitor drugs. If a CYP2D6 inhibitor is prescribed or discontinued after titration to the appropriate atomoxetine dose has occurred, the clinical response and tolerability should be re- evaluated for that patient to determine if dose adjustment is needed.
Caution is advised when combining atomoxetine with potent inhibitors of cytochrome P450 enzymes other than CYP2D6 in patients who are poor CYP2D6 metabolisers as the risk of clinically relevant increases in atomoxetine exposure in vivo is unknown
Salbutamol (or other beta2 agonists):
Atomoxetine should be administered with caution to patients treated with high dose nebulised or systemically administered salbutamol (or other beta2 agonists) because cardiovascular effects can be potentiated.
Contradictory findings regarding this interaction were found. Systemically administered Salbutamol (600 μg i.v. over 2 hrs) in combination with atomoxetine (60 mg twice daily for 5 days) induced increases in heart rate and blood pressure. This effect was most marked after the initial coadministration of salbutamol and atomoxetine but returned towards baseline at the end of 8 hours. However, in a separate study the effects on blood pressure and heart rate of a standard inhaled dose of salbutamol (200 μg) were not increased by the short term coadministration of atomoxetine (80 mg once daily for 5 days) in a study of healthy Asian adults who were extensive atomoxetine metabolisers. Similarly heart rate after multiple inhalations of salbutamol (800 μg) did not differ in the presence or absence of atomoxetine.
Attention should be paid to monitoring heart rate and blood pressure, and dose adjustments may be justified for either atomoxetine or salbutamol (or other beta2 agonists) in the event of significant increases in heart rate and blood pressure during coadministration of these drugs.
There is the potential for an increased risk of QT interval prolongation when atomoxetine is administered with other QT prolonging drugs, (such as neuroleptics, class IA and III anti arrhythmics, moxifloxacin, erythromycin, methadone mefloquine, tricyclic antidepressants, lithium or cisapride) drugs that cause electrolyte imbalance (such as thiazide diuretics) and drugs that inhibit CYP2D6.
Seizures are a potential risk with atomoxetine. Caution is advised with concomitant use of medicinal drugs which are known to lower the seizure threshold (such as tricyclic antidepressants or SSRIs, neuroleptics, phenothiazines or butyrophenone, mefloquine, chloroquine, buproprion or tramadol). (see section 4.4). In addition, caution is advised when stopping concomitant treatment with benzodiazepines due to potential withdrawal seizures.
Anti-hypertensive drugs
Atomoxetine should be used cautiously with antihypertensive drugs. Because of a possible increase in blood pressure, atomoxetine may decrease the effectiveness of antihypertensive drugs / drugs used to treat hypertension. Attention should be paid to monitoring of blood pressure and review of treatment of atomoxetine or antihypertensive drugs may be justified in the case of significant changes of blood pressure.
Pressor agents or drugs that increase blood pressure
Because of possible increase in effects on blood pressure, atomoxetine should be used cautiously with pressor agents or drugs that may increase blood pressure (such as salbutamol). Attention should be paid to monitoring of blood pressure, and review of treatment for either atomoxetine or pressor agents may be justified in the case of significant change in blood pressure.
Drugs that Affect Noradrenaline:
Drugs that affect noradrenaline should be used cautiously when co-administered with atomoxetine because of the potential for additive or synergistic pharmacological effects. Examples include antidepressants such as imipramine, venlafaxine and mirtazapine, or the decongestants pseudoephedrine or phenylephrine.
Drugs that Affect Gastric pH:
Drugs that elevate gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) had no effect on atomoxetine bioavailability.
Drugs Highly Bound to Plasma Protein:
In vitro drug-displacement studies were conducted with atomoxetine and other highly bound drugs at therapeutic concentrations. Warfarin, acetylsalicylic acid, phenytoin, or diazepam did not affect the binding of atomoxetine to human albumin. Similarly, atomoxetine did not affect the binding of these compounds to human albumin.
4.6 Fertility, pregnancy and lactation
Pregnancy
Animal studies in general do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). For atomoxetine clinical data on exposed pregnancies are limited. Such data are insufficient to indicate either an association or a lack of association between atomoxetine and adverse pregnancy and/or lactation outcomes. Atomoxetine should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus.
