Olanzapine Sandoz 20 mg Film-coated Tablets

1. Name Of The Medicinal Product

Olanzapine Sandoz 20 mg Film-coated Tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 20 mg olanzapine.

Excipient: 225.75 mg lactose/film-coated tablet

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Film-coated tablet

Pink, oval (13 mm length), with a breaking notch on both sides.

The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

Adults

Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.

Olanzapine is indicated for the treatment of moderate to severe manic episode.

In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the prevention of recurrence in patients with bipolar disorder (see section 5.1).

4.2 Posology And Method Of Administration

Adults

Schizophrenia: The recommended starting dose for olanzapine is 10 mg/day.

Manic episode: The starting dose is 15 mg as a single daily dose in monotherapy or 10 mg daily in combination therapy (see section 5.1).

Preventing recurrence in bipolar disorder: The recommended starting dose is 10 mg/day. For patients who have been receiving olanzapine for treatment of manic episode, continue therapy for preventing recurrence at the same dose. If a new manic, mixed, or depressive episode occurs, olanzapine treatment should be continued (with dose optimisation as needed), with supplementary therapy to treat mood symptoms, as clinically indicated.

During treatment for schizophrenia, manic episode, and recurrence prevention in bipolar disorder, daily dosage may subsequently be adjusted on the basis of individual clinical status within the range 5-20 mg/day. An increase to a dose greater than the recommended starting dose is advised only after appropriate clinical reassessment and should generally occur at intervals of not less than 24 hours. Olanzapine can be given without regard for meals, as absorption is not affected by food. Gradual tapering of the dose should be considered when discontinuing olanzapine.

Paediatric population

Olanzapine is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy. A greater magnitude of weight gain, lipid and prolactin alterations has been reported in short term studies of adolescent patients than in studies of adult patients (see sections 4.4, 4.8, 5.1 and 5.2).

Elderly

A lower starting dose (5 mg/day) is not routinely indicated but should be considered for those 65 and over when clinical factors warrant (see also section 4.4).

Renal and/or hepatic impairment

A lower starting dose (5 mg) should be considered for such patients. In cases of moderate hepatic insufficiency (cirrhosis, Child-Pugh class A or B), the starting dose should be 5 mg and only increased with caution.

Gender

The starting dose and dose range need not be routinely altered for female patients relative to male patients.

Smokers

The starting dose and dose range need not be routinely altered for non-smokers relative to smokers.

When more than one factor is present which might result in slower metabolism (female gender, geriatric age, non-smoking status), consideration should be given to decreasing the starting dose. Dose escalation, when indicated, should be conservative in such patients.

(See also section 4.5 and section 5.2.)

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients. Patients with known risk for narrow-angle glaucoma.

4.4 Special Warnings And Precautions For Use

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored during this period.

Dementia-related psychoses and/or behavioural disturbances

Olanzapine is not approved for the treatment of dementia-related psychosis and/or behavioural disturbances, and is not recommended for use in this particular group of patients because of an increase in mortality and the risk of cerebrovascular accident. In placebo-controlled clinical trials (6-12 weeks duration) of elderly patients (mean age 78 years) with dementia-related psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidence of death in olanzapine-treated patients compared to patients treated with placebo (3.5% versus 1.5%, respectively). The higher incidence of death was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk factors that may predispose this patient population to increased mortality include age >65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was higher in olanzapine-treated than in placebo-treated patients, independent of these risk factors.

In the same clinical trials, cerebrovascular adverse events (CVAE, e.g. stroke, transient ischaemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with olanzapine compared to patients treated with placebo (1.3% versus 0.4%, respectively). All olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing risk factors. Age >75 years and vascular/mixed type dementia were identified as risk factors for CVAE in association with olanzapine treatment. The efficacy of olanzapine was not established in these trials.

Parkinson's disease

The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo (see section 4.8), and olanzapine was not more effective than placebo in the treatment of psychotic symptoms. In these trials, patients were initially required to be stable on the lowest effective dose of anti-Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and titrated to a maximum of 15 mg/day based on investigator judgement.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicinal products, including olanzapine, must be discontinued.

Hyperglycaemia and diabetes

Hyperglycaemia and/or development or exacerbation of diabetes, occasionally associated with ketoacidosis or coma, has been reported rarely, including some fatal cases (see section 4.8). In some cases, a prior increase in body weight has been reported, which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with any antipsychotic medicinal products, including olanzapine, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly.

Lipid alterations

Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebo-controlled clinical trials (see section 4.8). Lipid alterations should be managed as clinically appropriate, particularly in dyslipidemic patients and in patients with risk factors for the development of lipid disorders. Patients treated with any antipsychotic medicinal products, including olanzapine, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines.

Anticholinergic activity

While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials revealed a low incidence of related events. However, as clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.

Hepatic function

Transient, asymptomatic elevations of hepatic aminotransferases, alanine transferase (ALT), aspartate transferase (AST), have been seen commonly, especially in early treatment. Caution should be exercised and follow-up organized in patients with elevated ALT and/or AST, in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic medicinal products. In cases where hepatitis (including hepatocellular, cholestatic, or mixed liver injury) has been diagnosed, olanzapine treatment should be discontinued.

Neutropenia

Caution should be exercised in patients with low leucocyte and/or neutrophil counts for any reason, in patients receiving medicinal products known to cause neutropenia, in patients with a history of drug-induced bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant illness, radiation therapy or chemotherapy, and in patients with hypereosinophilic conditions or with myeloproliferative disease. Neutropenia has been reported commonly when olanzapine and valproate are used concomitantly (see section 4.8).

Discontinuation of treatment

Acute symptoms, such as sweating, insomnia, tremor, anxiety, nausea, or vomiting, have been reported very rarely (<0.01%) when olanzapine is stopped abruptly.

QT interval

In clinical trials, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF]

Thromboembolism

Temporal association of olanzapine treatment and venous thromboembolism has very rarely (<0.01%) been reported. A causal relationship between the occurrence of venous thromboembolism and treatment with olanzapine has not been established. However, since patients with schizophrenia often present with acquired risk factors for venous thromboembolism, all possible risk factors of VTE, e.g., immobilisation of patients, should be identified and preventive measures undertaken.

General CNS activity

Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicinal products and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonise the effects of direct and indirect dopamine agonists.

Seizures

Olanzapine should be used cautiously in patients who have a history of seizures or are subject to factors which may lower the seizure threshold. Seizures have been reported to occur rarely in patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures were reported.

Tardive dyskinesia

In comparator studies of one year or less duration, olanzapine was associated with a statistically significant lower incidence of treatment emergent dyskinesia. However, the risk of tardive dyskinesia increases with long-term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.

Postural hypotension

Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. As with other antipsychotics, it is recommended that blood pressure is measured periodically in patients over 65 years.

Sudden cardiac death

In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychotics included in a pooled analysis.

Paediatric population

Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic parameters and increases in prolactin levels. Long-term outcomes associated with these events have not been studied and remain unknown (see sections 4.8 and 5.1).

Lactose

Olanzapine film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Paediatric population

Interaction studies have only been performed in adults.

Potential interactions affecting olanzapine

Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.

Induction of CYP1A2

The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead to reduced olanzapine concentrations. Only slight to moderate increase in olanzapine clearance has been observed. The clinical consequences are likely to be limited, but clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary (see section 4.2).

Inhibition of CYP1A2

Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine C_max following fluvoxamine was 54% in female non-smokers and 77% in male smokers. The mean increase in olanzapine AUC was 52% and 108%, respectively. A lower starting dose of olanzapine should be considered in patients who are using fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.

