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Back To Vidyya Reminyl Product Characterisitics


Information Valid In The UK - Drug Under Review In The US

Summary of Product Characteristics  

1.             NAME OF THE MEDICINAL PRODUCT

REMINYLtm4 mg Tablets

REMINYLtm 8mg Tablets

REMINYLtm 12mg Tablets

2.            QUALITATIVE AND QUANTITATIVE COMPOSITION

Each REMINYL 4 mg tablet contains 4 mg galantamine (as hydrobromide).

Each REMINYL 8 mg tablet contains 8 mg galantamine (as hydrobromide).

Each REMINYL 12 mg tablet contains 12 mg galantamine (as hydrobromide).

 

For excipients, see 6.1.

3.            PHARMACEUTICAL FORM

Film-coated tablet.

- 4 mg galantamine as off-white, circular, biconvex tablets with the inscription “JANSSEN” on one side and “G4” on the other side;

- 8 mg galantamine as pink, circular, biconvex tablets with the inscription “JANSSEN” on one side and “G8” on the other side;

- 12 mg galantamine as orange-brown, circular, biconvex tablets with the inscription “JANSSEN” on one side and “G12” on the other side;

4.             CLINICAL PARTICULARS

4.1.             Therapeutic indications

Galantamine is indicated for the symptomatic treatment of mild to moderately severe dementia of the Alzheimer type.

4.2.             Posology and method of administration

Adults/Elderly

Administration

Galantamine should be administered twice a day, preferably with morning and evening meals.

Starting dose

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

Maintenance dose

-   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.

-   Maintenance treatment can be continued for as long as therapeutic benefit for the patient exists. Therefore, the clinical benefit of galantamine should be reassessed on a regular basis. Discontinuation should be considered when evidence of a therapeutic effect is no longer present.

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

Children

Galantamine is not recommended for use in children.

Hepatic impairment

Galantamine plasma levels may be increased in patients with moderate to severe hepatic impairment. In patients with moderately impaired hepatic function, 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 b.i.d. for at least 4 weeks. In these patients, daily doses should not exceed 8 mg b.i.d.. In patients with severe hepatic impairment (Child-Pugh score greater than 9), the use of galantamine is contraindicated (see section 4.3). No dosage adjustment is required for patients with mild hepatic impairment.

Renal impairment

For patients with a creatinine clearance greater than 9 ml/min no dosage adjustment is required. In patients with severe renal impairment (creatinine clearance less than 9 ml/min), the use of galantamine is contraindicated (see section 4.3)

Concomitant treatment

In patients treated with potent CYP2D6 or CYP3A4 inhibitors (e.g. ketoconazole) dose reductions can be considered (see section 4.5).

4.3.             Contra-indications

- Galantamine should not be administered to patients with a known hypersensitivity to galantamine hydrobromide or to any excipients used in the formulations.

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

4.4.             Special warnings and precautions for use

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 drug intake by the patient.

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.

The use of galantamine in patients with other types of dementia or other type of memory impairment has not been investigated.

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

Cardiovascular conditions: 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 who use drugs that significantly reduce heart rate concomitantly, such as digoxin and beta blockers.

Gastrointestinal conditions: patients at increased risk of developing peptic ulcers, e.g. those with a history of ulcer disease or those predisposed to these conditions, should be monitored for symptoms. The use of galantamine is not recommended in patients with gastro-intestinal obstruction or recovering from gastro-intestinal surgery.

Neurological Conditions: cholinomimetics are believed to have some potential to cause generalised convulsions. However, seizure activity may also be a manifestation of Alzheimer’s Disease. In clinical trials there was no increase in incidence of convulsions with galantamine compared with placebo.

Pulmonary Conditions: cholinomimetics should be prescribed with care for patients with a history of severe asthma or obstructive pulmonary disease.

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

Anaesthesia: galantamine, as a cholinomimetic is likely to exaggerate succinylcholinetype muscle relaxation during anaesthesia.

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

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

4.5.             Interaction with other MEDICINAL PRODUCTS and other forms of interaction

Pharmacodynamic interactions

Because of its mechanism of action, galantamine should not be given concomitantly with other cholinomimetics. Galantamine antagonises the effect of anticholinergic medication. As expected with cholinomimetics, a pharmacodynamic interaction is possible with drugs that significantly reduce the heart rate (e.g. digoxin and beta blockers).
Galantamine, as a cholinomimetic, is likely to exaggerate succinylcholine-type muscle relaxation during anaesthesia.

Pharmacokinetic interactions

Multiple metabolic pathways and renal excretion are involved in the elimination of galantamine.

Concomitant administration with food slows the absorption rate of galantamine but does not affect the extent of absorption. It is recommended that galantamine be taken with food in order to minimise cholinergic side effects.

Other drugs affecting the metabolism of galantamine

Formal drug interaction studies showed an increase in galantamine bioavailability of about 40% during co-administration of paroxetine (a potent CYP2D6 inhibitor) and of 30% and 12% during co-treatment with ketoconazole and erythromycin (both CYP3A4 inhibitors). Therefore, during initiation of treatment with potent inhibitors of CYP2D6 (e.g. quinidine, paroxetine, fluoxetine or fluvoxamine) or CYP3A4 (e.g. ketoconazole, ritonavir) patients may experience an increased incidence of cholinergic side effects, predominantly nausea and vomiting. Under these circumstances, based on tolerability, a reduction of the galantamine maintenance dose can be considered (see section 4.2).