Breast-feeding
Atomoxetine and/or its metabolites were excreted in the milk of rats. It is not known if atomoxetine is excreted in human milk. Because of the lack of data, atomoxetine should be avoided during breast-feeding.
4.7 Effects on ability to drive and use machines
Data on the effects on the ability to drive and use machines are limited. Atomoxetine has a minor influence on the ability to drive and use machines. Atomoxetine has been associated with increased rates of fatigue, somnolence, and dizziness relative to placebo in paediatric and adult patients. Patients should be advised to use caution when driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected by atomoxetine.
4.8 Undesirable effects
Paediatric population:
Summary of the safety profile
In paediatric placebo-controlled trials, headache, abdominal pain1 and decreased appetite are the adverse events most commonly associated with atomoxetine, and are reported by about 19%, 18% and 16% of patients respectively, but seldom lead to atomoxetine discontinuation (discontinuation rates are 0.1% for headache, 0.2% for abdominal pain and 0.0% for decreased appetite). Abdominal pain and decreased appetite are usually transient.
Associated with decreased appetite, some patients experienced growth retardation early in therapy in terms of both weight and height gain. On average, after an initial decrease in weight and height gain, patients treated with atomoxetine recovered to mean weight and height as predicted by group baseline data over the long-term treatment.
Nausea, vomiting and somnolence2 can occur in about 10% to 11% of patients particularly during the first month of therapy. However, these episodes were usually mild to moderate in severity and transient, and did not result in a significant number of discontinuation from therapy (discontinuation rates ≤ 0.5%).
In both paediatric and adult placebo-controlled trials, patients taking atomoxetine experienced increases in heart rate, systolic and diastolic blood pressure (see section 4.4).
Because of its effect on noradrenergic tone, orthostatic hypotension (0.2%) and syncope (0.8%) have been reported in patients taking atomoxetine. Atomoxetine should be used with caution in any condition that may predispose patients to hypotension.
The following table of undesirable effects is based on adverse event reporting and laboratory investigations from clinical trials and post marketing spontaneous reports in children and adolescents:
Tabulated list of adverse reactions
Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).
System Organ Class | Very common | Common | Uncommon | Rare |
Metabolism and nutrition disorders | Appetite decreased. | Anorexia (loss of appetite). | ||
| Psychiatric disorders | Irritability, mood swings, insomnia3, agitation *, anxiety, depression and depressed mood *, tics *. | Suicide-related events, aggression, hostility, emotional lability*, Psychosis (including hallucinations)* | ||
Nervous system disorders | Headache, somnolence2. | Dizziness. | Syncope, tremor, migraine, paraesthesia*, hypoaesthesia*, Seizure**. | |
| Eye disorders | Mydriasis. | Vision blurred. | ||
| Cardiac disorders | Palpitations, sinus tachycardia. QT interval prolongation | |||
Vascular disorders | Raynaud’s phenomenon. | |||
Respiratory, thoracic and mediastinal disorders | Dyspnoea (See section 4.4) |
Gastro intestinal disorders | Abdominal pain1, vomiting, nausea. | Constipation, dyspepsia. | ||
| Hepatobiliary disorders | Blood bilirubin increased*. | Abnormal/increa sed liver function tests, jaundice, hepatitis, liver injury, acute hepatic failure*. | ||
Skin and subcutaneous tissue disorders | Dermatitis, pruritus, rash. | Hyperhidrosis, allergic reactions. | ||
Renal and urinary disorders | Urinary hesitation, urinary retention. | |||
Reproductive system and breast disorders | Priapism, male genital pain. | |||
General disorders and administration site conditions | Fatigue, lethargy. Chest pain (see section 4.4). | Asthenia. | ||
| Investigations | Blood pressure increased4, heart rate increased4. | Weight decreased. |