Decreased bioavailability

Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60% and should be taken at least 2 hours before or after olanzapine.

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have not been found to significantly affect the pharmacokinetics of olanzapine.

Potential for olanzapine to affect other medicinal products

Olanzapine may antagonise the effects of direct and indirect dopamine agonists.

Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4). Thus, no particular interaction is expected, as verified through in vivo studies, where no inhibition of metabolism of the following active substances was found: tricyclic antidepressant (representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2), or diazepam (CYP3A4 and 2C19).

Olanzapine showed no interaction when co-administered with lithium or biperiden.

Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is required after the introduction of concomitant olanzapine.

General CNS activity

Caution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression.

The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson's disease and dementia is not recommended (see section 4.4).

QTc interval

Caution should be used if olanzapine is being administered concomitantly with medicinal products known to increase QTc interval (see section 4.4).

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.

Spontaneous reports have been very rarely received on tremor, hypertonia, lethargy, and sleepiness, in infants born to mothers who had used olanzapine during the 3^rd trimester.

Breast feeding

In a study in breast-feeding, healthy women, olanzapine was excreted in breast milk. Mean infant exposure (mg/kg) at steady-state was estimated to be 1.8% of the maternal olanzapine dose (mg/kg). Patients should be advised not to breast-feed an infant if they are taking olanzapine.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Because olanzapine may cause somnolence and dizziness, patients should be cautioned about operating machinery, including motor vehicles.

4.8 Undesirable Effects

Adults

The most frequently (seen in

The following table lists the adverse reactions and laboratory investigations observed from spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows:

Very common (

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)

Not known (cannot be estimated from the available data)

Very common	Common	Uncommon	Not known
Blood and the lymphatic system disorders
	Eosinophilia	Leukopenia Neutropenia	Thrombocytopenia
Immune system disorders
			Allergic reaction
Metabolism and nutrition disorders
Weight gain1	Elevated cholesterol levels2,3 Elevated glucose levels4 Elevated triglyceride levels2,5 Glucosuria Increased appetite		Development or exacerbation of diabetes occasionally associated with ketoacidosis or coma, including some fatal cases (see section 4.4) Hypothermia
Nervous system disorders
Somnolence	Dizziness Akathisia6 Parkinsonism6 Dyskinesia6		Seizures where in most cases a history of seizures or risk factors for seizures were reported Neuroleptic malignant syndrome (see section 4.4)
			Dystonia (including oculogyration) Tardive dyskinesia Discontinuation symptoms7
Cardiac disorders
		Bradycardia QTc prolongation (see section 4.4)	Ventricular tachycardia/fibrillation, sudden death (see section 4.4)
Vascular disorders
	Orthostatic hypotension		Thromboembolism (including pulmonary embolism and deep vein thrombosis)
Gastrointestinal disorders
	Mild, transient anticholinergic effects including constipation and dry mouth		Pancreatitis
Hepato-biliary disorders
	Transient, asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in early treatment (see section 4.4)		Hepatitis (including hepatocellular, cholestatic or mixed liver injury)
Skin and subcutaneous tissue disorders
	Rash	Photosensitivity reaction Alopecia
Musculoskeletal and connective tissue disorders
			Rhabdomyolysis
Renal and urinary disorders
		Urinary incontinence	Urinary hesitation
Reproductive system and breast disorders
			Priapism
General disorders and administration site conditions
	Asthenia Fatigue Oedema
Investigations
Elevated plasma prolactin levels8		High creatine phosphokinase Increased total bilirubin	Increased alkaline phosphatase

¹ Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Following short term treatment (median duration 47 days), weight gain

² Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

³ Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high (

⁴ Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (

⁵ Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high (

⁶ In clinical trials, the incidence of parkinsonism and dystonia in olanzapine-treated patients was numerically higher, but not statistically significantly different from placebo. Olanzapine-treated patients had a lower incidence of parkinsonism, akathisia and dystonia compared with titrated doses of haloperidol. In the absence of detailed information on the pre-existing history of individual acute and tardive extrapyramidal movement disorders, it can not be concluded at present that olanzapine produces less tardive dyskinesia and/or other tardive extrapyramidal syndromes.

⁷ Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been reported when olanzapine is stopped abruptly.

⁸ In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of normal range in approximately 30% of olanzapine treated patients with normal baseline prolactin value. In the majority of these patients the elevations were generally mild, and remained below two times the upper limit of normal range. Generally in olanzapine-treated patients potentially associated breast- and menstrual related clinical manifestations (e.g. amenorrhoea, breast enlargement, galactorrhea in females, and gynaecomastia/breast enlargement in males) were uncommon. Potentially associated sexual function-related adverse reactions (e.g. erectile dysfunction in males and decreased libido in both genders) were commonly observed.

Long-term exposure (at least 48 weeks)

The proportion of patients who had adverse, clinically significant changes in weight gain, glucose, total/LDL/HDL cholesterol or triglycerides increased over time. In adult patients who completed 9-12 months of therapy, the rate of increase in mean blood glucose slowed after approximately 6 months.

Additional information on special populations

In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher incidence of death and cerebrovascular adverse reactions compared to placebo (see also section 4.4). Very common adverse reactions associated with the use of olanzapine in this patient group were abnormal gait and falls. Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations and urinary incontinence were observed commonly.

In clinical trials in patients with drug-induced (dopamine agonist) psychosis associated with Parkinson's disease, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo.

In one clinical trial in patients with bipolar mania, valproate combination therapy with olanzapine resulted in an incidence of neutropenia of 4.1%; a potential contributing factor could be high plasma valproate levels. Olanzapine administered with lithium or valproate resulted in increased levels (

Paediatric population

Olanzapine is not indicated for the treatment of children and adolescent patients below 18 years. Although no clinical studies designed to compare adolescents to adults have been conducted, data from the adolescent trials were compared to those of the adult trials.

The following table summarises the adverse reactions reported with a greater frequency in adolescent patients (aged 13-17 years) than in adult patients or adverse reactions only identified during short-term clinical trials in adolescent patients. Clinically significant weight gain (

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows:

Very common (

Common (

Metabolism and nutrition disorders Very common: Weight gain9, elevated triglyceride levels10, increased appetite. Common: Elevated cholesterol levels11

Nervous system disorders Very common: Sedation (including: hypersomnia, lethargy, somnolence).

Gastrointestinal disorders Common: Dry mouth

Hepato-biliary disorders Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4).

Investigations Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels12.

⁹ Following short term treatment (median duration 22 days), weight gain

¹⁰ Observed for fasting normal levels at baseline (< 1.016 mmol/l) which increased to high (

¹¹ Changes in total fasting cholesterol levels from normal at baseline (< 4.39 mmol/l) to high (

¹² Elevated plasma prolactin levels were reported in 47.4% of adolescent patients.

4.9 Overdose

Signs and symptoms

Very common symptoms in overdose (>10% incidence) include tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma.

Other medically significant sequelae of overdose include delirium, convulsion, coma, possible Neuroleptic Malignant Syndrome, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmias (<2% of overdose cases), and cardiopulmonary arrest. Fatal outcomes have been reported for acute overdoses as low as 450 mg, but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.

Management of overdose

There is no specific antidote for olanzapine. Induction of emesis is not recommended. Standard procedures for management of overdose may be indicated (i.e. gastric lavage, administration of activated charcoal). The concomitant administration of activated charcoal was shown to reduce the oral bioavailability of olanzapine by 50 to 60%.

