Galantamine (Systemic)


VA CLASSIFICATION
Primary: CN900

Commonly used brand name(s): Reminyl.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Dementia symptoms treatment adjunct{01}

Indications

Accepted

Dementia, Alzheimer-type, mild to moderate (treatment) —Galantamine is indicated for the treatment of mild to moderate dementia of the Alzheimer's type{01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    368.27{01}

Mechanism of action/Effect:

The cause of cognitive impairment in Alzheimer's Disease is not fully understood, it has been shown that acetylcholine producing neurons degenerate. The cholinergic loss has been correlated with cognitive impairment and a density of amyloid plaques.{01}

Galantamine is a tertiary alkaloid and it competes with and is a reversible inhibitor of acetylcholinesterase. The exact mechanism of galantamine is not known, but it is believed to enhance cholinergic function. {01}

There is no evidence that galantamine alters the underlying dementing process, and its effect may lessen as the disease progresses due to fewer cholinergic neurons remaining functionally intact.{01}

Absorption:

Galantamine is rapidly and completely absorbed. The absolute oral bioavailability is about 90%. Galantamine shows linear pharmacokinetics with doses ranging from 8 to 32 mg per day.{01}

Distribution:

Mean volume of distribution (Vol D) is 175 L.
{01}
Protein binding:

Low (18%){01}

Biotransformation:

Galantamine is metabolized by hepatic cytochrome P450 enzymes.{01}

Half-life:

Elimination— 7 Hours{01}

Time to peak concentration:

Approximately 1 hour{01}

Elimination:
    Renal. After intravenous or oral administration, about 20% of the dose was excreted as unchanged galantamine in the urine in 24 hours (renal clearance of about 65 mL/min), about 20–25% of the total plasma clearance of about 300 mL/min.{01}


Precautions to Consider

Carcinogenicity

In a 24 month oral carcinogenicity study done in rats a slight increase in endometrial carcinomas were observed at doses of 10 mg/kg/day (4 times the Maximum Recommended Human Dose [MRHD]) on a mg/m 2 basis or 6 times on a exposure [AUC] basis and 30 mg/kg/day (12 times the MRHD on a mg/m2 basis or 19 times on an AUC basis). No increases in neoplastic changes were seen 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 basis and AUC basis). {01}

Galantamine was not carcinogenic in a 6 month oral carcinogenicity study in transgenic (P 53 deficient) mice up to 20 mg/kg/day, or in a 24 month oral carcinogenicity study in male and female mice up to 10 mg/kg/day ( 2 times the MRHD on a mg/m2 basis and equivalent on a AUC basis).{01}

Mutagenicity

Galantamine was not shown to be genotoxic in the in vitro Ames S. typhimurium or E. coli reverse mutation assay, in vitro mouse lymphoma assay, in vivo micronucleus test in mice, or in vitro chromosome aberration assay in Chinese hamster ovary cells.{01}

Pregnancy/Reproduction
Fertility—
No evidence of impaired 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.{01}

Pregnancy—
Studies have not been done in humans. {01}

In a study where female rats were dosed from day 14 and male rats were dosed from day 60 prior to mating through the period of organogenesis, a slightly increased incidence of skeletal variations were observed at doses of 8 mg/kg/day ( 3 times the MRHD on a mg/m2 basis) and 16 mg/kg/day. In a study where pregnant rats were dosed from the beginning of organogenesis through day 21 and post partum, pup weights were decreased at 8 and 16 mg/kg/day, but no adverse effects on other postnatal developmental parameters were seen. The doses causing the above effects in rats produced slight maternal toxicity. No major malformations were caused in rats given up to 16 mg/kg/day. No drug related teratogenic effects were observed in rabbits given up to 40 mg/kg/day (32 times the MRHD on a mg/m 2 basis) during the period of organogenesis.{01}

FDA Pregnancy Category B{01}

Breast-feeding

It is not know whether galantamine is distributed into breast milk. However, there is no indication for use in nursing women.{01}

Pediatrics

No information is available on the relationship of age to the effects of galantamine. Safety and efficacy have not been established. Use in children is not recommended.{01}