2 Also includes abdominal pain upper, stomach discomfort, abdominal discomfort and epigastric discomfort.
3 Also includes sedation
4 Includes initial, middle and terminal (early morning wakening) insomnia 5 Heart rate and blood pressure findings are based on measured vital signs * See section 4.4
** See section 4.4 and section 4.5
CYP2D6 poor metabolisers (PM)
The following adverse events occurred in at least 2% of CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared with CYP2D6 extensive metaboliser (EM) patients: appetite decreased (24.1% of PMs, 17.0% of EMs); insomnia combined (including insomnia, middle insomnia and initial insomnia, 14.9% of PMs, 9.7% of EMs); depression combined (including depression, major depression, depressive symptom, depressed mood and dysphoria, 6.5% of PMs and 4.1% of EMs), weight decreased (7.3% of PMs, 4.4% of EMs), constipation 6.8% of PMs, 4.3% of EMs); tremor (4.5% of PMs, 0.9% of EMs); sedation (3.9% of PMs, 2.1% of EMs); excoriation (3.9% of PMs, 1.7% of EMs); enuresis (3.0% of PMs, 1.2% of EMs); conjunctivitis (2.5% of PMs, 1.2% of EMs); syncope (2.5% of PMs, 0.7% of EMs); early morning awakening (2.3% of PMs, 0.8% of EMs); mydriasis (2.0% of PMs, 0.6% of EMs). The following event did not meet the above criteria but is noteworthy: generalised anxiety disorder (0.8% of PMs and 0.1% of EMs). In addition, in trials lasting up to 10 weeks, weight loss was more pronounced in PM patients (mean of 0.6 kg in EM and 1.1kg in PM).
Adults:
Summary of the safety profile
In adult ADHD clinical trials, the following system organ classes had the highest frequency of adverse events during treatment with atomoxetine: gastrointestinal, nervous system and psychiatric disorders. The most common adverse events (≥5%) reported were appetite decreased (14.9%), insomnia (11.3%) headache (16.3%), dry mouth (18.4%) and nausea (26.7%). The majority of these events were mild or moderate in severity and the events most frequently reported as severe were nausea, insomnia, fatigue and headache. A complaint of urinary retention or urinary hesitancy in adults should be considered potentially related to atomoxetine.
The following table of undesirable effects is based on adverse event reporting and laboratory investigations from clinical trials and post marketing spontaneous reports in adults.
Tabulated list of adverse reactions
Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).
| System Organ | Very common | Common | Uncommon |
Rare
| Class | |||
Metabolism and nutrition disorders | Appetite decreased. | ||
| Psychiatric disorders | Insomnia2. | Agitation*, libido decreased, sleep disorder, depression and depressed mood*, anxiety, | Suicide-related events*, aggression, hostility and emotional lability*, restlessness, tics*. |
Psychosis
(including hallucinations) *.
Nervous system disorders | Headache. | Dizziness, dysgeusia, paraesthesia, somnolence (including sedation), tremor. | Syncope, migraine. hypoaesthesia *. |
Seizure**.
| Eye Disorders | Vision blurred. | ||
Cardiac disorders | Palpitations, tachycardia. | QT interval prolongation** |
Vascular disorders | Flushing, hot flush. | Peripheral coldness. |
Raynaud’s phenomenon.
Respiratory, thoracic and mediastinal disorders | Dyspnoea (see section 4.4). | ||
Gastrointestinal disorders | Dry mouth, nausea. | Abdominal pain1, constipation, dyspepsia, flatulence, vomiting. | |
Hepatobiliary disorders |
Abnormal/increase liver function tests, jaundice, hepatitis, liver injury, acute
hepatic failure, blood bilirubin increased*.
Skin and subcutaneous tissue disorders | Dermatitis, hyperhydrosis, rash. | Allergic reactions4, pruritis, urticaria. | |
Musculoskeletal and connective tissue disorders | Muscle spasms. | ||
| Renal and urinary disorders | Dysuria, pollakuria, urinary hesitation, urinary retention. | Micturation urgency. | |
Reproductive system and | Dysmenorrhoea, ejaculation | Ejaculation failure, |
Priapism.