Symptomatic treatment and monitoring of vital organ function should be instituted according to clinical presentation, including treatment of hypotension and circulatory collapse and support of respiratory function. Do not use epinephrine, dopamine, or other sympathomimetic agents with beta-agonist activity, since beta stimulation may worsen hypotension. Cardiovascular monitoring is necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue until the patient recovers.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antipsychotics: diazepines, oxazepines and thiazepines

ATC code: N05A H03

Olanzapine is an antipsychotic, antimanic, and mood stabilising agent that demonstrates a broad pharmacologic profile across a number of receptor systems.

In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki; <100 nM) for serotonin 5HT_2A/2C, 5HT₃, 5HT₆; dopamine D₁, D₂, D₃, D₄, D₅; cholinergic muscarinic receptors m₁-m₅; alpha₁ adrenergic; and histamine H₁ receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine demonstrated a greater in vitro affinity for serotonin 5HT₂ than dopamine D₂ receptors and greater 5HT₂ than D₂ activity in in vivo models. Electrophysiological studies demonstrated that olanzapine selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases responding in an 'anxiolytic' test.

In a single oral dose (10 mg) Positron Emission Tomography (PET) study in healthy volunteers, olanzapine produced a higher 5HT_2A than dopamine D₂ receptor occupancy. In addition, a Single Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed that olanzapine-responsive patients had lower striatal D₂ occupancy than some other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsive patients.

In two of two placebo- and two of three comparator-controlled trials with over 2,900 schizophrenic patients presenting with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms.

In a multinational, double-blind, comparative study of schizophrenia, schizoaffective and related disorders, which included 1,481 patients with varying degrees of associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary analysis of baseline to endpoint mood score change demonstrated a statistically significant improvement (P = 0.001) favouring olanzapine (-6.0) versus haloperidol. (-3.1).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks.

In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also showed a statistically significant advantage over placebo in terms of preventing either recurrence into mania or recurrence into depression.

In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; P = 0.055).

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria.

Paediatric population

The experience in adolescents (ages 13 to 17 years) is limited to short term efficacy data in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no data on maintenance of effect and limited data on long term safety (see sections 4.4 and 4.8).

5.2 Pharmacokinetic Properties

Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food. Absolute oral bioavailability relative to intravenous administration has not been determined.

Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide, which does not pass the blood brain barrier. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites; both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic activity is from the parent, olanzapine. After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects varied on the basis of age and gender.

In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was prolonged (51.8 versus 33.8 hr) and the clearance was reduced (17.5 versus 18.2 l/hr). The pharmacokinetic variability observed in the elderly is within the range for the non-elderly. In 44 patients with schizophrenia >65 years of age, dosing from 5 to 20 mg/day was not associated with any distinguishing profile of adverse events.

In female versus male subjects, the mean elimination half-life was somewhat prolonged (36.7 versus 32.3 hr) and the clearance was reduced (18.9 versus 27.3 l/hr). However, olanzapine (5-20 mg) demonstrated a comparable safety profile in female (n = 467) as in male patients (n = 869).

In renally impaired patients (creatinine clearance <10 ml/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hr) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57% of radiolabelled olanzapine appeared in urine, principally as metabolites.

In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hr) was prolonged and clearance (18.0 l/hr) was reduced analogous to non-smoking healthy subjects (48.8 hr and 14.1 l/hr, respectively).

In non-smoking versus smoking subjects (males and females), the mean elimination half-life was prolonged (38.6 versus 30.4 hr) and the clearance was reduced (18.6 versus 27.7 l/hr).

The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.

The plasma protein binding of olanzapine was about 93% over the concentration range of about 7 to about 1,000 ng/ml. Olanzapine is bound predominantly to albumin and alpha₁-acid-glycoprotein.

Paediatric population

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents. Demographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents.

5.3 Preclinical Safety Data

Sumatriptan

Dosage Form: tablet
PRESCRIBING INFORMATION

Sumatriptan TABLETS, USP

Rx only

Sumatriptan Description

Sumatriptan tablets, USP contain Sumatriptan (as the succinate), a selective 5-hydroxytryptamine1 receptor subtype agonist. Sumatriptan succinate, USP is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure:

The molecular formula is C14H21N3O2S•C4H6O4, representing a molecular weight of 413.5. Sumatriptan succinate, USP is a white or almost white powder that is freely soluble in water, sparingly soluble in methanol and practically insoluble in methylene chloride. Each Sumatriptan tablet, USP for oral administration contains 35, 70, or 140 mg of Sumatriptan succinate, USP equivalent to 25, 50, or 100 mg of Sumatriptan, respectively. Each tablet also contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and talc.

Sumatriptan - Clinical Pharmacology

Mechanism of Action

Sumatriptan is an agonist for a vascular 5-hydroxytryptamine1 receptor subtype (probably a member of the 5-HT1D family) having only a weak affinity for 5-HT1A, 5-HT5A, and 5-HT7 receptors and no significant affinity (as measured using standard radioligand binding assays) or pharmacological activity at 5-HT2, 5-HT3, or 5-HT4 receptor subtypes or at alpha1-, alpha2-, or beta-adrenergic; dopamine1; dopamine2; muscarinic; or benzodiazepine receptors.

The vascular 5-HT1 receptor subtype that Sumatriptan activates is present on cranial arteries in both dog and primate, on the human basilar artery, and in the vasculature of human dura mater and mediates vasoconstriction. This action in humans correlates with the relief of migraine headache. In addition to causing vasoconstriction, experimental data from animal studies show that Sumatriptan also activates 5-HT1 receptors on peripheral terminals of the trigeminal nerve innervating cranial blood vessels. Such an action may also contribute to the antimigrainous effect of Sumatriptan in humans.

In the anesthetized dog, Sumatriptan selectively reduces the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance. In the cat, Sumatriptan selectively constricts the carotid arteriovenous anastomoses while having little effect on blood flow or resistance in cerebral or extracerebral tissues.

Pharmacokinetics

The mean maximum concentration following oral dosing with 25 mg is 18 ng/mL (range, 7 to 47 ng/mL) and 51 ng/mL (range, 28 to 100 ng/mL) following oral dosing with 100 mg of Sumatriptan. This compares with a Cmax of 5 and 16 ng/mL following dosing with a 5 and 20 mg intranasal dose, respectively. The mean Cmax following a 6 mg subcutaneous injection is 71 ng/mL (range, 49 to 110 ng/mL). The bioavailability is approximately 15%, primarily due to presystemic metabolism and partly due to incomplete absorption. The Cmax is similar during a migraine attack and during a migraine-free period, but the Tmax is slightly later during the attack, approximately 2.5 hours compared to 2 hours. When given as a single dose, Sumatriptan displays dose proportionality in its extent of absorption (area under the curve [AUC]) over the dose range of 25 to 200 mg, but the Cmax after 100 mg is approximately 25% less than expected (based on the 25 mg dose).

A food effect study involving administration of Sumatriptan tablets 100 mg to healthy volunteers under fasting conditions and with a high-fat meal indicated that the Cmax and AUC were increased by 15% and 12%, respectively, when administered in the fed state.

Plasma protein binding is low (14% to 21%). The effect of Sumatriptan on the protein binding of other drugs has not been evaluated, but would be expected to be minor, given the low rate of protein binding. The apparent volume of distribution is 2.4 L/kg.

The elimination half-life of Sumatriptan is approximately 2.5 hours. Radiolabeled 14C-Sumatriptan administered orally is largely renally excreted (about 60%) with about 40% found in the feces. Most of the radiolabeled compound excreted in the urine is the major metabolite, indole acetic acid (IAA), which is inactive, or the IAA glucuronide. Only 3% of the dose can be recovered as unchanged Sumatriptan.

In vitro studies with human microsomes suggest that Sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme, and inhibitors of that enzyme may alter Sumatriptan pharmacokinetics to increase systemic exposure. No significant effect was seen with an MAO-B inhibitor (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions).

