Natagal

Natagal® ER and Natagal® are indicated for the treatment of mild to moderate dementia of the Alzheimer's type.

RAZADYNE® ER and RAZADYNE® are indicated for the treatment of mild to moderate dementia of the Alzheimer's type.

Posology

Adults/Elderly

Before start of treatment

The diagnosis of probable Alzheimer type of dementia should be adequately confirmed according to current clinical guidelines.

Starting dose

The recommended starting dose is 8 mg/day (4 mg twice a day) for four weeks.

Maintenance dose

- The tolerance and dosing of Natagal should be reassessed on a regular basis, preferably within three months after start of treatment. Thereafter, the clinical benefit of Natagal and the patient's tolerance of treatment should be reassessed on a regular basis according to current clinical guidelines. Maintenance treatment can be continued for as long as therapeutic benefit is favourable and the patient tolerates treatment with Natagal. Discontinuation of Natagal should be considered when evidence of a therapeutic effect is no longer present or if the patient does not tolerate treatment.

The initial maintenance dose is 16 mg/day (8 mg twice a day) and patients should be maintained on 16 mg/day for at least 4 weeks.

An increase to the maintenance dose of 24 mg/day (12 mg twice a day) should be considered on an individual basis after appropriate assessment including evaluation of clinical benefit and tolerability.

- In individual patients not showing an increased response or not tolerating 24 mg/day, a dose reduction to 16 mg/day should be considered.

Treatment withdrawal

- There is no rebound effect after abrupt discontinuation of treatment (e.g. in preparation for surgery).

Renal impairment

Natagal plasma concentrations may be increased in patients with moderate to severe renal impairment.

For patients with a creatinine clearance >9 ml/min, no dosage adjustment is required.

The use of Natagal is contraindicated in patients with creatinine clearance less than 9 ml/min.

Hepatic impairment

Natagal plasma concentrations may be increased in patients with moderate to severe hepatic impairment.

In patients with moderately impaired hepatic function (Child-Pugh score 7-9), based on pharmacokinetic modelling, it is recommended that dosing should begin with 4 mg once daily, preferably taken in the morning, for at least one week. Thereafter, patients should proceed with 4 mg twice daily. for at least 4 weeks. In these patients, daily doses should not exceed 8 mg twice daily.

In patients with severe hepatic impairment (Child-Pugh score greater than 9), the use of Natagal is contraindicated. No dosage adjustment is required for patients with mild hepatic impairment.

Concomitant treatment

In patients treated with potent CYP2D6 or CYP3A4 inhibitors dose reductions can be considered.

Paediatric population

There is no relevant use of Natagal in the paediatric population.

Method of administration

Natagal oral solution should be administered orally twice a day, preferably with morning and evening meals. Ensure adequate fluid intake during treatment.

Posology

Adults/Elderly

Before start of treatment

The diagnosis of probable Alzheimer type of dementia should be adequately confirmed according to current clinical guidelines.

Starting dose

The recommended starting dose is 8 mg/day (4 mg twice a day) for 4 weeks.

Maintenance dose

The tolerance and dosing of galantamine should be reassessed on a regular basis, preferably within 3 months after start of treatment. Thereafter, the clinical benefit of galantamine and the patient's tolerance of treatment should be reassessed on a regular basis according to current clinical guidelines. Maintenance treatment can be continued for as long as therapeutic benefit is favourable and the patient tolerates treatment with galantamine. Discontinuation of galantamine should be considered when evidence of a therapeutic effect is no longer present or if the patient does not tolerate treatment.

The initial maintenance dose is 16 mg/day (8 mg twice a day) and patients should be maintained on 16 mg/day for at least 4 weeks.

An increase to the maintenance dose of 24 mg/day (12 mg twice a day) should be considered on an individual basis after appropriate assessment including evaluation of clinical benefit and tolerability.

In individual patients not showing an increased response or not tolerating 24 mg/day, a dose reduction to 16 mg/day should be considered.

Treatment withdrawal

There is no rebound effect after abrupt discontinuation of treatment (e.g. in preparation for surgery).

Renal impairment

Galantamine plasma concentrations may be increased in patients with moderate to severe renal impairment

For patients with a creatinine clearance >9 ml/min, no dosage adjustment is required.

The use of galantamine is contraindicated in patients with creatinine clearance less than 9 ml/min.

Hepatic impairment

Galantamine plasma concentrations may be increased in patients with moderate to severe hepatic impairment.

In patients with moderately impaired hepatic function (Child-Pugh score 7-9), based on pharmacokinetic modelling, it is recommended that dosing should begin with 4 mg once daily, preferably taken in the morning, for at least 1 week. Thereafter, patients should proceed with 4 mg twice-daily for at least 4 weeks. In these patients, daily doses should not exceed 8 mg twice daily.

In patients with severe hepatic impairment (Child-Pugh score greater than 9), the use of galantamine is contraindicated.

No dosage adjustment is required for patients with mild hepatic impairment.

Concomitant treatment

In patients treated with potent CYP2D6 or CYP3A4 inhibitors dose reductions can be considered.

Paediatric population

There is no relevant use of galantamine in the paediatric population.

Method of administration

Natagal tablets should be administered orally, twice a day, preferably with morning and evening meals. Ensure adequate fluid intake during treatment

Natagal® ER Extended-Release Capsules

Natagal® ER extended-release capsules should be administered once daily in the morning, preferably with food.

The recommended starting dosage of Natagal® ER is 8 mg/day. The dosage should be increased to the initial maintenance dose of 16 mg/day after a minimum of 4 weeks. A further increase to 24 mg/day should be attempted after a minimum of 4 weeks at 16 mg/day. Dosage increases should be based upon assessment of clinical benefit and tolerability of the previous dose.

The dosage of Natagal® ER shown to be effective in a controlled clinical trial is 16-24 mg/day.

Patients currently being treated with Natagal® tablets or oral solution can convert to Natagal® ER (extended-release capsules) by taking their last dose of Natagal® tablets or oral solution in the evening and starting Natagal® ER once daily treatment the next morning. Converting from Natagal® to Natagal® ER should occur at the same total daily dosage.

Natagal® Immediate-Release Tablets And Oral Solution

The dosage of Natagal® tablets shown to be effective in controlled clinical trials is 16-32 mg/day given as twice daily dosing. As the dosage of 32 mg/day is less well tolerated than lower dosages and does not provide increased effectiveness, the recommended dosage range is 16-24 mg/day given twice daily. The dosage of 24 mg/day did not provide a statistically significant greater clinical benefit than 16 mg/day. It is possible, however, that a daily dosage of 24 mg of Natagal® might provide additional benefit for some patients.

The recommended starting dosage of Natagal® tablets and oral solution is 4 mg twice a day (8 mg/day). The dosage should be increased to the initial maintenance dosage of 8 mg twice a day (16 mg/day) after a minimum of 4 weeks. A further increase to 12 mg twice a day (24 mg/day) should be attempted after a minimum of 4 weeks at 8 mg twice a day (16 mg/day).

Dosage increases should be based upon assessment of clinical benefit and tolerability of the previous dose.

Natagal® tablets and oral solution should be administered twice a day, preferably with morning and evening meals.

Patients and caregivers should be advised to ensure adequate fluid intake during treatment. If therapy has been interrupted for more than three days, the patient should be restarted at the lowest dosage and the dosage escalated to the current dose.

The abrupt withdrawal of Natagal® ER and Natagal® in those patients who had been receiving dosages in the effective range was not associated with an increased frequency of adverse events in comparison with those continuing to receive the same dosages of that drug. The beneficial effects of Natagal® ER and Natagal® are lost, however, when the drug is discontinued.

Dosage In Patients With Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh score of 7-9), the dosage should generally not exceed 16 mg/day. The use of Natagal® ER and Natagal® in patients with severe hepatic impairment (Child-Pugh score of 10-15) is not recommended.

Dosage In Patients With Renal Impairment

In patients with creatinine clearance of 9 to 59 mL/min, the dosage should generally not exceed 16 mg/day. In patients with creatinine clearance less than 9 mL/min, the use of Natagal® ER and Natagal® is not recommended.

RAZADYNE® ER Extended-Release Capsules

RAZADYNE® ER extended-release capsules should be administered once daily in the morning, preferably with food.

The recommended starting dosage of RAZADYNE® ER is 8 mg/day. The dosage should be increased to the initial maintenance dose of 16 mg/day after a minimum of 4 weeks. A further increase to 24 mg/day should be attempted after a minimum of 4 weeks at 16 mg/day. Dosage increases should be based upon assessment of clinical benefit and tolerability of the previous dose.

The dosage of RAZADYNE® ER shown to be effective in a controlled clinical trial is 16-24 mg/day.

Patients currently being treated with RAZADYNE® tablets or oral solution can convert to RAZADYNE® ER (extended-release capsules) by taking their last dose of RAZADYNE® tablets or oral solution in the evening and starting RAZADYNE® ER once daily treatment the next morning. Converting from RAZADYNE® to RAZADYNE® ER should occur at the same total daily dosage.