| breast disorders | disorder, erectile dysfunction, prostatitis, male genital pain. | menstruation irregular, orgasm abnormal. | |
General disorders and administration site conditions | Asthenia, fatigue, lethargy, chills feeling jittery, irritability, thirst. | Feeling cold. Chest pain (see section 4.4) | |
| Investigations | Blood pressure increased3, heart rate increased3. | Weight decreased. |
2 Also includes abdominal pain upper, stomach discomfort, abdominal discomfort and epigastric discomfort.
3 Also includes initial insomnia, middle insomnia and terminal (early morning wakening) insomnia.
4 Heart rate and blood pressure findings are based on measured vital signs. 5 Includes anaphylactic reactions and angioneurotic oedema. * See section 4.4
** See section 4.4 and section 4.5
CYP2D6 poor metabolisers (PM)
The following adverse events occurred in at least 2% of CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared with CYP2D6 extensive metaboliser (EM) patients: vision blurred (3.9% of PMs, 1.3% of EMs), dry mouth (34.5% of PMs, 17.4% of EMs), constipation (11.3% of PMs, 6.7% of EMs), feeling jittery (4.9% of PMs, 1.9% of EMs), decreased appetite (23.2% of PMs, 14.7% of EMs), tremor (5.4% of PMs, 1.2% of EMs), insomnia (19.2% of PMs, 11.3% of EMs), sleep disorder (6.9% of PMs, 3.4% of EMs), middle insomnia (5.4% of PMs, 2.7% of EMs), terminal insomnia (3% of PMs, 0.9% of EMs), urinary retention (5.9% of PMs, 1.2% of EMs), erectile dysfunction (20.9% of PMs, 8.9% of EMs), ejaculation disorder (6.1% of PMs, 2.2% of EMs), hyperhidrosis (14.8% of PMs, 6.8% of EMs), peripheral coldness (3% of PMs, 0.5% of EMs).
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 via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
Signs and symptoms
During postmarketing, there have been reports of non-fatal acute and chronic overdoses of atomoxetine alone. The most commonly reported symptoms accompanying acute and chronic overdoses were gastrointestinal symptoms somnolence, dizziness, tremor and abnormal behaviour. Hyperactivity and agitation have also been reported. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g. tachycardia, blood pressure increased, mydriasis, dry mouth) were also observed and reports of pruritus and rash have been received. Most events were mild to moderate. In some cases of overdose involving atomoxetine, seizures have been reported and very rarely QT prolongation. There have also been reports of fatal, acute overdoses involving a mixed ingestion of atomoxetine and at least one other drug.
There is limited clinical trial experience with atomoxetine overdose.
Management
An airway should be established. Activated charcoal may be useful in limiting absorption if the patient presents within 1 hour of ingestion. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. The patient should be observed for a minimum of 6 hours. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Bacterial and viral vaccines combined, ATC code: J07CA02
Immune response
The immune responses to Boostrix-IPV were evaluated in clinical trials carried out in subjects of different ages having different vaccination histories (see section 4.8).
The following immune responses were observed across studies one month post vaccination with Boostrix-IPV in children, adolescents and adults (Table 4).
Table 4: Immune response in children, adolescents and adults
| Antigen | Response | Children aged 3 to 8 years N=1195 | Adults, adolescents | ||||
| and children aged | |||||||
| from 10 years | |||||||
| onwards | |||||||
| N=923 | |||||||
| (% vaccinees) | (% vaccinees) | ||||||
| Diphtheria | ≥ 0.1 IU/ml ≥ 0.016 IU/ml (1) | 100% NA | 82.2 – 100% 87.7 – 100% (2) | ||||
| Tetanus | ≥ 0.1 IU/ml | 99.9 – 100% | 99.6 – 100% | ||||
| Pertussis | Booster response (3) | 84.6 – 90.6% 90.1 – 98.8% 94.2 – 96.6% | 79.8 – 94.0% 90.7 – 97.2% 90.0 – 96.7% | ||||
| Pertussis toxoid | |||||||
| Filamentous | |||||||
| haemagglutinin | |||||||
| Pertactin | |||||||
| Inactivated poliovirus | ≥8 ED50 | 98.8 – 100% 99.2 – 100% 99.4 – 100% | 99.6 – 100% 99.6 – 100% 99.1 – 100% | ||||
| type 1 | |||||||
| type 2 | |||||||
| type 3 | |||||||
N=number of subjects
(1) Percentage of subjects with antibody concentrations associated with protection against disease (≥ 0.1 IU/ml by ELISA assay or ≥ 0.016 IU/ml by an in-vitro Vero-cell neutralisation assay).
(2) This assay was not performed in study HPV-042.