Special Populations

Renal Impairment

The effect of renal impairment on the pharmacokinetics of Sumatriptan has not been examined, but little clinical effect would be expected as Sumatriptan is largely metabolized to an inactive substance.

Hepatic Impairment

The liver plays an important role in the presystemic clearance of orally administered Sumatriptan. Accordingly, the bioavailability of Sumatriptan following oral administration may be markedly increased in patients with liver disease. In 1 small study of hepatically impaired patients (N = 8) matched for sex, age, and weight with healthy subjects, the hepatically impaired patients had an approximately 70% increase in AUC and Cmax and a Tmax 40 minutes earlier compared to the healthy subjects (see DOSAGE AND ADMINISTRATION).

Age

The pharmacokinetics of oral Sumatriptan in the elderly (mean age, 72 years; 2 males and 4 females) and in patients with migraine (mean age, 38 years; 25 males and 155 females) were similar to that in healthy male subjects (mean age, 30 years) (see PRECAUTIONS: Geriatric Use).

Gender

In a study comparing females to males, no pharmacokinetic differences were observed between genders for AUC, Cmax, Tmax, and half-life.

Race

The systemic clearance and Cmax of Sumatriptan were similar in black (N = 34) and Caucasian (N = 38) healthy male subjects.

Drug Interactions

Monoamine Oxidase Inhibitors

Treatment with MAO-A inhibitors generally leads to an increase of Sumatriptan plasma levels (see CONTRAINDICATIONS and PRECAUTIONS).

Due to gut and hepatic metabolic first-pass effects, the increase of systemic exposure after coadministration of an MAO-A inhibitor with oral Sumatriptan is greater than after coadministration of the monoamine oxidase inhibitors (MAOI) with subcutaneous Sumatriptan. In a study of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous Sumatriptan. Under the conditions of this experiment, the result was a 2-fold increase in the area under the Sumatriptan plasma concentration x time curve (AUC), corresponding to a 40% increase in elimination half-life. This interaction was not evident with an MAO-B inhibitor.

A small study evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from a 25 mg oral Sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure.

Alcohol

Alcohol consumed 30 minutes prior to Sumatriptan ingestion had no effect on the pharmacokinetics of Sumatriptan.

Clinical Studies

The efficacy of Sumatriptan tablets in the acute treatment of migraine headaches was demonstrated in 3, randomized, double-blind, placebo-controlled studies. Patients enrolled in these 3 studies were predominately female (87%) and Caucasian (97%), with a mean age of 40 years (range, 18 to 65 years). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 4 hours after dosing. Associated symptoms such as nausea, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours postdose. A second dose of Sumatriptan tablets or other medication was allowed 4 to 24 hours after the initial treatment for recurrent headache. Acetaminophen was offered to patients in Studies 2 and 3 beginning at 2 hours after initial treatment if the migraine pain had not improved or worsened. Additional medications were allowed 4 to 24 hours after the initial treatment for recurrent headache or as rescue in all 3 studies. The frequency and time to use of these additional treatments were also determined. In all studies, doses of 25, 50, and 100 mg were compared to placebo in the treatment of migraine attacks. In 1 study, doses of 25, 50, and 100 mg were also compared to each other.

In all 3 trials, the percentage of patients achieving headache response 2 and 4 hours after treatment was significantly greater among patients receiving Sumatriptan tablets at all doses compared to those who received placebo. In 1 of the 3 studies, there was a statistically significant greater percentage of patients with headache response at 2 and 4 hours in the 50 or 100 mg group when compared to the 25 mg dose groups. There were no statistically significant differences between the 50 and 100 mg dose groups in any study. The results from the 3 controlled clinical trials are summarized in Table 1.

Comparisons of drug performance based upon results obtained in different clinical trials are never reliable. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.

Table 1. Percentage of Patients With Headache Response (No or Mild Pain) 2 and 4 Hours Following Treatment

	Placebo		Sumatriptan Tablets	Sumatriptan Tablets	Sumatriptan Tablets
			25 mg	50 mg	100 mg
	2 hr	4 hr	2 hr 4 hr	2 hr 4 hr	2 hr 4 hr
Study 1	27%	38%	52%* 67%*	61%*† 78%*†	62%*† 79%*†
	(N = 94)		(N = 298)	(N = 296)	(N = 296)
Study 2	26%	38%	52%* 70%*	50%* 68%*	56%* 71%*
	(N = 65)		(N = 66)	(N = 62)	(N = 66)
Study 3	17%	19%	52%* 65%*	54%* 72%*	57%* 78%*
	(N = 47)		(N = 48)	(N = 46)	(N = 46)

*p < 0.05 in comparison with placebo.

†p < 0.05 in comparison with 25 mg.

The estimated probability of achieving an initial headache response over the 4 hours following treatment is depicted in Figure 1.

Figure 1. Estimated Probability of Achieving Initial Headache Response Within 240 Minutes*

*The figure shows the probability over time of obtaining headache response (no or mild pain) following treatment with Sumatriptan. The averages displayed are based on pooled data from the 3 clinical controlled trials providing evidence of efficacy. Kaplan-Meier plot with patients not achieving response and/or taking rescue within 240 minutes censored to 240 minutes.

For patients with migraine-associated nausea, photophobia, and/or phonophobia at baseline, there was a lower incidence of these symptoms at 2 hours (Study 1) and at 4 hours (Studies 1, 2, and 3) following administration of Sumatriptan tablets compared to placebo.

As early as 2 hours in Studies 2 and 3 or 4 hours in Study 1, through 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.

Figure 2. The Estimated Probability of Patients Taking a Second Dose or Other Medication forMigraineOverthe 24 Hours FollowingtheInitialDoseofStudyTreatment *

*Kaplan-Meier plot based on data obtained in the 3 clinical controlled trials providing evidence of efficacy with patients not using additional treatments censored to 24 hours. Plot also includes patients who had no response to the initial dose. No remedication was allowed within 2 hours postdose.

There is evidence that doses above 50 mg do not provide a greater effect than 50 mg. There was no evidence to suggest that treatment with Sumatriptan was associated with an increase in the severity of recurrent headaches. The efficacy of Sumatriptan tablets was unaffected by presence of aura; duration of headache prior to treatment; gender, age, or weight of the patient; relationship to menses; or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants). There were insufficient data to assess the impact of race on efficacy.

INDICATIONS AND USAGE

Sumatriptan tablets, USP are indicated for the acute treatment of migraine attacks with or without aura in adults.

Sumatriptan tablets, USP are not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine (see CONTRAINDICATIONS). Safety and effectiveness of Sumatriptan tablets, USP have not been established for cluster headache, which is present in an older, predominantly male population.

Contraindications

Sumatriptan tablets should not be given to patients with history, symptoms, or signs of ischemic cardiac, cerebrovascular, or peripheral vascular syndromes. In addition, patients with other significant underlying cardiovascular diseases should not receive Sumatriptan tablets. Ischemic cardiac syndromes include, but are not limited to, angina pectoris of any type (e.g., stable angina of effort and vasospastic forms of angina such as the Prinzmetal variant), all forms of myocardial infarction, and silent myocardial ischemia.

Cerebrovascular syndromes include, but are not limited to, strokes of any type as well as transient ischemic attacks. Peripheral vascular disease includes, but is not limited to, ischemic bowel disease (seeWARNINGS).

Because Sumatriptan tablets may increase blood pressure, they should not be given to patients with uncontrolled hypertension.

