INIR Capsule Ref.[51183] Active ingredients: Atomoxetine

Allergic events: allergic reactions including rash, angioedema and urticaria, have been reported in patients taking INIR.

Suicide-related behaviour (suicide attempts and suicidal ideation), hostility (predominantly aggression, oppositional behaviours and anger) and emotional lability: has been reported in patients treated with INIR. Patients should be monitored for the appearance and worsening of such behaviours.

The possibility of serious psychiatric adverse events cannot be excluded.

There is evidence that the risk of psychiatric adverse events is increased in children with a personal history of mood disorders, or who have a family history of mood disorders.

Mood swings: INIR may increase the risk of mood swings including hostility and emotional lability.

Hepatic effects: INIR should be discontinued in patients with jaundice or laboratory evidence of liver injury and should not be restarted. Rarely, liver toxicity manifested by elevated hepatic enzymes and bilirubin with jaundice, has been reported. Signs and symptoms likely to indicate liver involvement include, pruritus, dark urine, jaundice, right upper quadrant tenderness or unexplained “flu-like” symptoms. Laboratory testing to determine liver enzyme levels and bilirubin should be done upon the first sign or symptom of possible liver involvement. Due to the seemingly idiosyncratic nature of the liver injury, routine monitoring of liver function is unlikely to be helpful in minimising the risk of such reactions.

Depression: INIR lacks efficacy as treatment modality in depression.

Growth and development: Weight gain and longitudinal growth should be monitored during treatment with INIR.

Cardiovascular effects: Many patients taking INIR experience a modest increase in pulse (mean <10 bpm) and/or increase in blood pressure (mean <5 mm Hg). INIR should be used with caution in patients with hypertension, tachycardia, cardiovascular or cerebrovascular disease. Orthostatic hypotension has also been reported. Use with caution in any condition that may predispose patients to hypotension, or conditions associated with abrupt heart rate or blood pressure changes.

Paediatric use: The safety and efficacy of INIR in paediatric patients less than 6 years of age have not been established. The efficacy of atomoxetine beyond 18 months of treatment and safety of INIR beyond 2 years of treatment have not been systematically evaluated.

Geriatric use: The safety and efficacy of INIR in geriatric patients have not been established.

Monoamine oxidase inhibitors (MAOIs)

See ‘CONTRA-INDICATIONS’.

Interactions with other medicines and other forms of interaction

Beta-adrenergic receptor agonists: INIR should be administered with caution to patients being treated with systemically administered (oral, inhaled or intravenous) salbutamol or other β-2 agonists, because the action of salbutamol on the cardiovascular system can be potentiated.

Cytochrome P450 enzyme: Atomoxetine did not cause clinically significant inhibition of induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6 and CYP2C9. Atomoxetine is principally metabolised by the CYP2D6 pathway. In CYP2D6 extensive metabolisers, inhibitors of CYP2D6 increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in CYP2D6 poor metabolisers.

In vitro studies suggest that co-administration of cytochrome P450 inhibitors to CYP2D6 poor metabolisers will not increase the plasma concentrations of atomoxetine.

Slower titration of atomoxetine may be necessary. No dosage adjustment of INIR is required when co-administered with CYP2D6 inhibitors.

Methylphenidate: Co-administration of methylphenidate with INIR did not increase cardiovascular effects beyond those seen with methylphenidate administration alone.

Pressor medicines: Because of possible effects on blood pressure, INIR should be used cautiously with pressor medicines.

Medicines that affect gastric pH: Medicines that elevate gastric pH (magnesium hydroxide/aluminium hydroxide, omeprazole) had no effect on atomoxetine bioavailability.

Alcohol: Consumption of ethanol with INIR did not change the intoxicating effects of ethanol.

Midazolam: Co-administration of INIR (60 mg BID for 12 days) with midazolam, a model compound for CYP3A4 metabolised medicines (single dose of 5 mg), resulted in 15% increase in AUC of midazolam.

No dose adjustment is recommended for medicines metabolized by CYP3A.

Medicines that affect norepinephrine (noradrenaline): Medicines that affect norepinephrine should be used cautiously when co-administered with INIR because of the potential for additive or synergistic pharmacological effects.

Medicines highly bound to plasma protein: In vitro medicine-displacement studies were conducted with INIR and other highly bound medicines at therapeutic concentrations. INIR did not affect the binding of warfarin, acetylsalicylic acid, phenytoin or diazepam to human albumin. Similarly, these compounds did not affect the binding of INIR to human albumin.

Pregnancy

No adequate and well-controlled studies have been conducted with INIR in pregnant women.

Lactation

INIR and/or its metabolites were excreted in the milk of rats. It is not known if INIR is excreted in human milk.

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 INIR.

Table 1. Side effects in Child and Adolescent patients:

¹ Also includes upper abdominal pain, stomach and epigastric discomfort
² Also includes sedation

Table 2. Side effects in Adult patients:

¹ Also includes upper abdominal pain, stomach and epigastric discomfort
² Also includes sedation
^* Post-marketing experience: The following events have been reported: aggression, hostility, suicidal ideation, anger, suicidal behavior, abnormal liver function tests, jaundice and hepatitis* (see ‘WARNINGS AND SPECIAL PRECAUTIONS’).

Investigations: increased blood pressure.

Vascular disorders: peripheral vascular instability and/or Raynaud’s phenomenon, potential to worsen pre-existing Raynaud’s phenomenon.

Urogenital system: painful or prolonged penile erection, male genital pain, urinary hesitation and urinary retention in children and adolescents.

Nervous system disorders: syncope, paraesthesia in children and adolescents, hypoaesthesia.

Psychiatric disorders: sensory disturbances including hallucinations.

General disorders and administration site conditions: lethargy.