(3) Booster response defined as:
for initially seronegative subjects, antibody concentrations at least four times the cut-off
(post-vaccination concentration ≥ 20 El.U/ml);
- for initially seropositive subjects with Pre booster vaccination concentration ≥ 5 El.U/ml and < 20 El.U/ml: an increase in antibody concentrations of at least four times the Pre booster vaccination concentration.
for initially seropositive subjects with Pre booster vaccination concentration ≥ 20 El.U/ml:
an increase in antibody concentrations of at least two times the Pre booster vaccination concentration
As with other adult-type Td vaccines, Boostrix-IPV induces higher seroprotection rates and higher titres of both anti-D and anti-T antibodies in children and adolescents as compared to adults.
Persistence of the immune response
The following seroprotection/seropositivity rates were observed five years after vaccination with Boostrix-IPV in children and 10 years after vaccination with Boostrix-IPV in adolescents and adults (Table 5).
Table 5: Persistence of immune response in children, adolescents and adults
| Antigen | Seroprotection/ seropositivity | Percentages | Percentages meeting criteria 10 years after vaccination of adolescents and adults (aged 15 years onwards) (N=63) | |||||
| meeting criteria 5 | ||||||||
| years after | ||||||||
| vaccination of | ||||||||
| children (aged 4-8 | ||||||||
| years) | ||||||||
| (N=344) | ||||||||
| (% vaccinees) | (% vaccinees) | |||||||
| Diphtheria | ≥ 0.1 IU/ml | 89.4%* | 81.0%** | |||||
| Tetanus | ≥ 0.1 IU/ml | 98.5% | 98.4% | |||||
| Pertussis | ≥ 5 EL.U/ml | 40.9% 99.7% 97.1% | 78.7% 100% 88.7% | |||||
| Pertussis toxoid | ||||||||
| Filamentous | ||||||||
| haemagglutinin | ||||||||
| Pertactin | ||||||||
| Inactivated poliovirus | ≥ 8 ED50 | 98.8% 99.7% 97.1% | 100% 100% 98.3% | |||||
| type 1 | ||||||||
| type 2 | ||||||||
| type 3 | ||||||||
*98.2% of subjects with antibody concentrations associated with protection against disease ≥ 0.016 IU/ml by an in-vitro Vero-cell neutralisation assay.
**92.1% of subjects with antibody concentrations associated with protection against disease ≥ 0.01 IU/ml by an in-vitro Vero-cell neutralisation assay.
Immune response after a repeat dose
The immunogenicity of Boostrix-IPV, administered 5 years after a first booster dose of Boostrix-IPV at 4 to 8 years of age, has been evaluated. One month post vaccination, > 99 % of subjects were seropositive against pertussis and seroprotected against diphtheria, tetanus and all three poliovirus types.
In adults, one dose of Boostrix-IPV administered 10 years after the previous dose, elicited a protective immune response in > 96.8% of the subjects (for the diphtheria antigen) and in 100% of the subjects (for the tetanus and polio antigens). The booster response against the pertussis antigens was between 74.2 and 98.4%.
Immune response in subjects without prior or with unknown vaccination history
After administration of one dose of Boostrix (dTpa component of Boostrix-IPV) to 83 adolescents aged from 11 to 18 years, without previous pertussis vaccination and no vaccination against diphtheria and tetanus in the previous 5 years, all subjects were seroprotected against tetanus and diphtheria. The seropositivity rate after one dose varied between 87% and 100% for the different pertussis antigens.
After administration of one dose of Boostrix-IPV to 140 adults ≥ 40 years of age (including those who have never been vaccinated or whose vaccination status was unknown), that had not received any diphtheria and tetanus containing vaccine in the past 20 years, more than 96.4% of adults were seropositive for all three pertussis antigens and 77.7% and 95.7% were seroprotected against diphtheria and tetanus respectively.
Efficacy in protecting against pertussis
The pertussis antigens contained in Boostrix-IPV are an integral part of the paediatric acellular pertussis combination vaccine (Infanrix), for which efficacy after primary vaccination has been demonstrated in a household contact efficacy study. The antibody titres to all three pertussis components following vaccination with Boostrix-IPV are at least as high or higher than those observed during the household contact efficacy trial. Based on these comparisons, Boostrix-IPV would provide protection against pertussis, however the degree and duration of protection afforded by the vaccine are undetermined.