RAZADYNE® Immediate-Release Tablets And Oral Solution

The dosage of RAZADYNE® tablets shown to be effective in controlled clinical trials is 16-32 mg/day given as twice daily dosing. As the dosage of 32 mg/day is less well tolerated than lower dosages and does not provide increased effectiveness, the recommended dosage range is 16-24 mg/day given twice daily. The dosage of 24 mg/day did not provide a statistically significant greater clinical benefit than 16 mg/day. It is possible, however, that a daily dosage of 24 mg of RAZADYNE® might provide additional benefit for some patients.

The recommended starting dosage of RAZADYNE® tablets and oral solution is 4 mg twice a day (8 mg/day). The dosage should be increased to the initial maintenance dosage of 8 mg twice a day (16 mg/day) after a minimum of 4 weeks. A further increase to 12 mg twice a day (24 mg/day) should be attempted after a minimum of 4 weeks at 8 mg twice a day (16 mg/day).

Dosage increases should be based upon assessment of clinical benefit and tolerability of the previous dose.

RAZADYNE® tablets and oral solution should be administered twice a day, preferably with morning and evening meals.

Patients and caregivers should be advised to ensure adequate fluid intake during treatment. If therapy has been interrupted for more than three days, the patient should be restarted at the lowest dosage and the dosage escalated to the current dose.

The abrupt withdrawal of RAZADYNE® ER and RAZADYNE® in those patients who had been receiving dosages in the effective range was not associated with an increased frequency of adverse events in comparison with those continuing to receive the same dosages of that drug. The beneficial effects of RAZADYNE® ER and RAZADYNE® are lost, however, when the drug is discontinued.

Dosage In Patients With Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh score of 7-9), the dosage should generally not exceed 16 mg/day. The use of RAZADYNE® ER and RAZADYNE® in patients with severe hepatic impairment (Child-Pugh score of 10-15) is not recommended.

Dosage In Patients With Renal Impairment

In patients with creatinine clearance of 9 to 59 mL/min, the dosage should generally not exceed 16 mg/day. In patients with creatinine clearance less than 9 mL/min, the use of RAZADYNE® ER and RAZADYNE® is not recommended.

Because no data are available on the use of Natagal in patients with severe hepatic impairment (Child-Pugh score greater than 9) and creatinine clearance less than 9 ml/min, Natagal is contraindicated in these populations. Natagal is contraindicated in patients who have both significant renal and hepatic dysfunction.

Because no data are available on the use of galantamine in patients with severe hepatic impairment (Child-Pugh score greater than 9) and in patients with creatinine clearance less than 9 ml/min, galantamine is contraindicated in these populations. Galantamine is contraindicated in patients who have both significant renal and hepatic dysfunction.

Natagal® ER and Natagal® are contraindicated in patients with known hypersensitivity to galantamine hydrobromide or to any excipients used in the formulation.

RAZADYNE® ER and RAZADYNE® are contraindicated in patients with known hypersensitivity to galantamine hydrobromide or to any excipients used in the formulation.

Types of dementia

Natagal is indicated for a patient with mild to moderately severe dementia of the Alzheimer type. The benefit of Natagal in patients with other types of dementia or other types of memory impairment has not been demonstrated. In 2 clinical trials of two years duration in individuals with so called mild cognitive impairment (milder types of memory impairment not fulfilling the criteria of Alzheimer's dementia), Natagal therapy failed to demonstrate any benefit either in slowing cognitive decline or reducing the clinical conversion to dementia. The mortality rate in the Natagal group was significantly higher than in the placebo group, 14/1026 (1.4%) patients on Natagal and 3 /1022 (0.3%) patients on placebo. The deaths were due to various causes. About half of the Natagal deaths appeared to result from various vascular causes (myocardial infarction, stroke, and sudden death). The relevance of this finding for the treatment of patients with Alzheimer's dementia is unknown.

No increased mortality in the Natagal group was observed in a long term, randomized, placebo controlled study in 2045 patients with mild to moderate Alzheimer´s disease. The mortality rate in the placebo group was significantly higher than in the Natagal group. There were 56/1021 (5.5%) deaths in patients on placebo and 33/1024 (3.2%) deaths in patients on Natagal (hazard ratio and 95% confidence intervals of 0.58 [0.37 , 0.89]; p=0.011).

A diagnosis of Alzheimer's dementia should be made according to current guidelines by an experienced physician. Therapy with Natagal should occur under the supervision of a physician and should only be initiated if a caregiver is available who will regularly monitor medicinal product intake by the patient.

Serious skin reactions

Serious skin reactions (Stevens-Johnson syndrome and acute generalized exanthematous pustulosis) have been reported in patients receiving Natagal. It is recommended that patients be informed about the signs of serious skin reactions, and that use of Natagal be discontinued at the first appearance of skin rash.

Weight monitoring

Patients with Alzheimer's disease lose weight. Treatment with cholinesterase inhibitors, including Natagal, has been associated with weight loss in these patients. During therapy, patient's weight should be monitored.

Conditions requiring caution

As with other cholinomimetics, Natagal should be given with caution in the following conditions:

Cardiac disorders:

Because of their pharmacological action, cholinomimetics may have vagotonic effects on heart rate (e.g. bradycardia). The potential for this action may be particularly important to patients with 'sick sinus syndrome' or other supraventricular cardiac conduction disturbances or in those who use medicinal products that significantly reduce heart rate concomitantly, such as digoxin and beta blockers or for patients with an uncorrected electrolyte disturbance (e.g. hyperkalaemia, hypokalaemia).

Caution should therefore be exercised when administering Natagal to patients with cardiovascular diseases, e.g. immediate post- myocardial infarction period, new-onset atrial fibrillation, second degree heart block or greater, unstable angina pectoris, or congestive heart failure, especially NYHA group III - IV.

In a pooled analysis of placebo-controlled studies in patients with Alzheimer dementia treated with Natagal an increased incidence of certain cardiovascular adverse events were observed.

Gastrointestinal disorders:

Patients at increased risk of developing peptic ulcers, e.g. those with a history of ulcer disease or those predisposed to these conditions, including those receiving concurrent non-steroidal anti-inflammatory drugs (NSAIDS),should be monitored for symptoms. The use of Natagal is not recommended in patients with gastro-intestinal obstruction or recovering from gastro-intestinal surgery.

Nervous system disorders:

Seizures have been reported with Natagal. Seizure activity may also be a manifestation of Alzheimer's disease. In rare cases an increase in cholinergic tone may worsen Parkinsonian symptoms. In a pooled analysis of placebo-controlled studies in patients with Alzheimer's dementia treated with Natagal cerebrovascular events were uncommonly observed. This should be considered when administering Natagal to patients with cerebrovascular disease.

Respiratory, thoracic and mediastinal disorders:

Cholinomimetics should be prescribed with care for patients with a history of severe asthma or obstructive pulmonary disease or active pulmonary infections (e.g. pneumonia).

Renal and urinary disorders:

The use of Natagal is not recommended in patients with urinary outflow obstruction or recovering from bladder surgery.

Surgical and medical procedures: Natagal, as a cholinomimetic is likely to exaggerate succinylcholinetype muscle relaxation during anaesthesia, especially in cases of pseudocholinesterase deficiency.

Excipient of Natagal 4 mg/ml oral solution:

This product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Methyl-/Propyl-para-hydroxybenzoate may cause allergic reactions (possibly delayed).

Types of dementia

Natagal is indicated for a patient with mild to moderately severe dementia of the Alzheimer type. The benefit of galantamine in patients with other types of dementia or other types of memory impairment has not been demonstrated. In 2 clinical trials of 2 years duration in individuals with so called mild cognitive impairment (milder types of memory impairment not fulfilling the criteria of Alzheimer dementia), galantamine therapy failed to demonstrate any benefit either in slowing cognitive decline or reducing the clinical conversion to dementia. The mortality rate in the galantamine group was significantly higher than in the placebo group, 14/1026 (1.4%) patients on galantamine and 3 /1022 (0.3%) patients on placebo. The deaths were due to various causes. About half of the galantamine deaths appeared to result from various vascular causes (myocardial infarction, stroke, and sudden death). The relevance of this finding for the treatment of patients with Alzheimer's dementia is unknown.

No increased mortality in the galantamine group was observed in a long-term, randomized, placebo-controlled study in 2045 patients with mild to moderate Alzheimer´s disease. The mortality rate in the placebo group was significantly higher than in the galantamine group. There were 56/1021 (5.5%) deaths in patients on placebo and 33/1024 (3.2%) deaths in patients on galantamine (hazard ratio and 95% confidence intervals of 0.58 [0.37 - 0.89]; p=0.011).

A diagnosis of Alzheimer's dementia should be made according to current guidelines by an experienced physician. Therapy with galantamine should occur under the supervision of a physician and should only be initiated if a caregiver is available who will regularly monitor medicinal product intake by the patient.