Concurrent administration of MAO-A inhibitors or use within 2 weeks of discontinuation of MAO-A inhibitor therapy is contraindicated (seeCLINICAL PHARMACOLOGY: Drug InteractionsandPRECAUTIONS: Drug Interactions).

Sumatriptan tablets should not be administered to patients with hemiplegic or basilar migraine.

Sumatriptan tablets and any ergotamine-containing or ergot-type medication (like dihydroergotamine or methysergide) should not be used within 24 hours of each other, nor should Sumatriptan and another 5-HT1agonist.

Sumatriptan tablets are contraindicated in patients with hypersensitivity to Sumatriptan or any of their components.

Sumatriptan tablets are contraindicated in patients with severe hepatic impairment.

Warnings

Sumatriptan tablets should only be used where a clear diagnosis of migraine headache has been established.

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events

Sumatriptan should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) (seeCONTRAINDICATIONS). It is strongly recommended that Sumatriptan not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history or electrocardiographic investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, Sumatriptan should not be administered (seeCONTRAINDICATIONS).

For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of Sumatriptan tablets take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received Sumatriptan. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following Sumatriptan tablets, in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of Sumatriptan and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use Sumatriptan.

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to Sumatriptan.

Drug-Associated Cardiac Events and Fatalities

Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of Sumatriptan succinate injection or Sumatriptan tablets. Considering the extent of use of Sumatriptan in patients with migraine, the incidence of these events is extremely low.

The fact that Sumatriptan can cause coronary vasospasm, that some of these events have occurred in patients with no prior cardiac disease history and with documented absence of CAD, and the close proximity of the events to Sumatriptan use support the conclusion that some of these cases were caused by the drug. In many cases, however, where there has been known underlying coronary artery disease, the relationship is uncertain.

Premarketing Experience With Sumatriptan

Of 6,348 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of oral Sumatriptan, 2 experienced clinical adverse events shortly after receiving oral Sumatriptan that may have reflected coronary vasospasm. Neither of these adverse events was associated with a serious clinical outcome.

Among the more than 1,900 patients with migraine who participated in premarketing controlled clinical trials of subcutaneous Sumatriptan, there were 8 patients who sustained clinical events during or shortly after receiving Sumatriptan that may have reflected coronary artery vasospasm. Six of these 8 patients had ECG changes consistent with transient ischemia, but without accompanying clinical symptoms or signs. Of these 8 patients, 4 had either findings suggestive of CAD or risk factors predictive of CAD prior to study enrollment.

Among approximately 4,000 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of Sumatriptan nasal spray, 1 patient experienced an asymptomatic subendocardial infarction possibly subsequent to a coronary vasospastic event.

Postmarketing Experience With Sumatriptan

Serious cardiovascular events, some resulting in death, have been reported in association with the use of Sumatriptan succinate injection or Sumatriptan tablets. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by Sumatriptan or to reliably assess causation in individual cases. On clinical grounds, the longer the latency between the administration of Sumatriptan and the onset of the clinical event, the less likely the association is to be causative. Accordingly, interest has focused on events beginning within 1 hour of the administration of Sumatriptan.

Cardiac events that have been observed to have onset within 1 hour of Sumatriptan administration include: coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia and ventricular fibrillation, cardiac arrest, and death.

Some of these events occurred in patients who had no findings of CAD and appear to represent consequences of coronary artery vasospasm. However, among domestic reports of serious cardiac events within 1 hour of Sumatriptan administration, almost all of the patients had risk factors predictive of CAD and the presence of significant underlying CAD was established in most cases (see CONTRAINDICATIONS).

Drug-Associated Cerebrovascular Events and Fatalities

Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with oral or subcutaneous Sumatriptan, and some have resulted in fatalities. The relationship of Sumatriptan to these events is uncertain. In a number of cases, it appears possible that the cerebrovascular events were primary, Sumatriptan having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should also be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., cerebrovascular accident, transient ischemic attack).

Other Vasospasm-Related Events

Sumatriptan may cause vasospastic reactions other than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported. Very rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of Sumatriptan. Visual disorders may also be part of a migraine attack.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome may occur with triptans, including treatment with Sumatriptan, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with Sumatriptan and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Increase in Blood Pressure

Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients with and without a history of hypertension. Sumatriptan is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS). Sumatriptan should be administered with caution to patients with controlled hypertension as transient increases in blood pressure and peripheral vascular resistance have been observed in a small proportion of patients.

Concomitant Drug Use

In patients taking MAO-A inhibitors, Sumatriptan plasma levels attained after treatment with recommended doses are 7-fold higher following oral administration than those obtained under other conditions. Accordingly, the coadministration of Sumatriptan tablets and an MAO-A inhibitor is contraindicated (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).

Hypersensitivity

Hypersensitivity (anaphylaxis/anaphylactoid) reactions have occurred on rare occasions in patients receiving Sumatriptan. Such reactions can be life threatening or fatal. In general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens (see CONTRAINDICATIONS).

Precautions

General

Chest discomfort and jaw or neck tightness have been reported following use of Sumatriptan tablets and have also been reported infrequently following administration of Sumatriptan nasal spray. Chest, jaw, or neck tightness is relatively common after administration of Sumatriptan succinate injection. Only rarely have these symptoms been associated with ischemic ECG changes. However, because Sumatriptan may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following Sumatriptan should be evaluated for the presence of CAD or a predisposition to Prinzmetal variant angina before receiving additional doses of Sumatriptan, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud syndrome following Sumatriptan should be evaluated for atherosclerosis or predisposition to vasospasm (see WARNINGS).

Sumatriptan should also be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as impaired hepatic or renal function.

There have been rare reports of seizure following administration of Sumatriptan. Sumatriptan should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

Care should be taken to exclude other potentially serious neurologic conditions before treating headache in patients not previously diagnosed with migraine headache or who experience a headache that is atypical for them. There have been rare reports where patients received Sumatriptan for severe headaches that were subsequently shown to have been secondary to an evolving neurologic lesion (see WARNINGS).

For a given attack, if a patient does not respond to the first dose of Sumatriptan, the diagnosis of migraine should be reconsidered before administration of a second dose.

Binding to Melanin-Containing Tissues

In rats treated with a single subcutaneous dose (0.5 mg/kg) or oral dose (2 mg/kg) of radiolabeled Sumatriptan, the elimination half-life of radioactivity from the eye was 15 and 23 days, respectively, suggesting that Sumatriptan and/or its metabolites bind to the melanin of the eye. Because there could be an accumulation in melanin-rich tissues over time, this raises the possibility that Sumatriptan could cause toxicity in these tissues after extended use. However, no effects on the retina related to treatment with Sumatriptan were noted in any of the oral or subcutaneous toxicity studies. Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects.

Corneal Opacities

Sumatriptan causes corneal opacities and defects in the corneal epithelium in dogs; this raises the possibility that these changes may occur in humans. While patients were not systematically evaluated for these changes in clinical trials, and no specific recommendations for monitoring are being offered, prescribers should be aware of the possibility of these changes (see ANIMAL TOXICOLOGY).

Information for Patients

See PATIENT INFORMATION at the end of this labeling for the text of the detachable leaflet provided for patients.

Patients should be cautioned about the risk of serotonin syndrome with the use of Sumatriptan or other triptans, especially during combined use with SSRIs or SNRIs.

Laboratory Tests

No specific laboratory tests are recommended for monitoring patients prior to and/or after treatment with Sumatriptan.

Drug Interactions

Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome

Cases of life-threatening serotonin syndrome have been reported during combined use of SSRIs or SNRIs and triptans (see WARNINGS).

Ergot-Containing Drugs

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and Sumatriptan within 24 hours of each other should be avoided (see CONTRAINDICATIONS).

