FLUVOXAMINE
Fluvoxamine, Proxalutamide, and Ivermectin: 100% success
1 min read
I'm very bullish on two drug combos since it is rare for a single drug to be 100% successful.
For example all of these combos should have near 100% success against hospitalization, death, and long-haul COVID symptoms:
1. Proxalutamide and fluvoxamine
2. Proxalutamide and ivermectin
3. Fluvoxamine and ivermectin
Proxalutamide on its own has had 100% success in both inpatients and outpatients (100% for men, 90% for women).
Fluvoxamine has been 100% successful in two randomized trials. That 100% success rate was replicated in the real-world prescribing experience of Syed Haider who has been prescribing IVM+FLV for over 100 patients now. So 100% three times in a row, all by independent researchers.
Ivermectin alone has also had its share of 100% successes, e.g., in Argentina in the Carvallo study. There was a recent study in JAMA claiming ivermectin doesn't work, but see https://osf.io/u7ewz/ and https://www.youtube.com/watch?v=VwqCuqCE4aU.
Steve Kirsch
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New report describes positive results
of generic drug in treating COVID
Medical journal publishes details on fluvoxamine
Berkeley, CA (Feb. 1, 2021) – The Covid Early Treatment Fund (CETF) www.treatearly.org announced today that the medical journal Open Forum Infectious Diseases published a report that outlines the success in using a generic drug – fluvoxamine – to prevent complications of COVID-19.
“This
real-world evidence study provides additional independent confirmation that
fluvoxamine is highly effective in preventing hospitalization and death from
COVID,’’ said Steve Kirsch, a Silicon Valley high-tech entrepreneur and the
founder of CETF, a charitable organization that funds outpatient trials of
existing drugs. “Repurposed drugs always have had the potential to be the
fastest and least expensive way out of this pandemic. Fluvoxamine was again
shown to be 100% effective in preventing hospitalization and death, and we are
urging the medical community to consider these confirmatory results.”
The report by Dr. David Seftel, CEO of Enable Biosciences and a reviewer for the National Institutes of Health, and Dr. David Boulware, a professor and infectious disease physician-scientist at the University of Minnesota’s School of Medicine, discusses the real-world experience of using fluvoxamine to treat workers after a COVID-19 outbreak in November and December at Golden Gate Fields, a Berkeley, Ca., horse-racing track.
Dr. Seftel, the track
physician, offered fluvoxamine to infected employees after learning about the
100% success rate in avoiding hospitalization in a Phase 2 randomized controlled trial published on
November 12, 2020, in the Journal of the American Medical Association. None of the
77 employees at Golden Gate Fields who opted to take fluvoxamine required
hospitalization, compared with a 12.5% hospitalization rate for the 48
employees who declined the drug. In addition, after 2 weeks, none of the treatment group had
any COVID symptoms while 60% of the group who declined the drug had 1 or more
COVID symptoms.
“This is one of the
most extraordinary therapeutic effects I’ve witnessed in my 25 years of
practicing medicine,’’ said Dr. Seftel. “There is no doubt in my mind that
fluvoxamine significantly helped the workers at Golden Gates Fields battle this
virus. In every case, respiratory decline reversed within about three days
after starting the drug.”
The paper states: “Overall,
fluvoxamine appears promising as early treatment for COVID-19 to prevent
clinical deterioration requiring hospitalization and to prevent possible long-haul
symptoms persisting beyond 2 weeks.’’
Dr. Boulware previously
led the randomized clinical trial that disproved hydroxychloroquine is an
effective treatment for COVID-19.
The Golden Gate Fields
experience with fluvoxamine confirmed earlier findings from a 152-patient
randomized clinical trial at the Washington University School of Medicine in
St. Louis. In that outpatient trial, Dr. Eric Lenze and colleagues found that
fluvoxamine was 100% effective in preventing respiratory deterioration that
normally would require hospitalization compared with an 8.3% hospitalization
rate in the placebo group.
Fluvoxamine, an
antidepressant, is in the class of selective serotonin reuptake
inhibitors, which work by increasing levels of serotonin within the brain.
Lenze said the benefits of taking fluvoxamine appear to greatly outweigh any
risks.