Serious skin reactions

Serious skin reactions (Stevens-Johnson syndrome and acute generalized exanthematous pustulosis) have been reported in patients receiving Natagal. It is recommended that patients be informed about the signs of serious skin reactions, and that use of Natagal be discontinued at the first appearance of skin rash.

Weight monitoring

Patients with Alzheimer's disease lose weight. Treatment with cholinesterase inhibitors, including galantamine, has been associated with weight loss in these patients. During therapy, patient's weight should be monitored.

Conditions requiring caution

As with other cholinomimetics, galantamine should be given with caution in the following conditions:

Cardiac disorders

Because of their pharmacological action, cholinomimetics may have vagotonic effects on heart rate, including bradycardia and all types of atrioventricular node block. The potential for this action may be particularly important to patients with 'sick sinus syndrome' or other supraventricular cardiac conduction disturbances or in those who use medicinal products that significantly reduce heart rate concomitantly, such as digoxin and beta blockers or for patients with an uncorrected electrolyte disturbance (e.g. hyperkalaemia, hypokalaemia). Caution should therefore be exercised when administering galantamine to patients with cardiovascular diseases, e.g. immediate post-myocardial infarction period, new-onset atrial fibrillation, second degree heart block or greater, unstable angina pectoris, or congestive heart failure, especially NYHA group III - IV.

In a pooled analysis of placebo-controlled studies in patients with Alzheimer's dementia treated with galantamine an increased incidence of certain cardiovascular adverse events were observed.

Gastrointestinal disorders

Patients at increased risk of developing peptic ulcers, e.g. those with a history of ulcer disease or those predisposed to these conditions, including those receiving concurrent non-steroidal anti-inflammatory drugs (NSAIDS), should be monitored for symptoms. The use of galantamine is not recommended in patients with gastro-intestinal obstruction or recovering from gastro-intestinal surgery.

Nervous system disorders

Seizures have been reported with galantamine.. Seizure activity may also be a manifestation of Alzheimer's disease. In rare cases an increase in cholinergic tone may worsen Parkinsonian symptoms.

In a pooled analysis of placebo-controlled studies in patients with Alzheimer's dementia treated with galantamine cerebrovascular events were uncommonly observed. This should be considered when administering galantamine to patients with cerebrovascular disease.

Respiratory, thoracic and mediastinal disorders

Cholinomimetics should be prescribed with care for patients with a history of severe asthma or obstructive pulmonary disease or active pulmonary infections (e.g. pneumonia).

Renal and urinary disorders

The use of galantamine is not recommended in patients with urinary outflow obstruction or recovering from bladder surgery.

Surgical and medical procedures

Galantamine, as a cholinomimetic, is likely to exaggerate succinylcholine- type muscle relaxation during anaesthesia, especially in cases of pseudocholinesterase deficiency.

Excipients of Natagal film- coated tablets

Orange yellow S aluminium lake (E110), present in the 12 mg tablet, may cause allergic reactions.

Natagal tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Serious Skin Reactions

Serious skin reactions (Stevens-Johnson syndrome and acute generalized exanthematous pustulosis) have been reported in patients receiving Natagal® ER and Natagal®. Inform patients and caregivers that the use of Natagal® ER or Natagal® should be discontinued at the first appearance of a skin rash, unless the rash is clearly not drug-related. If signs or symptoms suggest a serious skin reaction, use of this drug should not be resumed and alternative therapy should be considered.

Anesthesia

Galantamine, as a cholinesterase inhibitor, is likely to exaggerate the neuromuscular blocking effects of succinylcholine-type and similar neuromuscular blocking agents during anesthesia.

Cardiovascular Conditions

Because of their pharmacological action, cholinesterase inhibitors have vagotonic effects on the sinoatrial and atrioventricular nodes, leading to bradycardia and AV block. Bradycardia and all types of heart block have been reported in patients both with and without known underlying cardiac conduction abnormalities. Therefore, all patients should be considered at risk for adverse effects on cardiac conduction.

Patients treated with galantamine up to 24 mg/day using the recommended dosing schedule showed a dose-related increase in risk of syncope (placebo 0.7% [2/286]; 4 mg twice daily 0.4% [3/692]; 8 mg twice daily 1.3% [7/552]; 12 mg twice daily 2.2% [6/273]).

Gastrointestinal Conditions

Through their primary action, cholinomimetics may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those with an increased risk for developing ulcers, e.g., those with a history of ulcer disease or patients using concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of galantamine have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Galantamine, as a predictable consequence of its pharmacological properties, has been shown to produce nausea, vomiting, diarrhea, anorexia, and weight loss. During therapy, the patient's weight should be monitored.

Genitourinary Conditions

Although this was not observed in clinical trials with galantamine, cholinomimetics may cause bladder outflow obstruction.

Neurological Conditions

Seizures: Cholinesterase inhibitors are believed to have some potential to cause generalized convulsions. Seizure activity may also be a manifestation of Alzheimer's disease. Patients with Alzheimer's disease should be monitored closely for seizures while taking galantamine.

Pulmonary Conditions

Because of its cholinomimetic action, galantamine should be prescribed with care to patients with a history of severe asthma or obstructive pulmonary disease. Respiratory function should be monitored closely for the occurrence of respiratory adverse effects.

Deaths In Subjects With Mild Cognitive Impairment (MCI)

In two randomized placebo controlled trials of 2 years duration in patients with mild cognitive impairment (MCI), a total of 13 patients on galantamine (n=1026) and 1 patient on placebo (n=1022) died. The deaths were due to various causes which could be expected in an elderly population; about half of the galantamine deaths appeared to result from various vascular causes (myocardial infarction, stroke, and sudden death).

Although the difference in mortality between galantamine-and placebo-treated groups in these two studies was significant, the results are highly discrepant with other studies of galantamine. Specifically, in these two MCI studies, the mortality rate in the placebo-treated patients was markedly lower than the rate in placebo-treated patients in trials of galantamine in Alzheimer's disease or other dementias (0.7 per 1000 person years compared to 22-61 per 1000 person years, respectively). Although the mortality rate in the galantamine-treated MCI patients was also lower than that observed in galantamine-treated patients in Alzheimer's disease and other dementia trials (10.2 per 1000 person years compared to 23-31 per 1000 person years, respectively), the relative difference was much less. When the Alzheimer's disease and other dementia studies were pooled (n=6000), the mortality rate in the placebo group numerically exceeded that in the galantamine group. Furthermore, in the MCI studies, no patients in the placebo group died after 6 months, a highly unexpected finding in this population.

Individuals with mild cognitive impairment demonstrate isolated memory impairment greater than expected for their age and education, but do not meet current diagnostic criteria for Alzheimer's disease.

Non-Clinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In a 24-month oral carcinogenicity study in rats, an increase in endometrial adenocarcinomas was observed at 10 mg/kg/day (4 times the MRHD of 24 mg/day on a mg/m² basis or 6 times on a plasma exposure [AUC] basis) and 30 mg/kg/day (12 times MRHD on a mg/m² basis or 19 times on an AUC basis). No increase in neoplastic changes was observed in females at 2.5 mg/kg/day (equivalent to the MRHD on a mg/m² basis or 2 times on an AUC basis) or in males up to the highest dose tested of 30 mg/kg/day (12 times the MRHD on a mg/m² and AUC basis).

Galantamine was not carcinogenic in a 6-month carcinogenicity study in transgenic (P 53-deficient) mice at oral doses up to 20 mg/kg/day, or in a 24-month carcinogenicity study in mice at oral doses up to 10 mg/kg/day (equivalent to the MRHD on a plasma AUC basis).

Mutagenesis

Galantamine was negative in a battery of in vitro (bacterial reverse mutation, mouse lymphoma tk, and chromosomal aberration in mammalian cells) and in vivo (mouse micronucleus) genotoxicity assays.

Impairment of Fertility

No impairment of fertility was seen in rats given up to 16 mg/kg/day (7 times the MRHD on a mg/m² basis) for 14 days prior to mating in females and for 60 days prior to mating in males.

Use In Specific Populations

Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. In studies conducted in animals, administration of galantamine during pregnancy resulted in developmental toxicity (increased incidence of morphological abnormalities and decreased growth in offspring) at doses similar to or greater than those used clinically. Natagal® ER and Natagal® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In rats, administration of galantamine (oral doses of 2, 8, or 16 mg/kg/day), from day 14 (females) or day 60 (males) prior to mating and continuing in females through the period of organogenesis, resulted in an increased incidence of fetal skeletal variations at the two highest doses. The no-effect dose for embryo-fetal developmental toxicity in rats (2 mg/kg/day) is approximately equal to the maximum recommended human dose (MRHD of 24 mg/day) on a body surface area (mg/m²) basis. When galantamine (oral doses of 4, 12, 28, or 48 mg/kg/day) was administered to pregnant rabbits throughout the period of organogenesis, small increases in fetal visceral malformations and skeletal variations were observed at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rabbits (28 mg/kg/day) is approximately 20 times the MRHD on a mg/m² basis. In a study in which pregnant rats were orally dosed with galantamine (2, 8, or 16 mg/kg/day) from the beginning of organogenesis through day 21 post-partum, pup weights were decreased at birth and during the lactation period at the two highest doses. The no-effect dose for pre-and postnatal developmental toxicity in rats (2 mg/kg/day) is approximately equal to the MRHD on a mg/m² basis.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Natagal® ER and Natagal® is administered to a nursing woman.