Effect of galantamine on the metabolism of other drugs

Therapeutic doses of galantamine (12 mg b.i.d.) had no effect on the kinetics of digoxin and warfarin (see also pharmacodynamic interactions).

4.6.             Pregnancy and lactation

Pregnancy

For galantamine no clinical data on exposed pregnancies are available. Animal studies indicate a slightly delayed development in foetuses and neonates (see section 5.3). Caution should be exercised when prescribing to pregnant women.

Lactation

It is not known whether galantamine is excreted in human breast milk and there are no studies in lactating women. Therefore, women on galantamine should not breast-feed.

4.7.             Effects on ability to drive and use machines

Galantamine may cause dizziness and somnolence, which could affect the ability to drive or use machines, especially during the first weeks after initiation of treatment.

4.8.             Undesirable effects

The most common adverse events (incidence ³ 5% and twice the frequency of placebo) were nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, anorexia, fatigue, dizziness, headache, somnolence and weight decrease. Women were found to be more susceptible to nausea, vomiting and anorexia.

Other common adverse events (incidence ³ 5% and ³ placebo) were confusion, fall, injury, insomnia, rhinitis and urinary tract infection.

The majority of these adverse events occurred during the titration period. Nausea and vomiting, the most frequent adverse events, lasted less than a week in most cases and the majority of patients had only one episode. Prescription of anti-emetics and ensuring adequate fluid intake may be useful in these instances.

Tremor was an infrequent treatment related event. Syncope and severe bradycardia have been reported.

4.9.             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.

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 i.v. 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.

5.             PHARMACOLOGICAL PROPERTIES

5.1.             Pharmacodynamic properties

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

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 judged to have the best benefit/risk and were retained as recommended maintenance doses. Galantamine’s efficacy 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.

 

At least 4 points improvement from baseline in ADAS-Cog/11 and

 

CIBIC-plus Unchanged+Improved

 

Change in DAD ³ 0

GAL-USA-1 and GAL-INT-1 (Month 6)

Change in ADCS/ADLInventory ³ 0

GAL-USA-10 (Month 5)

 




n (%) of

Comparison
with placebo




n (%) of

Comparison
with placebo

Treatment

N

responder

Diff (95%CI)

p-value

N

responder

Diff (95%CI)

p-value

Classical ITT

 

 

 

 

 

 

 

 

Placebo

422

21 (5.0)

¾

¾

273

18 ( 6.6)

¾

¾

Gal 16 mg/day

¾

¾

¾

¾

266

39 (14.7)

8.1 (3, 13)

0.003

Gal 24 mg/day

424

60 (14.2)

9.2 (5, 13)

<0.001

262

40 (15.3)

8.7 (3, 14)

0.002

Trad. LOCF*

 

 

 

 

 

 

 

 

Placebo

412

23 (5.6)

¾

¾

261

17 (6.5)

¾

¾

Gal 16 mg/day

¾

¾

¾

¾

253

36 (14.2)

7.7 (2, 13)

0.005

Gal 24 mg/day

399

58 (14.5)

8.9 (5, 13)

<0.001

253

40 (15.8)

9.3 (4, 15)

0.001

      CMH test of difference from placebo.

*   LOCF: Last Observation Carried Forward.

 

5.2.             Pharmacokinetic properties

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.

general characteristics of galantamine

Absorption

The absorption is rapid, with a tmax 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%.

Metabolism

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 i.v. 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 b.i.d., 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 b.i.d. In patients taking 12 or 16 mg b.i.d., no accumulation of galantamine was observed between months 2 and 6.

characteristics in patients

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.

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% (see section 4.2).

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  ³ 9 ml/min. Therefore, no increase in adverse events is expected and no dosage adjustments are needed (see section 4.2).

 

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 b.i.d. These results indicate that maximal effects may be obtained at the studied doses.

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 (see section 4.5).

5.3.             PRECLINICAL SAFETY DATA

Preclinical data reveal no special hazard for humans other than those expected from the pharmacodynamic effect of galantamine. This assumption is 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 which are below the threshold of toxicity in the pregnant females.

6.             PHARMACEUTICAL PARTICULARS

6.1.            List of excipients

Tablet core:

Colloidal anhydrous silica, crospovidone, lactose monohydrate, magnesium stearate and microcrystalline cellulose.

Film-coating:

Hypromellose, propylene glycol, talc and titanium dioxide (E171).

The 4 mg tablets also contain yellow ferric oxide (E172).  The 8mg tablets contain red ferric oxide (E172).  The 12mg tablets contain red ferric oxide and orange yellow S aluminium lake (E110).

6.2.             Incompatibilities

Not applicable.

6.3.             Shelf life

2 years.

6.4.             Special precautions for storage

No special precautions for storage.

6.5.             Nature and contents of container

The tablets are packaged in a PVC-PE-PVDC/Alu blister that hold 14 tablets.

Available pack sizes: 4 mg: 14 tablets;  8mg:  14 or 56 tablets;  12mg:  56 or 168 tablets.

6.6.             Instructions for use AND handling

No special requirements.

7.             MARKETING AUTHORIZATION HOLDER

Shire Pharmaceuticals Limited, East Anton, Andover, Hampshire SP10 5RG. UK.

8.             MARKETING AUTHORIZATION NUMBER(S)

4mg tablets:          PL 08557/0039

8mg tablets          PL 08557/0040

12mg tablets:          PL 08557/0041


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Editor: Susan K. Boyer, RN
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