Geriatrics


Data from studies in patients with Alzheimer's disease indicate that the galantamine concentrations are 30 to 40% higher than in healthy young subjects.{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anesthesia    (galantamine is likely to exaggerate the neuromuscular blockade effects of succinylcholine-type and similar neuromuscular blocking agents during anesthesia. )

{01}
Anticholinergics    (concurrent use may decrease the effects of these medications{01})


Cimetidine or
Paroxetine    (may increase the bioavailability of galantamine)

{01}
Bethanechol or
Cholinergic agonists, other or
Cholinesterase inhibitors, other or
Neuromuscular blocking agents, similar or
Succinylcholine    (synergistic effect with concurrent use of cholinesterase inhibitors and succinylcholine, other cholinesterase inhibitors, similar neuromuscular blocking agents, or cholinergic agonists such as bethanechol)

{01}
Erythromycin or
Ketoconazole    (concurrent use may increase the area under the curve for galantamine)

{01}
Nonsteroidal anti-inflammatory drugs (NSAIDs){01}    (galantamine may increase gastric acid secretion, which may contribute to gastrointestinal irritation; patient should be monitored for occult gastrointestinal bleeding)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Known hypersensitivity to galantamine{01}
Risk-benefit should be considered when the following medical problems exist
» Asthma, active or history of    (because of the cholinomimetic action of galantamine, caution should be used)

{01}
» Cardiovascular conditions such as{01}
Bradycardia or
Heart block    (vagotonic effect on heart may exacerbate pre-existing conditions)


» Epilepsy or history of seizures{01}    (galantamine may have some potential to cause generalized convulsions)


» Urinary tract obstruction{01}    (may cause bladder outflow obstruction)


» Ulcers, active or history of{01}    (increased gastric acid secretion may exacerbate or reactivate condition )


Note: Because of their pharmacological action, cholinesterase inhibitors 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 at increased risk for developing ulcers (e.g. those with a history of ulcer or those receiving concurrent anti-inflammatory drugs [NSAIDs]).{01}



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Gastrointestinal effects    (galantamine has been shown to produce nausea, vomiting, diarrhea, anorexia and weight loss.)

{01}


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Anorexia (loss of appetite ; weight loss){01}
    
diarrhea {01}
    
nausea {01}
    
vomiting {01}
    
weight decrease
{01}
Incidence less frequent
    
Abdominal Pain {01}
    
anemia (pale skin ; troubled breathing, exertional ; unusual bleeding or bruising ; unusual tiredness or weakness){01}
    
bradycardia ( slow or irregular heartbeat (less than 50 beats per minute); lightheadedness ; dizziness or fainting ; unusual tiredness )
    
dizziness {01}
    
dyspepsia {01}(indigestion)
    
fatigue ( unusual tiredness or weakness){01}
    
headache {01}
    
hematuria (blood in urine ; lower back pain; pain or burning while urinating){01}
    
insomnia (sleeplessness; trouble sleeping ; unable to sleep){01}
    
rhinitis (stuffy nose)
    
somnolence ( sleepiness ; unusual drowsiness){01}
    
syncope ( high or low blood pressure; dizziness; light-headedness ; feeling faint){01}
    
tremor {01}





Overdose
For specific information on agents used in the management of galantamine toxicity or overdose, see Atropinein the Anticholinergics/Antispasmodics (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Bradycardia (slow heart beat ){01}
    
convulsions and collapse (seizures){01}
    
defecation {01}
    
hypotension ( low blood pressure; dizziness; fainting ){01}
    
gastrointestinal cramping {01}
    
increased salivation (drooling ; watering of the mouth){01}
    
increased sweating {01}
    
lacrimation ( tearing of the eyes){01}
    
muscle weakness or fasciculations {01}
    
respiratory depression (slow or troubled breathing)— increasing muscular weakness may affect respiratory muscles, resulting in death{01}
    
severe nausea and vomiting {01}
    
urination {01}


Note: The clinical effects mentioned above are symptoms of cholinergic crisis.{01}


Treatment of overdose


To enhance elimination:
It is not know whether galantamine and it's metabolites can be removed by dialysis.{01}



Specific treatment:
Tertiary anticholinergics may be used as an antidote for galantamine overdosage. See the package insert or Atropinein the Anticholinergics/Antispasmodics (Systemic)monograph for specific dosing guidelines.