“A good way of thinking
about SSRI risk is like if you took an aspirin a day for two weeks,’’ he said. “It is benign, but if you
happened to get in a car accident or have a bad fall in those two weeks, you'd
be more prone to bleed. But if SSRIs help against COVID, their benefits far
outweigh any risks. No medication is 100% safe, but these are pretty
close.’’
CETF is funding a Phase
3 clinical trial to examine the efficacy of using fluvoxamine for the early
treatment of COVID. The trial began in December and is seeking volunteers. Enrollment is free, and you can participate from the comfort of your
home. For more information on how to enroll, go to stopcovidtrial.wustl.edu
To
learn more about CETF's mission or to donate to expedite the fight against
COVID-19, visit www.treatearly.org
MEDIA
CONTACTS:
David Satterfield
G.F.BUNTING+CO
Russ Stanton
G.F.BUNTING+CO
Executive
Summary
The two
clinical trials, one randomized, the other pseudo-randomized
The Lenze fluvoxamine RCT that was published in JAMA that showed a 100% success rate in preventing hospitalization
was confirmed a week later at the massive 300 person outbreak at Golden Gate
fields.
Dr. David Seftel read about
the Lenze trial, and applied the result to a large COVID outbreak at Golden
Gate Fields just 3 days after the Lenze trial was published in JAMA. Seftel was
able to duplicate the 100% protection from hospitalization and death in
the treatment group, vs. a 12.5% hospitalization/death rate for the No
treatment group. There were 113 patients in the initial OFID paper submission,
but 12 more were added later, N=125. Latest draft submitted to OFID.
Phase 3 trial
There is a Phase 3 trial of
880 patients that is enrolling now: stopcovidtrial.com.
Effect size
For both trials, the
average effect size was 100%. Because Seftel’s study was pseudo-randomized but
with the randomization giving the treatment arm arguably higher risk patients,
the combined p-value is estimated at .0001.
Fisher exact test on the
combined data suggests that there is a 95% chance that the effect size
is at least a 72% reduction in hospitalization rate.
Independently, infectious
disease doctors who are familiar with the evidence have speculated that the
true effect size (protection from hospitalization vs. placebo) is 75% or
more.
Dosing
The Lenze trial used 50mg
day 1, then 100mg BID, and increased the dose to 100mg TID as tolerated.
Seftel used a 50mg BID
dosing for 14 days. No side effects were reported at that dose for his
patients, although some patients will experience mild nausea at that dose. Most
people reversed symptoms within 1-3 days of getting the drug in his study.
Generally, the greater the symptoms, the longer it took to reverse.
50mg QD dosing was used in
one case with mild symptoms, symptoms reversed in just 24 hours and continued
to improve.
Observational
studies
There are five independent observational studies (2 in France, 1 in Germany, 2 in the US (TriNetX and Stanford)) all
showing statistically significant effect of the SSRI and the differential
effect of the sigma1 agonist property of fluvoxamine.
Mechanisms of
action
There are at least seven Mechanisms of action. From the French observational data (see the very last page), it appears that the biggest effect is
limiting serotonin release (any SSRI will do that). This alone will give a 50%
effect size and explains why all of the the SSRIs are effective including those
that do not activate the Sigma1 receptor (e.g., Paroxetine). The next
major effect is that fluvoxamine activates the sigma-1 receptor. S1R can essentially
turn off IRE1, so IRE1 will not activate XBP1, so that the cytokine production
will decrease. This gives another 50% of benefit (note that the US study
in the observational section shows only a 30% additional benefit).
The virus activates platelets
which release serotonin which justifies using SSRIs to vacuum up the serotonin
before it can cause havoc. See the directory on serotonin.
Real-world
result reporting
There is a fluvoxamine results reporting form where any doctor from anywhere in the world can report their results
with fluvoxamine. You can return later and update your statistics. This creates
a central world-wide repository of outcomes. But few people know about it so
there isn’t any data yet. We know of less than a dozen physicians prescribing
fluvoxamine, all without a failure to reverse symptoms, but most haven’t used
the form.
Restricted access directory
There is a restricted access directory containing
the KOL presentation and Mechanisms of action. Please contact stk@treatearly.org for access. These files
have unpublished data or data in which public view rights have not been
secured.
Anecdotal evidence :
Steve
Kirsch
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posts
High
tech serial entrepreneur and medical philanthropist.