Monoamine Oxidase-A Inhibitors

MAO-A inhibitors reduce Sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of Sumatriptan tablets in patients receiving MAO-A inhibitors is contraindicated (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).

Drug/Laboratory Test Interactions

Sumatriptan tablets are not known to interfere with commonly employed clinical laboratory tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In carcinogenicity studies, rats and mice were given Sumatriptan by oral gavage (rats, 104 weeks) or drinking water (mice, 78 weeks). Average exposures achieved in mice receiving the highest dose (target dose of 160 mg/kg/day) were approximately 40 times the exposure attained in humans after the maximum recommended single oral dose of 100 mg. The highest dose administered to rats (160 mg/kg/day, reduced from 360 mg/kg/day during week 21) was approximately 15 times the maximum recommended single human oral dose of 100 mg on a mg/m2 basis. There was no evidence of an increase in tumors in either species related to Sumatriptan administration.

Mutagenesis

Sumatriptan was not mutagenic in the presence or absence of metabolic activation when tested in 2 gene mutation assays (the Ames test and the in vitro mammalian Chinese hamster V79/HGPRT assay). In 2 cytogenetics assays (the in vitro human lymphocyte assay and the in vivo rat micronucleus assay) Sumatriptan was not associated with clastogenic activity.

Impairment of Fertility

In a study in which male and female rats were dosed daily with oral Sumatriptan prior to and throughout the mating period, there was a treatment-related decrease in fertility secondary to a decrease in mating in animals treated with 50 and 500 mg/kg/day. The highest no-effect dose for this finding was 5 mg/kg/day, or approximately one half of the maximum recommended single human oral dose of 100 mg on a mg/m2 basis. It is not clear whether the problem is associated with treatment of the males or females or both combined. In a similar study by the subcutaneous route there was no evidence of impaired fertility at 60 mg/kg/day, the maximum dose tested, which is equivalent to approximately 6 times the maximum recommended single human oral dose of 100 mg on a mg/m2 basis.

Pregnancy

Pregnancy Category C. In reproductive toxicity studies in rats and rabbits, oral treatment with Sumatriptan was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to rabbits, Sumatriptan has been shown to be embryolethal. There are no adequate and well-controlled studies in pregnant women. Therefore, Sumatriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In assessing this information, the following findings should be considered.

Embryolethality

When given orally or intravenously to pregnant rabbits daily throughout the period of organogenesis, Sumatriptan caused embryolethality at doses at or close to those producing maternal toxicity. In the oral studies this dose was 100 mg/kg/day, and in the intravenous studies this dose was 2 mg/kg/day. The mechanism of the embryolethality is not known. The highest no-effect dose for embryolethality by the oral route was 50 mg/kg/day, which is approximately 9 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. By the intravenous route, the highest no-effect dose was 0.75 mg/kg/day, or approximately one tenth of the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

The intravenous administration of Sumatriptan to pregnant rats throughout organogenesis at 12.5 mg/kg/day, the maximum dose tested, did not cause embryolethality. This dose is equivalent to the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. Additionally, in a study in rats given subcutaneous Sumatriptan daily prior to and throughout pregnancy at 60 mg/kg/day, the maximum dose tested, there was no evidence of increased embryo/fetal lethality. This dose is equivalent to approximately 6 times the maximum recommended single human oral dose of 100 mg on a mg/m2 basis.

Teratogenicity

Oral treatment of pregnant rats with Sumatriptan during the period of organogenesis resulted in an increased incidence of blood vessel abnormalities (cervicothoracic and umbilical) at doses of approximately 250 mg/kg/day or higher. The highest no-effect dose was approximately 60 mg/kg/day, which is approximately 6 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. Oral treatment of pregnant rabbits with Sumatriptan during the period of organogenesis resulted in an increased incidence of cervicothoracic vascular and skeletal abnormalities. The highest no-effect dose for these effects was 15 mg/kg/day, or approximately 3 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

A study in which rats were dosed daily with oral Sumatriptan prior to and throughout gestation demonstrated embryo/fetal toxicity (decreased body weight, decreased ossification, increased incidence of rib variations) and an increased incidence of a syndrome of malformations (short tail/short body and vertebral disorganization) at 500 mg/kg/day. The highest no-effect dose was 50 mg/kg/day, or approximately 5 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. In a study in rats dosed daily with subcutaneous Sumatriptan prior to and throughout pregnancy, at a dose of 60 mg/kg/day, the maximum dose tested, there was no evidence of teratogenicity. This dose is equivalent to approximately 6 times the maximum recommended single human oral dose of 100 mg on a mg/m2 basis.

Pup Deaths

Oral treatment of pregnant rats with Sumatriptan during the period of organogenesis resulted in a decrease in pup survival between birth and postnatal day 4 at doses of approximately 250 mg/kg/day or higher. The highest no-effect dose for this effect was approximately 60 mg/kg/day, or 6 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

Oral treatment of pregnant rats with Sumatriptan from gestational day 17 through postnatal day 21 demonstrated a decrease in pup survival measured at postnatal days 2, 4, and 20 at the dose of 1,000 mg/kg/day. The highest no-effect dose for this finding was 100 mg/kg/day, approximately 10 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. In a similar study in rats by the subcutaneous route there was no increase in pup death at 81 mg/kg/day, the highest dose tested, which is equivalent to 8 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

Nursing Mothers

Sumatriptan is excreted in human breast milk following subcutaneous administration. Infant exposure to Sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with Sumatriptan tablets.

Pediatric Use

Safety and effectiveness of Sumatriptan tablets in pediatric patients under 18 years of age have not been established; therefore, Sumatriptan tablets are not recommended for use in patients under 18 years of age.

Two controlled clinical trials evaluating Sumatriptan nasal spray (5 to 20 mg) in pediatric patients aged 12 to 17 years enrolled a total of 1,248 adolescent migraineurs who treated a single attack. The studies did not establish the efficacy of Sumatriptan nasal spray compared to placebo in the treatment of migraine in adolescents. Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults.

Five controlled clinical trials (2 single attack studies, 3 multiple attack studies) evaluating oral Sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These studies did not establish the efficacy of oral Sumatriptan compared to placebo in the treatment of migraine in adolescents. Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse events in these patients appeared to be both dose- and age-dependent, with younger patients reporting events more commonly than older adolescents.

Postmarketing experience documents that serious adverse events have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal Sumatriptan. These reports include events similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral Sumatriptan; clinical signs occurred within 1 day of drug administration. Since clinical data to determine the frequency of serious adverse events in pediatric patients who might receive injectable, oral, or intranasal Sumatriptan are not presently available, the use of Sumatriptan in patients aged younger than 18 years is not recommended.

Geriatric Use

The use of Sumatriptan in elderly patients is not recommended because elderly patients are more likely to have decreased hepatic function, they are at higher risk for CAD, and blood pressure increases may be more pronounced in the elderly (see WARNINGS).

Adverse Reactions

Serious cardiac events, including some that have been fatal, have occurred following the use of Sumatriptan succinate injection or tablets. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation(seeCONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).

Significant hypertensive episodes, including hypertensive crises, have been reported on rare occasions in patients with or without a history of hypertension (see WARNINGS).

Incidence in Controlled Clinical Trials

Oramorph Oral Solution

Oramorph Oral Solution 10 mg/5 ml

(morphine sulphate)

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects gets troublesome or serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What ORAMORPH Oral Solution is and what it is used for


• 2. Before you take ORAMORPH Oral Solution


• 3. How to take ORAMORPH Oral Solution


• 4. Possible side effects


• 5. How to store ORAMORPH Oral Solution


• 6. Further information

What Oramorph Oral Solution Is And What It Is Used For

The name of your medicine is ORAMORPH Oral Solution 10 mg/5 ml (called ORAMORPH in this leaflet).