Passive protection against pertussis in infants (below 3 months of age) born to mothers vaccinated during pregnancy
In a randomised, cross-over, placebo-controlled study, higher pertussis antibody concentrations were demonstrated at delivery in the cord blood of babies born to mothers vaccinated with Boostrix (dTpa group; N=291) versus placebo (control group; N=292) at 27-36 weeks of pregnancy. The cord blood geometric mean concentrations of antibodies against the pertussis antigens PT, FHA and PRN were respectively 46.9, 366.1, 301.8 IU/ml in the dTpa group and 5.5, 22.7, 14.6 IU/ml in the control group. This corresponds to antibody titres that are 8, 16 and 21 times higher in the cord blood of babies born to vaccinated mothers versus controls. These antibody titres may provide passive protection against pertussis, as shown by observational effectiveness studies.
Immunogenicity in infants and toddlers born to mothers vaccinated during pregnancy
The immunogenicity of GlaxoSmithKline’s diphtheria, tetanus, hepatitis B, inactivated poliovirus, Haemophilus influenzae type b conjugate vaccine (Infanrix hexa) in infants and toddlers born to healthy mothers vaccinated with Boostrix at 27-36 weeks of pregnancy was evaluated in two clinical studies.
Infanrix hexa was co-administered with a 13-valent pneumococcal conjugate vaccine to infants for primary vaccination (n=268); and to the same infants/toddlers from 11 to 18 months as booster dose (n=229).
Post-primary and post-booster vaccination, immunological data did not show clinically relevant interference of maternal vaccination with Boostrix on the infant’s and toddler’s responses to diphtheria, tetanus, hepatitis B, inactivated poliovirus, Haemophilus influenzae type b or pneumococcal antigens.
Lower antibody concentrations against pertussis antigens post-primary (PT, FHA and PRN) and post-booster (PT, FHA) vaccination were observed in infants and toddlers born to mothers vaccinated with Boostrix during pregnancy. The fold-increases of anti-pertussis antibody concentrations from the pre-booster to the 1-month post-booster time point were in the same range for infants and toddlers born to mothers vaccinated with Boostrix or with placebo, demonstrating effective priming of the immune system. In the absence of correlates of protection for pertussis, the clinical relevance of these observations remains to be fully understood. However, current epidemiological data on pertussis disease following the implementation of dTpa maternal immunisation do not suggest any clinical relevance of this immune interference.
Effectiveness in the protection against pertussis disease in infants born to women vaccinated during pregnancy
Boostrix or Boostrix-IPV vaccine effectiveness (VE) was evaluated in three observational studies, in UK, Spain and Australia. The vaccine was used during the third trimester of pregnancy to protect infants below 3 months of age against pertussis disease, as part of a maternal vaccination programme.
Details of each study design and results are provided in Table 6.
Table 6: VE against pertussis disease for infants below 3 months of age born to mothers vaccinated during the third trimester of pregnancy with Boostrix/Boostrix-IPV
| Study location | Vaccine | Study design | Vaccination Effectiveness |
| UK | Boostrix- IPV | Retrospective, screening method | 88% (95% CI: 79, 93) |
| Spain | Boostrix | Prospective, matched case-control | 90.9% (95% CI: 56.6, 98.1) |
| Australia | Boostrix | Prospective, matched case-control | 69% (95% CI: 13, 89) |
CI: confidence interval
If maternal vaccination occurs within two weeks before delivery, vaccine effectiveness in the infant may be lower than the figures in the table.
5.2 Pharmacokinetic properties
The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults. The pharmacokinetics of atomoxetine have not been evaluated in children under 6 years of age.
Absorption: Atomoxetine is rapidly and almost completely absorbed after oral administration, reaching mean maximal observed plasma concentration (Cmax) approximately 1 to 2 hours after dosing. The absolute bioavailability of atomoxetine following oral administration ranged from 63% to 94% depending upon inter- individual differences in the modest first pass metabolism. Atomoxetine can be administered with or without food.
Distribution: Atomoxetine is widely distributed and is extensively (98%) bound to plasma proteins, primarily albumin.
