A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Namenda Side Effects, and Drug Interactions - Memantine
Namenda Side Effects, and Drug Interactions - Memantine
SIDE EFFECTS
The experience described in this section derives from studies
in patients with Alzheimer’s disease and vascular dementia.
Adverse Events Leading to Discontinuation: In placebo-controlled
trials in which dementia patients received doses of NAMENDA up to 20 mg/day,
the likelihood of discontinuation because of an adverse event was the same in
the NAMENDA group as in the placebo group. No individual adverse event was associated
with the discontinuation of treatment in 1% or more of NAMENDA treated patients
and at a rate greater than placebo.
Adverse Events Reported in Controlled Trials: The reported
adverse events in NAMENDA (memantine hydrochloride) trials reflect experience
gained under closely monitored conditions in a highly selected patient population.
In actual practice or in other clinical trials, these frequency estimates may
not apply, as the conditions of use, reporting behavior and the types of patients
treated may differ. Table 1 lists treatment-emergent signs and symptoms that
were reported in at least 2% of patients in placebo-controlled dementia trials
and for which the rate of occurrence was greater for patients treated with
NAMENDA than for those treated with placebo. No adverse event
occurred at a frequency of at least 5% and twice the placebo rate.
|
Table 1: Adverse Events Reported in Controlled Clinical
Trials in at Least 2% of Patients Receiving NAMENDA and at a Higher Frequency
than Placebo-treated Patients.
|
|
Body System
|
Placebo
|
NAMENDA
|
|
Adverse Event
|
(N = 922)
|
(N = 940)
|
| |
%
|
%
|
|
Body as a Whole
|
|
Fatigue
|
1
|
2
|
|
Pain
|
1
|
3
|
|
Cardiovascular System
|
|
Hypertension
|
2
|
4
|
|
Central and Peripheral Nervous System
|
|
Dizziness
|
5
|
7
|
|
Headache
|
3
|
6
|
|
Gastrointestinal System
|
|
Constipation
|
3
|
5
|
|
Vomiting
|
2
|
3
|
|
Musculoskeletal System
|
|
Back pain
|
2
|
3
|
|
Psychiatric Disorders
|
|
Confusion
|
5
|
6
|
|
Somnolence
|
2
|
3
|
|
Hallucination
|
2
|
3
|
|
Respiratory System
|
|
Coughing
|
3
|
4
|
|
Dyspnea
|
1
|
2
|
Other adverse events occurring with an incidence of at least
2% in NAMENDA-treated patients but at a greater or equal rate on placebo were
agitation, fall, inflicted injury, urinary incontinence, diarrhea, bronchitis,
insomnia, urinary tract infection, influenza-like symptoms, gait abnormal, depression,
upper respiratory tract infection, anxiety, peripheral edema, nausea, anorexia,
and arthralgia.
The overall profile of adverse events and the incidence rates
for individual adverse events in the subpopulation of patients with moderate
to severe Alzheimer’s disease were not different from the profile and incidence
rates described above for the overall dementia population.
Vital Sign Changes: NAMENDA and placebo groups
were compared with respect to (1) mean change from baseline in vital signs (pulse,
systolic blood pressure, diastolic blood pressure, and weight) and (2) the incidence
of patients meeting criteria for potentially clinically significant changes
from baseline in these variables. There were no clinically important changes
in vital signs in patients treated with NAMENDA. A comparison of supine and
standing vital sign measures for NAMENDA and placebo in elderly normal subjects
indicated that NAMENDA treatment is not associated with orthostatic changes.
Laboratory Changes: NAMENDA and placebo groups
were compared with respect to (1) mean change from baseline in various serum
chemistry, hematology, and urinalysis variables and (2) the incidence of patients
meeting criteria for potentially clinically significant changes from baseline
in these variables. These analyses revealed no clinically important changes
in laboratory test parameters associated with NAMENDA treatment.
ECG Changes: NAMENDA and placebo groups were
compared with respect to (1) mean change from baseline in various ECG parameters
and (2) the incidence of patients meeting criteria for potentially clinically
significant changes from baseline in these variables. These analyses revealed
no clinically important changes in ECG parameters associated with NAMENDA treatment.
Other Adverse Events Observed During Clinical Trials
NAMENDA has been administered to approximately 1350 patients
with dementia, of whom more than 1200 received the maximum recommended dose
of 20 mg/day. Patients received NAMENDA treatment for periods of up to 884 days,
with 862 patients receiving at least 24 weeks of treatment and 387 patients
receiving 48 weeks or more of treatment.
Treatment emergent signs and symptoms that occurred during
8 controlled clinical trials and 4 open-label trials were recorded as adverse
events by the clinical investigators using terminology of their own choosing.
To provide an overall estimate of the proportion of individuals having similar
types of events, the events were grouped into a smaller number of standardized
categories using WHO terminology, and event frequencies were calculated across
all studies.
All adverse events occurring in at least two patients are included,
except for those already listed in Table 1, WHO terms too general to be informative,
minor symptoms or events unlikely to be drug-caused, e.g., because they are
common in the study population. Events are classified by body system and listed
using the following definitions: frequent adverse events – those occurring in
at least 1/100 patients; infrequent adverse events – those occurring in 1/100
to 1/1000 patients. These adverse events are not necessarily related to NAMENDA
treatment and in most cases were observed at a similar frequency in placebo-treated
patients in the controlled studies.
Body as a Whole: Frequent: syncope. Infrequent:
hypothermia, allergic reaction.
Cardiovascular System: Frequent: cardiac failure.
Infrequent: angina pectoris, bradycardia, myocardial infarction, thrombophlebitis,
atrial fibrillation, hypotension, cardiac arrest, postural hypotension, pulmonary
embolism, pulmonary edema.