• It contains a medicine called morphine sulphate. This belongs to a group of medicines called ‘opioid analgesics’


• It is used to relieve severe pain

Before You Take Oramorph Oral Solution

Do not take ORAMORPH if:

• You are allergic (hypersensitive) to morphine sulphate or any of the other ingredients of ORAMORPH (listed in Section 6 below)


• You have problems with your lungs or breathing such as ‘hypoventilation’ or ‘Chronic Obstructive Pulmonary Disorder’ (COPD)


• You are having an asthma attack


• You have sudden or recent liver problems


• You have recently had a head injury


• You have something called ‘phaeochromocytoma’. This is a rare tumour which is not malignant


• You have fits (convulsions) or raised pressure inside your skull


• The person taking the medicine is in a deep and prolonged unconscious state (coma)


• You are addicted to alcohol or have recently consumed large amounts of alcohol


• You are taking or have in the last two weeks taken medication to treat depression such as monoamine-oxidase inhibitors (MAOI)


• You have paralytic ileus (loss of intestinal movement)

Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist.

Take special care with ORAMORPH

Check with your doctor or pharmacist before taking your medicine if:

• You are pregnant, trying to become pregnant or if you are breast-feeding


• You have had an operation within the last 24 hours


• You have a particular lung problem that causes shortness of breath called emphysema


• You have shock (circulatory failure)


• You have asthma


• You have gall bladder problems


• You have long term (chronic) liver or kidney problems


• You are a man who has prostate problems


• You have an under-active thyroid gland or swelling of your skin (myxoedema)


• Your spine is unusually curved (kyphoscoliosis)


• You have bowel problems


• You have an under-active adrenal gland (adrenocortical insufficiency)


• You are very overweight

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking ORAMORPH.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines that you buy without a prescription and herbal medicines. This is because ORAMORPH can affect the way some other medicines work. Also some other medicines can affect the way ORAMORPH works.

In particular tell your doctor or pharmacist if you are taking any of the following medicines:

• Medicines to help you sleep, make you feel less anxious or calm you down such as tranquilisers, hypnotics, sedatives, antipsychotics or tricyclic antidepressants


• Anaesthetics - used during operations


• Domperidone and metoclopramide – for feeling sick (nausea) and being sick (vomiting)


• Mexiletine and esmolol – for controlling heart rhythm


• Ritonavir – for HIV infections


• Cimetidine – for stomach ulcers, indigestion or heartburn


• Monoamine oxidase inhibitors (MAOIs) - for depression


• Voriconazole - for some fungal infections


• Gabapentin - for epilepsy and long lasting pain caused by damage to the nerves

Taking ORAMORPH with food and drink

You should avoid alcohol whilst taking this medicine.

Pregnancy and breast-feeding

Talk to your doctor before taking this medicine if you are pregnant, trying to become pregnant or if you are breast-feeding.

If you take this medicine during pregnancy or while breast-feeding, it may slow down the baby’s breathing. If you take this medicine for a long time whilst pregnant, it may mean that the baby will be born showing signs of withdrawal.

Operations and anaesthetics

Tell your doctor or pharmacist if you are due to have an operation or an anaesthetic or if you have had an operation or an anaesthetic within the last 24 hours.

Driving and using machines

You may feel drowsy while taking this medicine. If this happens, do not drive or use any tools or machines.

Important information about some of the ingredients of ORAMORPH

This medicine contains:

• 
  Ethanol (Alcohol): This product contains 10 volume % ethanol (alcohol). Each dose contains up to 0.81 g of alcohol which is equivalent to 20 ml beer or 8.3 ml wine


• 
  Sucrose: This product contains 30 g of sucrose in the 100 ml bottle, 90 g of sucrose in the 300 ml bottle, and 150 g of sucrose in the 500 ml bottle. When taken according to the dosage recommendations each dose supplies up to 3 g of sucrose. You should not take this product if you have a bowel condition that makes you intolerant to some sugars such as fructose, glucose, galactose or sucrose


• 
  Methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) - These may cause allergic reactions in some people that could occur some time after taking this medicine. The signs may include swelling of the mouth and face, sudden breathing difficulties and your blood pressure being lower than normal

How To Take Oramorph Oral Solution

Always take this medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Taking this medicine

• Take this medicine by mouth


• Use a 5 ml plastic spoon to measure your dose


• They are available from your pharmacist

How much to take

Your doctor will decide the amount of medicine to give you.

Adults

• The usual dose is 5 to 10 ml (one to two teaspoons) every four hours

Children 6 to 12 years

• The most that should be taken is 2.5 to 5 ml (half to one teaspoon) every four hours

Children 1 to 5 years

• The most that should be taken is 2.5 ml (half a teaspoon) every four hours

Children under 1 year

• Do not give this medicine to children under 1 year

Being given more or less of this medicine

• For some people, it may be necessary for the doctor to give a higher dose


• For other people (for example the elderly, people with kidney or liver problems and people that should not be sedated) the doctor may decide to use a lower dose

Your body may get used to the medicine (tolerance)

• Do not take more than your doctor has prescribed


• If you have been taking your medicine for some time you may find that it does not seem to be working as well as it did. If this happens, talk to your doctor

If you take more ORAMORPH than you should

If you take more of this medicine than you should, talk to a doctor or go to a hospital straight away. Take the medicine pack with you. This is so the doctor knows what you have taken.

If you take more than you should, the following effects may happen:

• The black circle in the centre of your eyes (pupil) gets smaller


• You breath more slowly


• You have low blood pressure

In more severe cases, very high doses could cause your blood circulation to slow down and cause unconsciousness for a long time, or even death. In children a high dose may cause fits (convulsions).

If you forget to take ORAMORPH

• If you forget a dose, take it as soon as you remember it and take your next dose at the usual time


• If it is nearly time for the next dose, skip the missed dose. This is because the time between doses should be at least 4 hours


• Do not take a double dose to make up for a forgotten dose

If you stop taking ORAMORPH

It is important to talk to your doctor if you want to stop taking your medicine. Do not stop taking your medicine suddenly. This is because your body may have got used to it. Also, you may need to have your dose lowered slowly.

Possible Side Effects

Like all medicines, ORAMORPH can cause side effects, although not everybody gets them. The following side effects may happen with this medicine:

Allergic reactions

If you have a severe allergic reaction, stop taking this medicine and see a doctor straight away. Signs may include swelling of the mouth and face, difficulty breathing, dizziness and skin reactions such as rash and itching.

Tell your doctor straight away if you notice the following side effects. You may need urgent medical treatment:

• Having a headache. This could be a sign of raised pressure inside your skull


• Feeling dizzy or unsteady when you stand up. This could be a sign of a temporary fall in blood pressure (orthostatic hypotension)


• Shallow breathing, with a slow heartbeat (bradycardia) and cold clammy skin


• Feeling restless, irritable or having changes in your mood


• Stomach pain caused by spasm (cramps) of the tubes that carry urine to the bladder or bile to the intestines

Other side effects

• Feeling sick (nausea) or being sick (vomiting)


• Constipation, which can be treated with appropriate laxatives


• Difficulty in passing water (urine)


• Feeling drowsy


• Dry mouth, sweating and flushing of your face


• Your heart rate getting faster (tachycardia) or slower (bradycardia) or fast and uneven (palpitations)


• Lower body temperature (hypothermia)


• Lowered sex drive


• Seeing or hearing things that are not there (hallucinations) or feeling confused


• Muscles feeling tense


• The black circle in the centre of your eyes (pupil) getting smaller (miosis)


• Dependence on ORAMORPH. This can happen with any morphine product

If any of the side effects gets troublesome or serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How To Store Oramorph Oral Solution

Keep out of the reach and sight of children.