Pediatric Use

The safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Eight double-blind, placebo-controlled clinical trials and 5 open-label trials in a total of 6519 patients have investigated Natagal® ER and Natagal® in the treatment of mild to moderate dementia of the Alzheimer's type. The mean age of patients enrolled in these clinical studies was 75 years; 78% of these patients were between 65 and 84 years of age, and 10% of patients were 85 years of age or older.

Hepatic Impairment

In patients with moderate hepatic impairment, a dosage adjustment is recommended. The use of Natagal® ER and Natagal® in patients with severe hepatic impairment is not recommended.

Renal Impairment

In patients with a creatinine clearance of 9 to 59 mL/min, a dosage adjustment is recommended. The use of Natagal® ER and Natagal® in patients with creatinine clearance less than 9 mL/min is not recommended.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Serious Skin Reactions

Serious skin reactions (Stevens-Johnson syndrome and acute generalized exanthematous pustulosis) have been reported in patients receiving RAZADYNE® ER and RAZADYNE®. Inform patients and caregivers that the use of RAZADYNE® ER or RAZADYNE® should be discontinued at the first appearance of a skin rash, unless the rash is clearly not drug-related. If signs or symptoms suggest a serious skin reaction, use of this drug should not be resumed and alternative therapy should be considered.

Anesthesia

Galantamine, as a cholinesterase inhibitor, is likely to exaggerate the neuromuscular blocking effects of succinylcholine-type and similar neuromuscular blocking agents during anesthesia.

Cardiovascular Conditions

Because of their pharmacological action, cholinesterase inhibitors have vagotonic effects on the sinoatrial and atrioventricular nodes, leading to bradycardia and AV block. Bradycardia and all types of heart block have been reported in patients both with and without known underlying cardiac conduction abnormalities. Therefore, all patients should be considered at risk for adverse effects on cardiac conduction.

Patients treated with galantamine up to 24 mg/day using the recommended dosing schedule showed a dose-related increase in risk of syncope (placebo 0.7% [2/286]; 4 mg twice daily 0.4% [3/692]; 8 mg twice daily 1.3% [7/552]; 12 mg twice daily 2.2% [6/273]).

Gastrointestinal Conditions

Through their primary action, cholinomimetics may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those with an increased risk for developing ulcers, e.g., those with a history of ulcer disease or patients using concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of galantamine have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Galantamine, as a predictable consequence of its pharmacological properties, has been shown to produce nausea, vomiting, diarrhea, anorexia, and weight loss. During therapy, the patient's weight should be monitored.

Genitourinary Conditions

Although this was not observed in clinical trials with galantamine, cholinomimetics may cause bladder outflow obstruction.

Neurological Conditions

Seizures: Cholinesterase inhibitors are believed to have some potential to cause generalized convulsions. Seizure activity may also be a manifestation of Alzheimer's disease. Patients with Alzheimer's disease should be monitored closely for seizures while taking galantamine.

Pulmonary Conditions

Because of its cholinomimetic action, galantamine should be prescribed with care to patients with a history of severe asthma or obstructive pulmonary disease. Respiratory function should be monitored closely for the occurrence of respiratory adverse effects.

Deaths In Subjects With Mild Cognitive Impairment (MCI)

In two randomized placebo controlled trials of 2 years duration in patients with mild cognitive impairment (MCI), a total of 13 patients on galantamine (n=1026) and 1 patient on placebo (n=1022) died. The deaths were due to various causes which could be expected in an elderly population; about half of the galantamine deaths appeared to result from various vascular causes (myocardial infarction, stroke, and sudden death).

Although the difference in mortality between galantamine-and placebo-treated groups in these two studies was significant, the results are highly discrepant with other studies of galantamine. Specifically, in these two MCI studies, the mortality rate in the placebo-treated patients was markedly lower than the rate in placebo-treated patients in trials of galantamine in Alzheimer's disease or other dementias (0.7 per 1000 person years compared to 22-61 per 1000 person years, respectively). Although the mortality rate in the galantamine-treated MCI patients was also lower than that observed in galantamine-treated patients in Alzheimer's disease and other dementia trials (10.2 per 1000 person years compared to 23-31 per 1000 person years, respectively), the relative difference was much less. When the Alzheimer's disease and other dementia studies were pooled (n=6000), the mortality rate in the placebo group numerically exceeded that in the galantamine group. Furthermore, in the MCI studies, no patients in the placebo group died after 6 months, a highly unexpected finding in this population.

Individuals with mild cognitive impairment demonstrate isolated memory impairment greater than expected for their age and education, but do not meet current diagnostic criteria for Alzheimer's disease.

Non-Clinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In a 24-month oral carcinogenicity study in rats, an increase in endometrial adenocarcinomas was observed at 10 mg/kg/day (4 times the MRHD of 24 mg/day on a mg/m² basis or 6 times on a plasma exposure [AUC] basis) and 30 mg/kg/day (12 times MRHD on a mg/m² basis or 19 times on an AUC basis). No increase in neoplastic changes was observed in females at 2.5 mg/kg/day (equivalent to the MRHD on a mg/m² basis or 2 times on an AUC basis) or in males up to the highest dose tested of 30 mg/kg/day (12 times the MRHD on a mg/m² and AUC basis).

Galantamine was not carcinogenic in a 6-month carcinogenicity study in transgenic (P 53-deficient) mice at oral doses up to 20 mg/kg/day, or in a 24-month carcinogenicity study in mice at oral doses up to 10 mg/kg/day (equivalent to the MRHD on a plasma AUC basis).

Mutagenesis

Galantamine was negative in a battery of in vitro (bacterial reverse mutation, mouse lymphoma tk, and chromosomal aberration in mammalian cells) and in vivo (mouse micronucleus) genotoxicity assays.

Impairment of Fertility

No impairment of fertility was seen in rats given up to 16 mg/kg/day (7 times the MRHD on a mg/m² basis) for 14 days prior to mating in females and for 60 days prior to mating in males.

Use In Specific Populations

Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. In studies conducted in animals, administration of galantamine during pregnancy resulted in developmental toxicity (increased incidence of morphological abnormalities and decreased growth in offspring) at doses similar to or greater than those used clinically. RAZADYNE® ER and RAZADYNE® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In rats, administration of galantamine (oral doses of 2, 8, or 16 mg/kg/day), from day 14 (females) or day 60 (males) prior to mating and continuing in females through the period of organogenesis, resulted in an increased incidence of fetal skeletal variations at the two highest doses. The no-effect dose for embryo-fetal developmental toxicity in rats (2 mg/kg/day) is approximately equal to the maximum recommended human dose (MRHD of 24 mg/day) on a body surface area (mg/m²) basis. When galantamine (oral doses of 4, 12, 28, or 48 mg/kg/day) was administered to pregnant rabbits throughout the period of organogenesis, small increases in fetal visceral malformations and skeletal variations were observed at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rabbits (28 mg/kg/day) is approximately 20 times the MRHD on a mg/m² basis. In a study in which pregnant rats were orally dosed with galantamine (2, 8, or 16 mg/kg/day) from the beginning of organogenesis through day 21 post-partum, pup weights were decreased at birth and during the lactation period at the two highest doses. The no-effect dose for pre-and postnatal developmental toxicity in rats (2 mg/kg/day) is approximately equal to the MRHD on a mg/m² basis.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RAZADYNE® ER and RAZADYNE® is administered to a nursing woman.

Pediatric Use

The safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Eight double-blind, placebo-controlled clinical trials and 5 open-label trials in a total of 6519 patients have investigated RAZADYNE® ER and RAZADYNE® in the treatment of mild to moderate dementia of the Alzheimer's type. The mean age of patients enrolled in these clinical studies was 75 years; 78% of these patients were between 65 and 84 years of age, and 10% of patients were 85 years of age or older.

Hepatic Impairment

In patients with moderate hepatic impairment, a dosage adjustment is recommended. The use of RAZADYNE® ER and RAZADYNE® in patients with severe hepatic impairment is not recommended.

Renal Impairment

In patients with a creatinine clearance of 9 to 59 mL/min, a dosage adjustment is recommended. The use of RAZADYNE® ER and RAZADYNE® in patients with creatinine clearance less than 9 mL/min is not recommended.

Natagal has minor to moderate influence on the ability to drive and use machines. Symptoms include dizziness and somnolence, especially during the first weeks after initiation of treatment.

Galantamine has a minor to moderate influence on the ability to drive and use machines. Symptoms include dizziness and somnolence, especially during the first weeks after initiation of treatment.

The table below reflects data obtained with Natagal in eight placebo-controlled, double-blind clinical trials (N=6,502), five open-label clinical trials (N=1,454), and from post marketing spontaneous reports. The most commonly reported adverse reactions were nausea (21%) and vomiting (11%). They occurred mainly during titration periods, lasted less than a week in most cases and the majority of patients had one episode. Prescription of anti-emetics and ensuring adequate fluid intake may be useful in these instances.