Monitoring:
Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when coadministered with quaternary anticholinergics.{01}



Supportive care:
General supportive measures should be utilized.{01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Galantamine (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to galantamine

Surgical
Galantamine is a cholinesterase inhibitor and may prolong or exaggerate succinylcholine-type muscle relaxation during anesthesia.
Other medical problems, especially asthma, cardiovascular conditions (such as bradycardia, hypotension), epilepsy or history of seizures, urinary tract obstruction, and peptic ulcer

Proper use of this medication
» Not taking more medication than the amount prescribed because of increased risk of adverse effects

Taking doses at regular intervals, preferably with meals

Taking doses at regular intervals for maximum efficacy

» Proper dosing
Taking as soon as possible if remembered within an hour or so; not taking if remembered later; not doubling doses

Proper storage

Precautions while using this medication
» Importance of complying with monitoring schedule and keeping appointments with physician and/or laboratory

Informing physician when new symptoms arise or when previously noted symptoms increase in severity

» Caution if any kind of surgery or emergency treatment is required; informing physician or dentist in charge that galantamine is being taken

» Caution if dizziness, clumsiness, or unsteadiness occurs

» Suspected overdose: Getting emergency help at once
{01}

Side/adverse effects
Signs of potential side effects, especially abdominal pain, anemia, anorexia, bradycardia, diarrhea, dizziness, dyspepsia, fatigue, headache, hematuria, insomnia, nausea, rhinitis, somnolence, syncope, tremors, vomiting, and weight loss


For oral dosing forms:
Dose escalation should follow a minimum of four weeks at the prior dose{01}.

If galantamine therapy has been interrupted for several days or longer, the patient should be restarted at the lowest dose and the dose escalated to their current dose.{01}

Galantamine should be taken twice a day, preferably with the morning and evening meal.{01}


Parenteral Dosage Forms

Note:  The available dosage form contains galantamine hydrobromide, but dosage and strength are expressed in terms of galantamine base.

GALANTAMINE TABLETS

Usual Adult Dose
Alzheimer's dementia
Oral, starting dose is 4 mg twice a day. After at least 4 weeks of treatment, if the dose is being tolerated well, the dose may be increased to 8 mg twice daily. Additional increases to 12 mg twice a day should be attempted after a minimum of 4 weeks at the previous dose{01}.


Note: For patients with moderate renal or hepatic impairment, the dose should not exceed 16 mg/day (8 mg twice a day). In patients with severe hepatic impairment (Child-Pugh score of 10–15) or severe renal impairment (ClCr < 9 mL/min), use is not recommended.{01}


Usual Pediatric Dose
Safety and efficacy have not been established.{01}

Usual Geriatric Dose
See Usual adult dose.

Strength(s) usually available
U.S.—


4 mg (Rx) [Reminyl (colloidal silicon dioxide) (crospovidone) ( hydroxypropyl methylcellulose) (lactose monohydrate ) (magnesium stearate) ( microcrystalline cellulose) (propylene glycol) (talc) (titanium dioxide) (yellow ferric oxide)]{01}


8 mg (Rx) [Reminyl (colloidal silicon dioxide) (crospovidone) ( hydroxypropyl methylcellulose) (lactose monohydrate ) (magnesium stearate) ( microcrystalline cellulose) (propylene glycol) (talc) (titanium dioxide) (red ferric oxide)]{01}


12 mg (Rx) [Reminyl (colloidal silicon dioxide) (crospovidone) ( hydroxypropyl methylcellulose) (lactose monohydrate ) (magnesium stearate) ( microcrystalline cellulose) (propylene glycol) (talc) (titanium dioxide) (red ferric oxide) (FD&C yellow #6 aluminum lake)]{01}

Packaging and storage:
Store at 25 °C (77 °F), excursions permitted to 15 to 30°C (59–86 °F). {01}

Auxiliary labeling:
   • Keep out of reach of children.{01}



Developed: 05/17/2001



References
  1. Product Information: Reminyl®, galantamine. Janssen Pharmaceutica Products, L.P., Titusville, NJ, (PI issued 3/2001) reviewed 4/2001.
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