Do not use this medicine after the expiry date which is stated on the bottle label and the outer carton. The expiry date refers to the last day of the month.

Do not store ORAMORPH above 25°C.

Store in the original container in order to protect from light.

Please return any remaining medicine to your pharmacist 3 months after first opening.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What ORAMORPH contains

• Each 5 ml contains 10 mg of morphine sulphate as the active ingredient


• The other ingredients are alcohol (ethanol), corn syrup, sucrose, methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216) and purified water

What ORAMORPH looks like and content of the pack

ORAMORPH is a solution and is available in bottles of 100, 250, 300 and 500 ml. The bottles come in cartons.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisation for ORAMORPH is held by:

Boehringer Ingelheim Limited

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

United Kingdom

and the solution is manufactured by:

Istituto de Angeli S.r.l.

at: Località Prulli Si Sotto n. 103/C

50066 Reggello (FI)

Italy

This leaflet was revised in April 2009.

© Boehringer Ingelheim Limited 2009

437736/GB/10

naloxone

Generic Name: naloxone (nah LOX own)

Brand Names: Narcan

What is naloxone?

Naloxone is an special narcotic drug that reverses the effects of other narcotic medicines.

Naloxone is used to reverse the effects of narcotic drugs used during surgery or to treat pain.

Naloxone may also be used to treat narcotic drug overdose or to diagnose narcotic drug addiction.

Naloxone may also be used for purposes not listed in this medication guide.

What is the most important information I should know about naloxone?

You should not use this medication if you are allergic to naloxone.

In an emergency situation it may not be possible before you are treated to tell your caregivers about your health conditions or if you are pregnant or breast feeding. Make sure any doctor caring for you afterward knows that you have received this medication.

Naloxone may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. If you are using any narcotic pain medication, the pain-relieving effects of the narcotic will be reversed while you are also receiving naloxone. Drinking alcohol can increase certain side effects of naloxone.

What should I discuss with my health care provider before using naloxone?

You should not use this medication if you are allergic to naloxone.

If possible before you receive naloxone, tell your doctor if you have:

• 
  

  heart disease;

  
  


• 
  

  seizures;

  
  


• 
  

  a history of head injury or brain tumor; or

  
  


• 
  

  a history of drug or alcohol addiction.

  
  

FDA pregnancy category C. It is not known whether naloxone will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether naloxone passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I use naloxone?

Naloxone is injected into a muscle or under the skin, or into a vein through an IV. You will receive this injection in a clinic or hospital setting.

Your breathing, blood pressure, oxygen levels, kidney function, and other vital signs will be watched closely while you are receiving naloxone. This will help your doctor determine how long to treat you with this medication.

What happens if I miss a dose?

Because you will receive naloxone in a clinical setting, you are not likely to miss a dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include seizure (convulsions), feeling light-headed, or fainting.

What should I avoid while using naloxone?

Naloxone may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Drinking alcohol can increase certain side effects of naloxone.

Naloxone side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

• 
  

  chest pain, fast or irregular heartbeats;

  
  


• 
  

  dry cough, wheezing, feeling short of breath;

  
  


• 
  

  sweating, severe nausea or vomiting;

  
  


• 
  

  severe headache, agitation, anxiety, confusion, ringing in your ears;

  
  


• 
  

  seizure (convulsions);

  
  


• 
  

  feeling like you might pass out; or

  
  


• 
  

  slow heart rate, weak pulse, fainting, slow breathing (breathing may stop).

  
  

If you are being treated for narcotic drug addiction, the expected symptoms of withdrawal would include:

• 
  

  feeling nervous, restless, or irritable;

  
  


• 
  

  body aches;

  
  


• 
  

  dizziness, weakness;

  
  


• 
  

  diarrhea, stomach pain, mild nausea;

  
  


• 
  

  fever, chills, goosebumps; or

  
  


• 
  

  sneezing, runny nose.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Naloxone Dosing Information

Usual Adult Dose for Opioid Overdose:

0.4 to 2 mg/dose IV/IM/subcutaneously. May repeat every 2 to 3 minutes as needed. Therapy may need to be reassessed if no response is seen after a cumulative dose of 10 mg.

Continuous infusion: 0.005 mg/kg loading dose followed by an infusion of 0.0025 mg/kg/hr.

Usual Pediatric Dose for Opioid Overdose:

Infants, Children, and Adolescents:
Opioid intoxication (full reversal):
IV (preferred) or Intraosseous (IO): Note: May be administered IM, Subcutaneous, or endotracheal tube (ET), but onset of action may be delayed, especially if patient has poor perfusion; ET preferred if IV or IO route not available; doses may need to be repeated.

Infants and Children less than or equal to 5 years or less than or equal to 20 kg: 0.1 mg/kg/dose; repeat every 2 to 3 minutes if needed; may need to repeat doses every 20 to 60 minutes.

Children greater than 5 years or greater than 20 kg and Adolescents: 2 mg/dose; if no response, repeat every 2 to 3 minutes; may need to repeat doses every 20 to 60 minutes.

ET: Optimal endotracheal dose unknown; current expert recommendations are 2 to 3 times the IV dose.

Manufacturer recommendations: IV (preferred), IM, Subcutaneous:
Initial: 0.01 mg/kg/dose; if no response, a subsequent dose of 0.1 mg/kg may be given
Note: If using IM or Subcutaneous route, dose should be given in divided doses.

Continuous IV infusion:
Children: If continuous infusion is required, calculate the initial dosage/hour based on the effective intermittent dose used and duration of adequate response seen; titrate dose; a range of 2.5 to 160 mcg/kg/hour has been reported; taper continuous infusion gradually to avoid relapse.

Respiratory depression [therapeutic opioid use (e.g., postanesthesia)]:
PALS Guidelines, 2010: IV: 0.001 to 0.005 mg/kg/dose; titrate to effect
Manufacturer recommendations: Initial: 0.005 to 0.01 mg/kg; repeat every 2 to 3 minutes as needed based on response.

Opioid-induced pruritus:
Children and Adolescents: Limited data available

What other drugs will affect naloxone?

If you are using any narcotic pain medication, the pain-relieving effects of the narcotic will be reversed while you are also receiving naloxone.

Tell your doctor about all other medicines you use, especially:

• 
  

  buprenorphine (Buprenex, Subutex);

  
  


• 
  

  methohexital (Brevital); or

  
  


• 
  

  narcotic pain medication such as codeine (Tylenol #3), hydrocodone (Lortab, Vicodin, Vicoprofen), hydromorphone (Dilaudid, Palladone), oxycodone (OxyContin, Percocet), fentanyl (Actiq, Duragesic), methadone (Methadose, Dolophine), morphine (Kadian, MS Contin, Oramorph), and many others.

  
  

This list is not complete and other drugs may interact with naloxone. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More naloxone resources

• Naloxone Side Effects (in more detail)
• Naloxone Dosage
• Naloxone Use in Pregnancy & Breastfeeding
• Naloxone Drug Interactions
• Naloxone Support Group
• 0 Reviews for Naloxone - Add your own review/rating

• Naloxone MedFacts Consumer Leaflet (Wolters Kluwer)


• Naloxone Prescribing Information (FDA)


• Naloxone Hydrochloride Monograph (AHFS DI)


• Narcan Prescribing Information (FDA)

Compare naloxone with other medications

• Opioid Overdose

Where can I get more information?

• Your pharmacist can provide more information about naloxone.

See also: naloxone side effects (in more detail)