Frequency estimate: Very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to <1/1,000) and very rare (< 1/10,000).

* Class-related effects reported with acetylcholinesterase-inhibitor antidementia drugs include convulsions/seizures

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard

The table below reflects data obtained with Natagal in eight placebo-controlled, double-blind clinical trials (N=6,502), five open-label clinical trials (N=1,454), and from postmarketing spontaneous reports. The most commonly reported adverse reactions were nausea (21%) and vomiting (11%). They occurred mainly during titration periods, lasted less than a week in most cases and the majority of patients had one episode. Prescription of anti-emetics and ensuring adequate fluid intake may be useful in these instances.

Frequency estimate: very common (>1/10); common (>1/100 to < 1/10); uncommon (>1/1,000 to < 1/100); rare (> 1/10,000 to <1/1,000); and very rare (<1/10,000).

* Class-related effects reported with acetylcholinesterase-inhibitor antidementia drugs include convulsions/seizures.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (Website: www.mhra.gov.uk/yellowcard ).

Serious adverse reactions are discussed in more detail in the following sections of the labeling:

• Serious skin reactions
• Cardiovascular Conditions
• Gastrointestinal Conditions
• Genitourinary Conditions
• Neurological Conditions
• Pulmonary Conditions
• Deaths in subjects with mild cognitive impairment (MCI)

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions in galantamine-treated patients from double-blind clinical trials ( ≥ 5%) were nausea, vomiting, diarrhea, dizziness, headache, and decreased appetite.

The most common adverse reactions associated with discontinuation ( ≥ 1%) in galantamine-treated patients from double-blind clinical trials were nausea (6.2%), vomiting (3.3%), decreased appetite (1.5%), and dizziness (1.3%).

The safety of the extended-release capsule and immediate-release tablet formulations of galantamine was evaluated in 3956 galantamine-treated patients who participated in 8 placebo-controlled clinical studies and 1454 subjects in 5 open-label clinical studies with mild to moderate dementia of the Alzheimer's type. In clinical studies, the safety profile of once-daily treatment with extended-release galantamine was similar in frequency and nature to that seen with tablets. The information presented in this section was derived from pooled double-blind studies and from pooled open-label data.

Commonly-Observed Adverse Reactions In Double-Blind, Placebo-Controlled Clinical Trials

Table 1 lists the adverse reactions reported in ≥ 1% of galantamine-treated patients in 8 placebo-controlled, double-blind clinical trials.

Table 1: Adverse Reactions Reported by ≥ 1% of Galantamine-Treated Patients in Pooled Placebo-Controlled, Double-Blind Clinical Trials

The majority of these adverse reactions occurred during the dose-escalation period. In those patients who experienced the most frequent adverse reaction, nausea, the median duration of the nausea was 5-7 days.

Other Adverse Reactions Observed In Clinical Trials Of Galantamine

The following adverse reactions occurred in < 1% of all galantamine-treated patients (N=3956) in the above double-blind, placebo-controlled clinical trial data sets. In addition, the following also includes all adverse reactions reported at any frequency rate in patients (N=1454) who participated in open-label studies. Adverse reactions listed in Table 1 above were not included below:

Metabolism and Nutrition Disorders: Dehydration

Nervous System Disorders: Dysgeusia, Hypersomnia, Paresthesia

Eye Disorders: Blurred vision

Cardiac Disorders: First degree atrioventricular block, Palpitations, Sinus bradycardia, Supraventricular extrasystoles

Vascular Disorders: Flushing, Hypotension

Gastrointestinal Disorders: Retching

Skin and Subcutaneous Tissue Disorders: Hyperhidrosis

Musculoskeletal and Connective Tissue Disorders: Muscular weakness

Discontinuations Due To Adverse Reactions

In the 8 placebo-controlled studies of adults, 418 (10.6%) galantamine-treated patients (N=3956) and 56 (2.2%) placebo patients (N=2546) discontinued due to an adverse reaction. Those events with an incidence of ≥ 0.5% in the galantamine-treated patients included nausea (245, 6.2%), vomiting (129, 3.3%), decreased appetite (60, 1.5%), dizziness (50, 1.3%), diarrhea (31, 0.8%), headache (29, 0.7%), and decreased weight (26, 0.7%). The only event with an incidence of ≥ 0.5% in placebo patients was nausea (17, 0.7%).

In the 5 open-label studies, 103 (7.1%) patients (N=1454) discontinued due to an adverse reaction. Those events with an incidence of ≥ 0.5% included nausea (43, 3.0%), vomiting (23, 1.6%), decreased appetite (13, 0.9%), headache (12, 0.8%), decreased weight (9, 0.6%), dizziness (8, 0.6%), and diarrhea (7, 0.5%).

Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of Natagal® ER and Natagal®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency:

Immune System Disorders: Hypersensitivity

Psychiatric Disorders: Hallucinations

Nervous System Disorders: Seizures

Ear and Labyrinth Disorders: Tinnitus

Cardiac Disorders: Complete atrioventricular block

Vascular Disorders: Hypertension

Hepatobiliary Disorders: Hepatitis, Increased hepatic enzyme

Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, Acute generalized exanthematous pustulosis, Erythema multiforme

Serious adverse reactions are discussed in more detail in the following sections of the labeling:

• Serious skin reactions
• Cardiovascular Conditions
• Gastrointestinal Conditions
• Genitourinary Conditions
• Neurological Conditions
• Pulmonary Conditions
• Deaths in subjects with mild cognitive impairment (MCI)

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions in galantamine-treated patients from double-blind clinical trials ( ≥ 5%) were nausea, vomiting, diarrhea, dizziness, headache, and decreased appetite.

The most common adverse reactions associated with discontinuation ( ≥ 1%) in galantamine-treated patients from double-blind clinical trials were nausea (6.2%), vomiting (3.3%), decreased appetite (1.5%), and dizziness (1.3%).

The safety of the extended-release capsule and immediate-release tablet formulations of galantamine was evaluated in 3956 galantamine-treated patients who participated in 8 placebo-controlled clinical studies and 1454 subjects in 5 open-label clinical studies with mild to moderate dementia of the Alzheimer's type. In clinical studies, the safety profile of once-daily treatment with extended-release galantamine was similar in frequency and nature to that seen with tablets. The information presented in this section was derived from pooled double-blind studies and from pooled open-label data.

Commonly-Observed Adverse Reactions In Double-Blind, Placebo-Controlled Clinical Trials

Table 1 lists the adverse reactions reported in ≥ 1% of galantamine-treated patients in 8 placebo-controlled, double-blind clinical trials.

Table 1: Adverse Reactions Reported by ≥ 1% of Galantamine-Treated Patients in Pooled Placebo-Controlled, Double-Blind Clinical Trials

The majority of these adverse reactions occurred during the dose-escalation period. In those patients who experienced the most frequent adverse reaction, nausea, the median duration of the nausea was 5-7 days.

Other Adverse Reactions Observed In Clinical Trials Of Galantamine

The following adverse reactions occurred in < 1% of all galantamine-treated patients (N=3956) in the above double-blind, placebo-controlled clinical trial data sets. In addition, the following also includes all adverse reactions reported at any frequency rate in patients (N=1454) who participated in open-label studies. Adverse reactions listed in Table 1 above were not included below:

Metabolism and Nutrition Disorders: Dehydration

Nervous System Disorders: Dysgeusia, Hypersomnia, Paresthesia

Eye Disorders: Blurred vision

Cardiac Disorders: First degree atrioventricular block, Palpitations, Sinus bradycardia, Supraventricular extrasystoles

Vascular Disorders: Flushing, Hypotension

Gastrointestinal Disorders: Retching

Skin and Subcutaneous Tissue Disorders: Hyperhidrosis

Musculoskeletal and Connective Tissue Disorders: Muscular weakness

Discontinuations Due To Adverse Reactions

In the 8 placebo-controlled studies of adults, 418 (10.6%) galantamine-treated patients (N=3956) and 56 (2.2%) placebo patients (N=2546) discontinued due to an adverse reaction. Those events with an incidence of ≥ 0.5% in the galantamine-treated patients included nausea (245, 6.2%), vomiting (129, 3.3%), decreased appetite (60, 1.5%), dizziness (50, 1.3%), diarrhea (31, 0.8%), headache (29, 0.7%), and decreased weight (26, 0.7%). The only event with an incidence of ≥ 0.5% in placebo patients was nausea (17, 0.7%).

In the 5 open-label studies, 103 (7.1%) patients (N=1454) discontinued due to an adverse reaction. Those events with an incidence of ≥ 0.5% included nausea (43, 3.0%), vomiting (23, 1.6%), decreased appetite (13, 0.9%), headache (12, 0.8%), decreased weight (9, 0.6%), dizziness (8, 0.6%), and diarrhea (7, 0.5%).

Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of RAZADYNE® ER and RAZADYNE®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency:

Immune System Disorders: Hypersensitivity

Psychiatric Disorders: Hallucinations

Nervous System Disorders: Seizures

Ear and Labyrinth Disorders: Tinnitus

Cardiac Disorders: Complete atrioventricular block

Vascular Disorders: Hypertension

Hepatobiliary Disorders: Hepatitis, Increased hepatic enzyme

Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, Acute generalized exanthematous pustulosis, Erythema multiforme

Symptoms

Signs and symptoms of significant overdosing of Natagal are predicted to be similar to those of overdosing of other cholinomimetics. These effects generally involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. In addition to muscle weakness or fasciculations, some or all of the signs of a cholinergic crisis may develop: severe nausea, vomiting, gastro-intestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, collapse and convulsions. Increasing muscle weakness together with tracheal hypersecretions and bronchospasm, may lead to vital airway compromise.

There have been post-marketing reports of Torsade de Pointes, QT prolongation, bradycardia, ventricular tachycardia and brief loss of consciousness in association with an inadvertent overdoses of Natagal. In one case where the dose was known, eight 4 mg tablets (32 mg total) were ingested on a single day.

Two additional cases of accidental ingestion of 32 mg (nausea, vomiting, and dry mouth; nausea, vomiting, and substernal chest pain) and one of 40 mg (vomiting) resulted in brief hospitalisations for observation with full recovery. One patient, who was prescribed 24 mg/day and had a history of hallucinations over the previous two years, mistakenly received 24 mg twice daily for 34 days and developed hallucinations requiring hospitalisation. Another patient, who was prescribed 16 mg/day of oral solution, inadvertently ingested 160 mg (40 ml) and experienced sweating, vomiting, bradycardia, and near-syncope one hour later, which necessitated hospital treatment. His symptoms resolved within 24 hours.

Treatment

As in any case of overdose, general supportive measures should be used. In severe cases, anticholinergics such as atropine can be used as a general antidote for cholinomimetics. An initial dose of 0.5 to 1.0 mg intravenously is recommended, with subsequent doses based on the clinical response.

Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control centre to determine the latest recommendations for the management of an overdose.

Symptoms

Signs and symptoms of significant overdosing of galantamine are predicted to be similar to those of overdosing of other cholinomimetics. These effects generally involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. In addition to muscle weakness or fasciculations, some or all of the signs of a cholinergic crisis may develop: severe nausea, vomiting, gastro-intestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, collapse and convulsions. Increasing muscle weakness together with tracheal hypersecretions and bronchospasm, may lead to vital airway compromise.

There have been post-marketing reports of torsade de pointes, QT prolongation, bradycardia, ventricular tachycardia and brief loss of consciousness in association with inadvertent overdoses of galantamine. In one case where the dose was known, eight 4 mg tablets (32 mg total) were ingested on a single day.

Two additional cases of accidental ingestion of 32 mg (nausea, vomiting, and dry mouth; nausea, vomiting, and substernal chest pain) and one of 40 mg (vomiting) resulted in brief hospitalisations for observation with full recovery. One patient, who was prescribed 24 mg/day and had a history of hallucinations over the previous two years, mistakenly received 24 mg twice daily for 34 days and developed hallucinations requiring hospitalisation. Another patient, who was prescribed 16 mg/day of oral solution, inadvertently ingested 160 mg (40 ml) and experienced sweating, vomiting, bradycardia, and near-syncope one hour later, which necessitated hospital treatment. His symptoms resolved within 24 hours.

Treatment

As in any case of overdose, general supportive measures should be used. In severe cases, anticholinergics such as atropine can be used as a general antidote for cholinomimetics. An initial dose of 0.5 to 1.0 mg intravenously is recommended, with subsequent doses based on the clinical response.

Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control centre to determine the latest recommendations for the management of an overdose.

Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug.

As in any case of overdose, general supportive measures should be utilized. Signs and symptoms of significant overdosing of galantamine are predicted to be similar to those of overdosing of other cholinomimetics. These effects generally involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. In addition to muscle weakness or fasciculations, some or all of the following signs of cholinergic crisis may develop: severe nausea, vomiting, gastrointestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved.

Tertiary anticholinergics such as atropine may be used as an antidote for Natagal® ER and Natagal® (galantamine hydrobromide) overdosage. Intravenous atropine sulfate titrated to effect is recommended at an initial dose of 0.5 to 1.0 mg i.v. with subsequent doses based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics. It is not known whether galantamine and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration). Dose-related signs of toxicity in animals included hypoactivity, tremors, clonic convulsions, salivation, lacrimation, chromodacryorrhea, mucoid feces, and dyspnea.

In one postmarketing report, one patient who had been taking 4 mg of galantamine daily for a week inadvertently ingested eight 4 mg tablets (32 mg total) on a single day. Subsequently, she developed bradycardia, QT prolongation, ventricular tachycardia and torsades de pointes accompanied by a brief loss of consciousness for which she required hospital treatment. Two additional cases of accidental ingestion of 32 mg (nausea, vomiting, and dry mouth; nausea, vomiting, and substernal chest pain) and one of 40 mg (vomiting), resulted in brief hospitalizations for observation with full recovery. One patient, who was prescribed 24 mg/day and had a history of hallucinations over the previous two years, mistakenly received 24 mg twice daily for 34 days and developed hallucinations requiring hospitalization. Another patient, who was prescribed 16 mg/day of oral solution, inadvertently ingested 160 mg (40 mL) and experienced sweating, vomiting, bradycardia, and near-syncope one hour later, which necessitated hospital treatment. His symptoms resolved within 24 hours.

Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug.

As in any case of overdose, general supportive measures should be utilized. Signs and symptoms of significant overdosing of galantamine are predicted to be similar to those of overdosing of other cholinomimetics. These effects generally involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. In addition to muscle weakness or fasciculations, some or all of the following signs of cholinergic crisis may develop: severe nausea, vomiting, gastrointestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved.

Tertiary anticholinergics such as atropine may be used as an antidote for RAZADYNE® ER and RAZADYNE® (galantamine hydrobromide) overdosage. Intravenous atropine sulfate titrated to effect is recommended at an initial dose of 0.5 to 1.0 mg i.v. with subsequent doses based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics. It is not known whether galantamine and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration). Dose-related signs of toxicity in animals included hypoactivity, tremors, clonic convulsions, salivation, lacrimation, chromodacryorrhea, mucoid feces, and dyspnea.

In one postmarketing report, one patient who had been taking 4 mg of galantamine daily for a week inadvertently ingested eight 4 mg tablets (32 mg total) on a single day. Subsequently, she developed bradycardia, QT prolongation, ventricular tachycardia and torsades de pointes accompanied by a brief loss of consciousness for which she required hospital treatment. Two additional cases of accidental ingestion of 32 mg (nausea, vomiting, and dry mouth; nausea, vomiting, and substernal chest pain) and one of 40 mg (vomiting), resulted in brief hospitalizations for observation with full recovery. One patient, who was prescribed 24 mg/day and had a history of hallucinations over the previous two years, mistakenly received 24 mg twice daily for 34 days and developed hallucinations requiring hospitalization. Another patient, who was prescribed 16 mg/day of oral solution, inadvertently ingested 160 mg (40 mL) and experienced sweating, vomiting, bradycardia, and near-syncope one hour later, which necessitated hospital treatment. His symptoms resolved within 24 hours.

Pharmacotherapeutic group: Antidementia drugs; ATC-code: N06DA04.

Mechanism of action

Natagal, a tertiary alkaloid is a selective, competitive and reversible inhibitor of acetylcholinesterase. In addition, Natagal enhances the intrinsic action of acetylcholine on nicotinic receptors, probably through binding to an allosteric site of the receptor. As a consequence, an increased activity in the cholinergic system associated with improved cognitive function can be achieved in patients with dementia of the Alzheimer type.

Clinical studies

The dosages of Natagal effective in placebo-controlled clinical trials with a duration of 5 to 6 months were 16, 24 and 32 mg/day. Of these doses 16 and 24 mg/day were determined to have the best benefit/risk relationship and are the recommended maintenance doses. The efficacy of Natagal has been shown using outcome measures which evaluate the three major symptom complexes of the disease and a global scale: the ADAS-Cog (a performance based measure of cognition), DAD and ADCS-ADL-Inventory (measurements of basic and instrumental Activities of Daily Living), the Neuropsychiatric Inventory (a scale that measures behavioural disturbances) and the CIBIC-plus (a global assessment by an independent physician based on a clinical interview with the patient and caregiver).

Composite responder analysis based on at least 4 points improvement in ADAS-Cog/11 compared to baseline and CIBIC-plus unchanged + improved (1-4), and DAD/ADL score unchanged + improved. See Table below.

Vascular dementia or Alzheimer's disease with cerebrovascular disease

The results of a 26-week double-blind placebo-controlled trial, in which patients with vascular dementia and patients with Alzheimer's disease and concomitant cerebrovascular disease (“mixed dementia”) were included, indicate that the symptomatic effect of Natagal is maintained in patients with Alzheimer's disease and concomitant cerebrovascular disease. In a post-hoc subgroup analysis, no statistically significant effect was observed in the subgroup of patients with vascular dementia alone.