Biotransformation: Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway. Individuals with reduced activity of this pathway (poor metabolisers) represent about 7% of the Caucasian population and, have higher plasma concentrations of atomoxetine compared with people with normal activity (extensive metabolisers). For poor metabolisers, AUC of atomoxetine is approximately 10-fold greater and Css, max is about 5- fold greater than extensive metabolisers. The major oxidative metabolite formed is 4- hydroxyatomoxetine that is rapidly glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine but circulates in plasma at much lower concentrations. Although 4-hydroxyatomoxetine is primarily formed by CYP2D6, in individuals that lack CYP2D6 activity, 4-hydroxyatomoxetine can be formed by several other cytochrome P450 enzymes, but at a slower rate. Atomoxetine does not inhibit or induce CYP2D6 at therapeutic doses.
Cytochrome P450 Enzymes: Atomoxetine did not cause clinically significant inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.
Elimination: The mean elimination half-life of atomoxetine after oral administration is 3.6 hours in extensive metabolisers and 21 hours in poor metabolisers. Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine. Linearity/non-linearity: pharmacokinetics of atomoxetine are linear over the range of doses studied in both extensive and poor metabolisers.
Special populations
Hepatic impairment results in a reduced atomoxetine clearance, increased atomoxetine exposure (AUC increased 2-fold in moderate impairment and 4-fold in severe impairment), and a prolonged half-life of parent drug compared to healthy controls with the same CYP2D6 extensive metaboliser genotype. In patients with moderate to severe hepatic impairment (Child Pugh Class B and C) initial and target doses should be adjusted (see section 4.2).
Atomoxetine mean plasma concentrations for end stage renal disease (ESRD) subjects were generally higher than the mean for healthy control subjects shown by Cmax (7% difference) and AUC0-∞ (about 65% difference) increases. After adjustment for body weight, the differences between the two groups are minimized. Pharmacokinetics of atomoxetine and its metabolites in individuals with ESRD suggest that no dose adjustment would be necessary (see section 4.2).
5.3 Preclinical safety data
Pre-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, or reproduction and development. Due to the dose limitation imposed by the clinical (or exaggerated pharmacological) response of the animals to the drug combined with metabolic differences among species, maximum tolerated doses in animals used in nonclinical studies produced atomoxetine exposures similar to or slightly above those that are achieved in CYP2D6 poor metabolizing patients at the maximum recommended daily dose.
A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioural and sexual development. Slight delays in onset of vaginal patency (all doses) and preputial separation (≥10 mg/kg/day) and slight decreases in epididymal weight and sperm number (≥10 mg/kg/day) were seen; however, there were no effects on fertility or reproductive performance. The significance of these findings to humans is unknown.
Pregnant rabbits were treated with up to 100 mg/kg/day of atomoxetine by gavage throughout the period of organogenesis. At this dose, in 1 of 3 studies, decrease in live foetuses, increase in early resorption, slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery were observed. These findings were observed at doses that caused slight maternal toxicity. The incidence of these findings is within historical control values. The no-effect dose for these findings was 30 mg/kg/day. Exposure (AUC) to unbound atomoxetine in rabbits, at 100 mg/kg/day was approximately 3.3 times (CYP2D6 extensive metabolisers) and 0.4 times (CYP2D6 poor metabolisers) those in humans at the maximum daily dose of 1.4 mg/kg/day. The findings in one of three rabbit studies were equivocal and the relevance to man is unknown.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsules content
Pregelatinized maize starch
Silica colloidal anhydrous
Dimeticone
Capsule shell
Atomoxetine Glenmark 80 mg hard capsules
Gelatin
Sodium Lauryl Sulfate
Titanium dioxide (E171)
Iron oxide red (E172)
Iron oxide yellow (E172)
Printing ink (black)
Shellac Glaze-45% (20% Esterified)
Iron Oxide Black (E172)
Propylene Glycol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Transparent PVC/PE/PCTFE-Aluminium foil blisters or PA/AL/PVC- Aluminium foil blisters in cardboard boxes.
Atomoxetine Glenmark 80 mg hard capsules are available in packs of 7, 28, 30 or 56 capsules.
Not all pack sizes may be marketed
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements
7 MARKETING AUTHORISATION HOLDER
Glenmark Pharmaceuticals Europe Limited
Laxmi House, 2B Draycott Avenue,
Kenton, Harrow,
Middlesex, HA3 0BU
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 25258/0275
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
29/10/2018
10 DATE OF REVISION OF THE TEXT
27/05/2020