Axura · 4.1 Therapeutic indications · 1

HOS-093172 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile In clinical trials in mild to severe dementia, involving 1,784 patients treated with Axura and 1,595 patients treated with placebo, the overall incidence rate of adverse reactions with Axura did not differ from those with placebo; the adverse reactions were usually mild to moderate in severity. The most frequently occurring adverse reactions with a higher incidence in the Axura group than in the placebo group were dizziness (6.3% vs 5.6%, respectively), headache (5.2% vs 3.9%), constipation (4.6% vs 2.6%), somnolence (3.4% vs 2.2%) and hypertension (4.1% vs 2.8%). The following Adverse Reactions listed in the Table below have been accumulated in clinical studies with Axura and since its introduction in the market. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Tabulated list of adverse reactions Adverse reactions are ranked according to system organ class, using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTION Infections and infestations Uncommon Fungal infections 6  SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTION Immune systeme disorders Common Drug hypersensitivity Psychiatric disorders Common Somnolence Uncommon Confusion Uncommon Hallucinations1 Not known Psychotic reactions2 Nervous system disorders Common Dizziness Common Balance disorder Uncommon Gait abnormal Very rare Seizures Cardiac disorders Uncommon Cardiac failure Vascular disorders Common Hypertension Uncommon Venous thrombosis/thromboemb

Auszug; vollständigen Abschnitt im Original lesen.

HOS-093178 · has-adverse-reaction-information · PDF-Seite 16

Summary of the safety profile In clinical trials in mild to severe dementia, involving 1,784 patients treated with Axura and 1,595 patients treated with placebo, the overall incidence rate of adverse reactions with Axura did not differ from those with placebo; the adverse reactions were usually mild to moderate in severity. The most frequently occurring adverse reactions with a higher incidence in the Axura group than in the placebo group were dizziness (6.3% vs 5.6%, respectively), headache (5.2% vs 3.9%), constipation (4.6% vs 2.6%), somnolence (3.4% vs 2.2%) and hypertension (4.1% vs 2.8%). The following Adverse Reactions listed in the Table below have been accumulated in clinical studies with Axura and since its introduction in the market. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Tabulated list of adverse reactions Adverse reactions are ranked according to system organ class, using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTION Infections and infestations Uncommon Fungal infections Immune systeme disorders Common Drug hypersensitivity Psychiatric disorders Common Somnolence Uncommon Confusion Uncommon Hallucinations1 Not known Psychotic reactions2 Nervous system disorders Common Dizziness Common Balance disorder Uncommon Gait abnormal Very rare Seizures Cardiac disorders Uncommon Cardiac failure Vascular disorders Common Hypertension Uncommon Venous thrombosis/thromboembolism Respiratory, thoracic and mediastinal Common Dyspnoea disorders Gastrointestinal disorde

Auszug; vollständigen Abschnitt im Original lesen.

HOS-093168 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-093174 · has-contraindication-information · PDF-Seite 14

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-093167 · has-indication-information · PDF-Seite 3

Treatment of patients with moderate to severe Alzheimer’s disease.

HOS-093173 · has-indication-information · PDF-Seite 13

Treatment of patients with moderate to severe Alzheimer’s disease.

HOS-093176 · has-interaction-information · PDF-Seite 15

Due to the pharmacological effects and the mechanism of action of memantine the following interactions may occur: • The mode of action suggests that the effects of L-dopa, dopaminergic agonists, and anticholinergics may be enhanced by concomitant treatment with NMDA-antagonists such as memantine. The effects of barbiturates and neuroleptics may be reduced. Concomitant administration of memantine with the antispasmodic agents, dantrolene or baclofen, can modify their effects and a dose adjustment may be necessary. • Concomitant use of memantine and amantadine should be avoided, owing to the risk of pharmacotoxic psychosis. Both compounds are chemically related NMDA-antagonists. The same may be true for ketamine and dextromethorphan (see also section 4.4). There is one published case report on a possible risk also for the combination of memantine and phenytoin. • Other active substances such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine that use the same renal cationic transport system as amantadine may also possibly interact with memantine leading to a potential risk of increased plasma levels. • There may be a possibility of reduced serum level of hydrochlorothiazide (HCT) when memantine is co-administered with HCT or any combination with HCT. • In post-marketing experience isolated cases with international normalized ratio (INR) increases have been reported in patients concomitantly treated with warfarin. Although no causal relationship has been established, close monitoring of prothrombin time or INR is advisable for patients concomitantly treated with oral anticoagulants. In single-dose pharmacokinetic (PK) studies in young healthy subjects no relevant active substance-active substance interaction of memantine with glyburide/metformin or donepezil was observed. In a clinical study in young healthy subjects no relevant effect of memantine on the pharmacokinetics of galantamine was observed. Memantine did not inhibit CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin containing monooxygenase, epoxide hydrolase or sulphation in vitro.