In a second 26-week placebo-controlled trial in patients with probable vascular dementia, no clinical benefit of Natagal treatment was demonstrated.

Pharmacotherapeutic group: Antidementia drugs, ATC-code: N06DA04.

Mechanism of action

Galantamine, a tertiary alkaloid is a selective, competitive and reversible inhibitor of acetylcholinesterase. In addition, galantamine enhances the intrinsic action of acetylcholine on nicotinic receptors, probably through binding to an allosteric site of the receptor. As a consequence, an increased activity in the cholinergic system associated with improved cognitive function can be achieved in patients with dementia of the Alzheimer type.

Clinical studies

The dosages of galantamine effective in placebo-controlled clinical trials with a duration of 5 to 6 months were 16, 24 and 32 mg/day. Of these doses 16 and 24 mg/day were determined to have the best benefit/risk relationship and are the recommended maintenance doses. The efficacy of galantamine has been shown using outcome measures which evaluate the three major symptom complexes of the disease and a global scale: the ADAS-Cog (a performance based measure of cognition), DAD and ADCS-ADL-Inventory (measurements of basic and instrumental Activities of Daily Living), the Neuropsychiatric Inventory (a scale that measures behavioural disturbances) and the CIBIC-plus (a global assessment by an independent physician based on a clinical interview with the patient and caregiver).

Composite responder analysis based on at least 4 points improvement in ADAS-Cog/11 compared to baseline and CIBIC-plus unchanged + improved (1-4), and DAD/ADL score unchanged + improved. See table below.

^# ITT: Intent To Treat

^†CMH test of difference from placebo.

* LOCF: Last Observation Carried Forward.

Vascular dementia or Alzheimer's disease with cerebrovascular disease

The results of a 26-week double-blind placebo-controlled trial, in which patients with vascular dementia and patients with Alzheimer's disease and concomitant cerebrovascular disease (“mixed dementia”) were included, indicate that the symptomatic effect of galantamine is maintained in patients with Alzheimer's disease and concomitant cerebrovascular disease. In a post-hoc subgroup analysis, no statistically significant effect was observed in the subgroup of patients with vascular dementia alone.

In a second 26-week placebo-controlled trial in patients with probable vascular dementia, no clinical benefit of galantamine treatment was demonstrated.

Natagal is an alkalinic compound with one ionisation constant (pKa 8.2). It is slightly lipophilic and has a partition coefficient (Log P) between n-octanol/buffer solution (pH 12) of 1.09. The solubility in water (pH 6) is 31 mg/ml. Natagal has three chiral centres, the S, R, S-form is the naturally occurring form. Natagal is partially metabolised by various cytochromes, mainly CYP2D6 and CYP3A4. Some of the metabolites formed during the degradation of Natagal have been shown to be active in vitro but are of no importance in vivo.

Absorption

The absorption is rapid, with a t_max of about 1 hour after both tablets and oral solution. The absolute bioavailability of Natagal is high, 88.5 ± 5.4%. The presence of food delays the rate of absorption and reduces C_max by about 25%, without affecting the extent of absorption (AUC).

Distribution

The mean volume of distribution is 175 L. Plasma protein binding is low, 18%.

Biotransformation

Up to 75% of Natagal dosed is eliminated via metabolism. In vitro studies indicate that CYP2D6 is involved in the formation of O-desmethylNatagal and CYP3A4 is involved in the formation of N-oxide-Natagal. The levels of excretion of total radioactivity in urine and faeces were not different between poor and extensive CYP2D6 metabolisers. In plasma from poor and extensive metabolisers, unchanged Natagal and its glucuronide accounted for most of the sample radioactivity. None of the active metabolites of Natagal (norNatagal, O-desmethylNatagal and O-desmethyl-norNatagal) could be detected in their unconjugated form in plasma from poor and extensive metabolisers after single dosing. NorNatagal was detectable in plasma from patients after multiple dosing, but did not represent more than 10% of the Natagal levels. In vitro studies indicated that the inhibition potential of Natagal with respect to the major forms of human cytochrome P450 is very low.

Elimination

Natagal plasma concentration declines bi-exponentially, with a terminal half-life in the order of 7-8 h in healthy subjects. Typical oral clearance in the target population is about 200 ml/min with intersubject variability of 30% as derived from the population analysis. Seven days after a single oral dose of 4 mg ³H-Natagal, 90-97% of the radioactivity is recovered in urine and 2.2 - 6.3% in faeces. After intravenous infusion and oral administration, 18-22% of the dose was excreted as unchanged Natagal in the urine in 24 hours, with a renal clearance of 68.4 ± 22 ml/min, which represents 20-25% of the total plasma clearance.

Dose-linearity

After repeated oral dosing of 12 and 16 mg Natagal twice daily as tablets, mean trough and peak plasma concentrations fluctuated between 29 - 97 ng/ml and 42 - 137 ng/ml. The pharmacokinetics of Natagal are linear in the dose range of 4 - 16 mg twice daily. In patients taking 12 or 16 mg twice daily, no accumulation of Natagal was observed between months 2 and 6.

Characteristics in patients with Alzheimer's disease

Data from clinical trials in patients indicate that the plasma concentrations of Natagal in patients with Alzheimer's disease are 30-40% higher than in healthy young subjects. Based upon the population pharmacokinetic analysis, clearance in female subjects is 20% lower as compared to males. No major effects of age per se or race are found on the Natagal clearance. The Natagal clearance in poor metabolisers of CYP2D6 is about 25% lower than in extensive metabolisers, but no bimodality in the population is observed. Therefore, the metabolic status of the patient is not considered to be of clinical relevance in the overall population.

Special populations

Renal impairment

Elimination of Natagal decreases with decreasing creatinine clearance as observed in a study with renally impaired subjects. Compared to Alzheimer patients, peak and trough plasma concentrations are not increased in patients with a creatinine clearance of >9 ml/min. Therefore, no increase in adverse events is expected and no dosage adjustments are needed.

Hepatic impairment

The pharmacokinetics of Natagal in subjects with mild hepatic impairment (Child-Pugh score of 5-6) were comparable to those in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh score of 7-9), AUC and half-life of Natagal were increased by about 30%.

Pharmacokinetic / pharmacodynamic relationship

No apparent correlation between average plasma concentrations and efficacy parameters (i.e. change in ADAS-Cog11 and CIBIC-plus at Month 6) were observed in the large Phase III trials with a dose-regimen of 12 and 16 mg twice daily.

Plasma concentrations in patients experiencing syncope were within the same range as in the other patients at the same dose.

The occurrence of nausea is shown to correlate with higher peak plasma concentrations.

Galantamine is an alkalinic compound with one ionisation constant (pKa 8.2). It is slightly lipophilic and has a partition coefficient (Log P) between n-octanol/buffer solution (pH 12) of 1.09. The solubility in water (pH 6) is 31 mg/ml. Galantamine has three chiral centres. The S, R, S-form is the naturally occurring form. Galantamine is partially metabolised by various cytochromes, mainly CYP2D6 and CYP3A4. Some of the metabolites formed during the degradation of galantamine have been shown to be active in vitro but are of no importance in vivo.

Absorption

The absorption is rapid, with a t_max of about 1 hour after both tablets and oral solution. The absolute bioavailability of galantamine is high, 88.5 ± 5.4%. The presence of food delays the rate of absorption and reduces Cmax by about 25%, without affecting the extent of absorption (AUC).

Distribution

The mean volume of distribution is 175 L. Plasma protein binding is low, 18%.

Biotransformation

Up to 75% of galantamine dosed is eliminated via metabolism. In vitro studies indicate that CYP2D6 is involved in the formation of O-desmethylgalantamine and CYP3A4 is involved in the formation of N-oxide-galantamine. The levels of excretion of total radioactivity in urine and faeces were not different between poor and extensive CYP2D6 metabolisers. In plasma from poor and extensive metabolisers, unchanged galantamine and its glucuronide accounted for most of the sample radioactivity. None of the active metabolites of galantamine (norgalantamine, O-desmethylgalantamine and O-desmethyl-norgalantamine) could be detected in their unconjugated form in plasma from poor and extensive metabolisers after single dosing. Norgalantamine was detectable in plasma from patients after multiple dosing, but did not represent more than 10% of the galantamine levels. In vitro studies indicated that the inhibition potential of galantamine with respect to the major forms of human cytochrome P450 is very low.

Elimination

Galantamine plasma concentration declines bi-exponentially, with a terminal half-life in the order of 7-8 h in healthy subjects. Typical oral clearance in the target population is about 200 ml/min with intersubject variability of 30% as derived from the population analysis. Seven days after a single oral dose of 4 mg ³H-galantamine, 90-97% of the radioactivity is recovered in urine and 2.2 - 6.3% in faeces. After intravenous infusion and oral administration, 18-22% of the dose was excreted as unchanged galantamine in the urine in 24 hours, with a renal clearance of 68.4 ± 22.0 ml/min, which represents 20-25% of the total plasma clearance.