Central and Peripheral Nervous System: Frequent:
transient ischemic attack, cerebrovascular accident vertigo, ataxia, hypokinesia.
Infrequent: paresthesia, convulsions, extrapyramidal disorder, hypertonia,
tremor, aphasia, hypoesthesia, abnormal coordination, hemiplegia, hyperkinesia,
involuntary muscle contractions, stupor, cerebral hemorrhage, neuralgia, ptosis,
neuropathy.
Gastrointestinal System: Infrequent: gastroenteritis,
diverticulitis, gastrointestinal hemorrhage, melena, esophageal ulceration.
Hemic and Lymphatic Disorders: Frequent: anemia.
Infrequent: leukopenia.
Metabolic and Nutritional Disorders: Frequent:
increased alkaline phosphatase, decreased weight. Infrequent: dehydration,
hyponatremia, aggravated diabetes mellitus.
Psychiatric Disorders: Frequent: aggressive reaction.
Infrequent: delusion, personality disorder, emotional lability, nervousness,
sleep disorder, libido increased, psychosis, amnesia, apathy, paranoid reaction,
thinking abnormal, crying abnormal, appetite increased, paroniria, delirium,
depersonalization, neurosis, suicide attempt.
Respiratory System: Frequent: pneumonia. Infrequent:
apnea, asthma, hemoptysis.
Skin and Appendages: Frequent: rash. Infrequent:
skin ulceration, pruritus, cellulitis, eczema, dermatitis, erythematous rash,
alopecia, urticaria
Special Senses: Frequent: cataract, conjunctivitis.
Infrequent: macula lutea degeneration, decreased visual acuity, decreased
hearing, tinnitus, blepharitis, blurred vision, corneal opacity, glaucoma, conjunctival
hemorrhage, eye pain, retinal hemorrhage, xerophthalmia, diplopia, abnormal
lacrimation, myopia, retinal detachment.
Urinary System: Frequent: frequent micturition.
Infrequent: dysuria, hematuria, urinary retention
ADVERSE EVENTS FROM OTHER SOURCES
Memantine has been commercially available outside the
United States since 1982, and has been evaluated in clinical trials including
trials in patients with neuropathic pain, Parkinson’s disease, organic brain
syndrome, and spasticity. The following adverse events of possible importance
for which there is inadequate data to determine the causal relationship have
been reported to be temporally associated with memantine treatment in
more than one patient and are not described elsewhere in labeling: acne, bone
fracture, carpal tunnel syndrome, claudication, hyperlipidemia, impotence, otitis
media, thrombocytopenia.
ANIMAL TOXICOLOGY
Memantine induced neuronal lesions (vacuolation and necrosis)
in the multipolar and pyramidal cells in cortical layers III and IV of the posterior
cingulate and retrosplenial neocortices in rats, similar to those which are
known to occur in rodents administered other NMDA receptor antagonists. Lesions
were seen after a single dose of memantine. In a study in which rats were given
daily oral doses of memantine for 14 days, the no-effect dose for neuronal necrosis
was 6 times the maximum recommended human dose on a mg/m2 basis.
The potential for induction of central neuronal vacuolation and necrosis by
NMDA receptor antagonists in humans is unknown.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: Memantine HCl is not a controlled
substance.
Physical and Psychological Dependence: Memantine HCl
is a low to moderate affinity uncompetitive NMDA antagonist that did not produce
any evidence of drug-seeking behavior or withdrawal symptoms upon discontinuation
in 2,504 patients who participated in clinical trials at therapeutic doses.
Post marketing data, outside the U.S., retrospectively collected, has provided
no evidence of drug abuse or dependence.
DRUG INTERACTIONS
N-methyl-D-aspartate (NMDA) antagonists: The combined
use of NAMENDA with other NMDA antagonists (amantadine, ketamine, and dextromethorphan)
has not been systematically evaluated and such use should be approached with
caution.
Effects of NAMENDA on substrates of microsomal enzymes:
In vitro studies conducted with marker substrates of CYP450 enzymes (CYP1A2,
-2A6, -2C9, -2D6, -2E1, -3A4) showed minimal inhibition of these enzymes by
memantine. No pharmacokinetic interactions with drugs metabolized by these enzymes
are expected.
Effects of inhibitors and/or substrates of microsomal enzymes
on NAMENDA: Memantine is predominantly renally eliminated, and drugs
that are substrates and/or inhibitors of the CYP450 system are not expected
to alter the metabolism of memantine.
Acetylcholinesterase (AChE) inhibitors: Co-administration
of NAMENDA with the AChE inhibitor donepezil HCl did not affect the pharmacokinetics
of either compound. In a 24-week controlled clinical study in patients with
moderate to severe Alzheimer’s disease, the adverse event profile observed with
a combination of memantine and donepezil was similar to that of donepezil alone.
Drugs eliminated via renal mechanisms: Because memantine
is eliminated in part by tubular secretion, co-administration of drugs that
use the same renal cationic system, including hydrochlorothiazide (HCTZ), triamterene
(TA), cimetidine, ranitidine, quinidine, and nicotine, could potentially result
in altered plasma levels of both agents. However, coadministration of NAMENDA
and HCTZ/TA did not affect the bioavailability of either memantine or
TA, and the bioavailability of HCTZ decreased by 20%.
Drugs that make the urine alkaline: The clearance of
memantine was reduced by about 80% under alkaline urine conditions at pH 8.
Therefore, alterations of urine pH towards the alkaline condition may lead to
an accumulation of the drug with a possible increase in adverse effects. Urine
pH is altered by diet, drugs (e.g. carbonic anhydrase inhibitors, sodium bicarbonate)
and clinical state of the patient (e.g. renal tubular acidosis or severe infections
of the urinary tract). Hence, memantine should be used with caution under these
conditions.
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