HOS-093170 · has-interaction-information · PDF-Seite 5

Due to the pharmacological effects and the mechanism of action of memantine the following interactions may occur: • The mode of action suggests that the effects of L-dopa, dopaminergic agonists, and anticholinergics may be enhanced by concomitant treatment with NMDA-antagonists such as memantine. The effects of barbiturates and neuroleptics may be reduced. Concomitant administration of memantine with the antispasmodic agents, dantrolene or baclofen, can modify their effects and a dose adjustment may be necessary. • Concomitant use of memantine and amantadine should be avoided, owing to the risk of pharmacotoxic psychosis. Both compounds are chemically related NMDA-antagonists. The same may be true for ketamine and dextromethorphan (see also section 4.4). There is one published case report on a possible risk also for the combination of memantine and phenytoin. • Other active substances such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine that use the same renal cationic transport system as amantadine may also possibly interact with memantine leading to a potential risk of increased plasma levels. • There may be a possibility of reduced serum level of hydrochlorothiazide (HCT) when memantine is co-administered with HCT or any combination with HCT. • In post-marketing experience isolated cases with international normalized ratio (INR) increases have been reported in patients concomitantly treated with warfarin. Although no causal relationship has been established, close monitoring of prothrombin time or INR is advisable for patients concomitantly treated with oral anticoagulants. 5 In single-dose pharmacokinetic (PK) studies in young healthy subjects no relevant active substance- active substance interaction of memantine with glyburide/metformin or donepezil was observed. In a clinical study in young healthy subjects no relevant effect of memantine on the pharmacokinetics of galantamine was observed. Memantine did not inhibit CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin containing monooxygenase, epoxide hydrolase or sulphation in vitro.

HOS-093171 · has-pregnancy-information · PDF-Seite 6

Pregnancy For memantine, no clinical data on exposed pregnancies are available. Animal studies indicate a potential for reducing intrauterine growth at exposure levels, which are identical or slightly higher than at human exposure (see section 5.3). The potential risk for humans is unknown. Memantine should not be used during pregnancy unless clearly necessary. Breast-feeding It is not known whether memantine is excreted in human breast milk but, taking into consideration the lipophilicity of the substance, this probably occurs. Women taking memantine should not breast-feed. Fertility No adverse effects of memantine were noted on non-clinical male and female fertility studies.

HOS-093177 · has-pregnancy-information · PDF-Seite 15

Pregnancy For memantine, no clinical data on exposed pregnancies are available. Animal studies indicate a potential for reducing intrauterine growth at exposure levels, which are identical or slightly higher than at human exposure (see section 5.3). The potential risk for humans is unknown. Memantine should not be used during pregnancy unless clearly necessary. Breast-feeding It is not known whether memantine is excreted in human breast milk but, taking into consideration the lipophilicity of the substance, this probably occurs. Women taking memantine should not breast-feed. 15 Fertility No adverse effects of memantine were noted on non-clinical male and female fertility studies.

HOS-093175 · has-warning-information · PDF-Seite 14

Caution is recommended in patients with epilepsy, former history of convulsions or patients with predisposing factors for epilepsy. Concomitant use of other N-methyl-D-aspartate (NMDA)-antagonists such as amantadine, ketamine or dextromethorphan should be avoided. These compounds act at the same receptor system as memantine, and therefore adverse reactions (mainly central nervous system (CNS)-related may be more frequent or more pronounced (see also section 4.5). Some factors that may raise urine pH (see section 5.2 “Elimination”) may necessitate careful monitoring of the patient. These factors include drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or a massive ingestion of alkalising gastric buffers. Also, urine pH may be elevated by states of renal tubulary acidosis (RTA) or severe infections of the urinary tract with Proteus bacteria. 14 In most clinical trials, patients with recent myocardial infarction, uncompensated congestive heart failure (NYHA III-IV), or uncontrolled hypertension were excluded. As a consequence, only limited data are available and patients with these conditions should be closely supervised. Excipients: The oral solution contains sorbitol. Patients with hereditary fructose intolerance (HFI) should not take this medicinal product. Furthermore, this medicine contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially potassium-free.

HOS-093169 · has-warning-information · PDF-Seite 5

Caution is recommended in patients with epilepsy, former history of convulsions or patients with predisposing factors for epilepsy. Concomitant use of N-methyl-D-aspartate(NMDA)-antagonists such as amantadine, ketamine or dextromethorphan should be avoided. These compounds act at the same receptor system as memantine, and therefore adverse reactions (mainly central nervous system (CNS)-related) may be more frequent or more pronounced (see also section 4.5). Some factors that may raise urine pH (see section 5.2 “Elimination”) may necessitate careful monitoring of the patient. These factors include drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or a massive ingestion of alkalising gastric buffers. Also, urine pH may be elevated by states of renal tubulary acidosis (RTA) or severe infections of the urinary tract with Proteus bacteria. In most clinical trials, patients with recent myocardial infarction, uncompensated congestive heart failure (NYHA III-IV), or uncontrolled hypertension were excluded. As a consequence, only limited data are available and patients with these conditions should be closely supervised. This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium- free’.