Dose-linearity

After repeated oral dosing of 12 and 16 mg galantamine twice-daily as tablets, mean trough and peak plasma concentrations fluctuated between 29 - 97 ng/ml and 42 - 137 ng/ml. The pharmacokinetics of galantamine are linear in the dose range of 4 - 16 mg twice-daily. In patients taking 12 or 16 mg twice-daily, no accumulation of galantamine was observed between months 2 and 6.

Characteristics in patients with Alzheimer's disease

Data from clinical trials in patients indicate that the plasma concentrations of galantamine in patients with Alzheimer's disease are 30-40% higher than in healthy young subjects. Based upon the population pharmacokinetic analysis, clearance in female subjects is 20% lower as compared to males. No major effects of age per se or race are found on the galantamine clearance. The galantamine clearance in poor metabolisers of CYP2D6 is about 25% lower than in extensive metabolisers, but no bimodality in the population is observed. Therefore, the metabolic status of the patient is not considered to be of clinical relevance in the overall population.

Special populations

Renal impairment

Elimination of galantamine decreases with decreasing creatinine clearance as observed in a study with renally impaired subjects. Compared to Alzheimer patients, peak and trough plasma concentrations are not increased in patients with a creatinine clearance of >9 ml/min. Therefore, no increase in adverse events is expected and no dosage adjustments are needed.

Hepatic impairment

The pharmacokinetics of galantamine in subjects with mild hepatic impairment (Child-Pugh score of 5-6) were comparable to those in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh score of 7-9), AUC and half-life of galantamine were increased by about 30%.

Pharmacokinetic/pharmacodynamic relationship

No apparent correlation between average plasma concentrations and efficacy parameters (i.e. change in ADAS-Cog11 and CIBIC-plus at Month 6) were observed in the large Phase III trials with a dose-regimen of 12 and 16 mg twice daily.

Plasma concentrations in patients experiencing syncope were within the same range as in the other patients at the same dose.

The occurrence of nausea is shown to correlate with higher peak plasma concentrations.

The pharmacokinetics of galantamine are linear over a dose range of 8-32 mg/day.

Absorption And Distribution

Galantamine is absorbed with time to peak concentration of about 1 hour. The absolute bioavailability of galantamine is about 90%. The bioavailability of the tablet formulation was the same as the bioavailability of the oral solution formulation. Food did not affect the AUC of

galantamine, but Cmax was decreased by 25% and Tmax was delayed by 1.5 hours, when galantamine was administered with food. The mean volume of distribution of galantamine is 175 L.

The plasma protein binding of galantamine is 18% at therapeutically relevant concentrations. In whole blood, galantamine is mainly distributed to blood cells (52.7%). The blood to plasma concentration ratio of galantamine is 1.2.

Metabolism And Elimination

Galantamine is metabolized by hepatic cytochrome P450 enzymes, glucuronidated, and excreted unchanged in the urine. In vitro studies indicate that cytochrome CYP2D6 and CYP3A4 were the major cytochrome P450 isoenzymes involved in the metabolism of galantamine, and inhibitors of both pathways increase oral bioavailability of galantamine modestly. O-demethylation, mediated by CYP2D6 was greater in extensive metabolizers of CYP2D6 than in poor metabolizers. In plasma from both poor and extensive metabolizers, however, unchanged galantamine and its glucuronide accounted for most of the sample radioactivity.

In studies of oral 3H-galantamine, unchanged galantamine and its glucuronide, accounted for most plasma radioactivity in poor and extensive CYP2D6 metabolizers. Up to 8 hours post-dose, unchanged galantamine accounted for 39-77% of the total radioactivity in the plasma, and galantamine glucuronide for 14-24%. By 7 days, 93-99% of the radioactivity had been recovered, with about 95% in urine and about 5% in the feces. Total urinary recovery of unchanged galantamine accounted for, on average, 32% of the dose and that of galantamine glucuronide for another 12% on average.

After i.v. or oral administration, about 20% of the dose was excreted as unchanged galantamine in the urine in 24 hours, representing a renal clearance of about 65 mL/min, about 20-25% of the total plasma clearance of about 300 mL/min. Galantamine has a terminal half-life of about 7 hours.

Natagal® ER 24 mg extended-release capsules administered once daily under fasting conditions are bioequivalent to Natagal® tablets 12 mg twice daily with respect to AUC24h and Cmin. The Cmax and Tmax of the extended-release capsules were lower and occurred later, respectively, compared with the immediate-release tablets, with Cmax about 25% lower and median Tmax occurring about 4.5-5.0 hours after dosing. Dose-proportionality is observed for Natagal® ER extended-release capsules over the dose range of 8 to 24 mg daily and steady state is achieved within a week. There was no effect of age on the pharmacokinetics of Natagal® ER extended-release capsules. CYP2D6 poor metabolizers had drug exposures that were approximately 50% higher than for extensive metabolizers.

There are no appreciable differences in pharmacokinetic parameters when Natagal® ER extended-release capsules are given with food compared to when they are given in the fasted state.

The pharmacokinetics of galantamine are linear over a dose range of 8-32 mg/day.

Absorption And Distribution

Galantamine is absorbed with time to peak concentration of about 1 hour. The absolute bioavailability of galantamine is about 90%. The bioavailability of the tablet formulation was the same as the bioavailability of the oral solution formulation. Food did not affect the AUC of

galantamine, but Cmax was decreased by 25% and Tmax was delayed by 1.5 hours, when galantamine was administered with food. The mean volume of distribution of galantamine is 175 L.

The plasma protein binding of galantamine is 18% at therapeutically relevant concentrations. In whole blood, galantamine is mainly distributed to blood cells (52.7%). The blood to plasma concentration ratio of galantamine is 1.2.

Metabolism And Elimination

Galantamine is metabolized by hepatic cytochrome P450 enzymes, glucuronidated, and excreted unchanged in the urine. In vitro studies indicate that cytochrome CYP2D6 and CYP3A4 were the major cytochrome P450 isoenzymes involved in the metabolism of galantamine, and inhibitors of both pathways increase oral bioavailability of galantamine modestly. O-demethylation, mediated by CYP2D6 was greater in extensive metabolizers of CYP2D6 than in poor metabolizers. In plasma from both poor and extensive metabolizers, however, unchanged galantamine and its glucuronide accounted for most of the sample radioactivity.

In studies of oral 3H-galantamine, unchanged galantamine and its glucuronide, accounted for most plasma radioactivity in poor and extensive CYP2D6 metabolizers. Up to 8 hours post-dose, unchanged galantamine accounted for 39-77% of the total radioactivity in the plasma, and galantamine glucuronide for 14-24%. By 7 days, 93-99% of the radioactivity had been recovered, with about 95% in urine and about 5% in the feces. Total urinary recovery of unchanged galantamine accounted for, on average, 32% of the dose and that of galantamine glucuronide for another 12% on average.

After i.v. or oral administration, about 20% of the dose was excreted as unchanged galantamine in the urine in 24 hours, representing a renal clearance of about 65 mL/min, about 20-25% of the total plasma clearance of about 300 mL/min. Galantamine has a terminal half-life of about 7 hours.

RAZADYNE® ER 24 mg extended-release capsules administered once daily under fasting conditions are bioequivalent to RAZADYNE® tablets 12 mg twice daily with respect to AUC24h and Cmin. The Cmax and Tmax of the extended-release capsules were lower and occurred later, respectively, compared with the immediate-release tablets, with Cmax about 25% lower and median Tmax occurring about 4.5-5.0 hours after dosing. Dose-proportionality is observed for RAZADYNE® ER extended-release capsules over the dose range of 8 to 24 mg daily and steady state is achieved within a week. There was no effect of age on the pharmacokinetics of RAZADYNE® ER extended-release capsules. CYP2D6 poor metabolizers had drug exposures that were approximately 50% higher than for extensive metabolizers.

There are no appreciable differences in pharmacokinetic parameters when RAZADYNE® ER extended-release capsules are given with food compared to when they are given in the fasted state.

Nonclinical data suggest no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Reproduction toxicity studies showed a slight delay in development in rats and rabbits, at doses that are below the threshold of toxicity in the pregnant females.

Non-clinical data suggest no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Reproduction toxicity studies showed a slight delay in development in rats and rabbits, at doses that are below the threshold of toxicity in the pregnant females.

To open the bottle and use the pipette:

The bottle comes with a child-proof cap, and should be opened as follows:

- Push the plastic screw cap down while turning it counter clockwise.

- Remove the unscrewed cap.

Insert the pipette into the bottle.

While holding the bottom ring, pull the top ring up to the mark corresponding to the number of millilitres you need to give.

Holding the bottom ring, remove the entire pipette from the bottle.

Empty the pipette directly into the mouth or into any non-alcoholic drink by sliding the upper ring down and drink it immediately.

Close the bottle.

Rinse the pipette with some water.

No special requirements.