LOS ALTOS HILLS, CA
Fluvoxamine dosing guidelines
Summary
We don’t know the right dose. Presumably, the protective effect is
proportional to the drug and the amount needed will vary individual by individual
and based on disease severity and when you are able to start to give the drug.
Because we don’t know, from a patient safety perspective, it makes sense
to give the highest dose that the patient can tolerate. Because of the short
half life, you can always back off the dose.
If there are any signs of serotonin syndrome (higher respiratory rate,
fatigue, bad diarrhea), then add in the cyproheptadine immediately to the mix.
Farid Jalali <f.jalali@me.com> writes:
There are
obviously variable degrees of SERT inhibition by different SSRIs, and people
also have variable polymorphisms in regards to 5HT transporter, as we very well
do know. So the answer is “we don’t know” who responds and by how much given
the polymorphisms in receptors and transporters of 5HT in different people.
This is probably why someone with severe COVID19 for 3 weeks comes out of ICU
unscathed from a pulmonary fibrosis standpoint, and similarly treated patient
never reaching ventilator status will end up having severe pulmonary fibrosis
after recovery. Serotonin is a highly implicated molecule in pulmonary
hypertension and pulmonary fibrosis. It won’t be the only molecule involved,
but it’s a very well known driver of pulmonary hypertension and fibrosis.
See this on the
polymorphism: https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.158.12.2074
Read this study
carefully please (in this landmark study resembling COVID19 IMO the most,
Fluoxetine was used for 3 weeks to deplete platelet 5HT - page E1552) https://www.pnas.org/content/pnas/115/7/E1550.full.pdf
Read this on
fibrosis and 5HT:
https://pubmed.ncbi.nlm.nih.gov/18321937/
https://www.hindawi.com/journals/mi/2018/7967868/
It’s very hard
to answer what the dosage should be. But the side effects may pile up at higher
dosages with SSRIs (very common) and may limit usage in real-world cases.
50mg BID dosing used by Seftel
David Seftel used 100mg BID for 1 day loading dose, then 50mg BID for
his first 35 patients.
This led to a significant number of people who complained about nausea.
Because Dr. Seftel wanted to ensure compliance, he backed off the loading dose.
For all but the first
35 patients, he has used:
50 mg BID for 14 days
This has worked 100% of the time in all 42 patients he used it for
including 8 crossover patients from the No Treatment group. In his patients,
there were no reported side effects at that dose in the patients treated by Dr.
Seftel, but we do know of one individual who complained of mild nausea at that
dose for the entire time she was on treatment.
Because the drug gets to half of the steady state value in 3 days, the
fact that Dr. Seftel uniformly saw patients resolve symptoms in 3 days suggests
that an effective steady state dose for COVID could be as low as 50mg QD (and a
50mg BID loading dose for the first day), which is just 1/6 of the dose
used for OCD. An even lower dose may be effective. However, this is based on
anecdotal data and needs to be proven in larger numbers. But this does suggest
that for patients who are leery of using an OCD drug and would refuse even a 50
mg BID, might accept a 50mg QD dosing schedule.
50mg QD dosing
I know of one patient, who was diagnosed shortly after getting COVID and
had relatively mild symptoms who tried the 50mg QD dose and her symptoms
resolved 80% after 24 hours and disappeared after 48 hours. This is a very
promising result that deserves further study
50mg QD, then 100mg BID dosing used in WashU
In the fluvoxamine RCT, the dosing was based on the FDA dose approved for OCD.
In this study, people started fluvoxamine at 50mg on the first night, then increased to 100mg twice daily. Later in the 15-day course, some patients increased to 100mg three times daily as tolerated. This rapid increase can cause side effects such as nausea, dizziness, and changes in sleep like insomnia. However, these side effects are usually mild and go away. Almost all patients in the study could take fluvoxamine for at least 5 days (and we don’t know if a 15-day course is needed).
Other than Dr. Seftel, we are aware of only two doctors who have
prescribed fluvoxamine off-label for COVID patients:
Karl E. Steinberg, MD
3 total, none hospitalized. All
high-risk.
I used the 50
mg bid dose. One patient who was also on routine tramadol had some
tachycardia and tremors that I thought might be serotonin syndrome. I
asked her what she wanted to do and she decided to cut back on the tramadol
while finishing out the fluvoxamine and that worked out for her.
Interestingly, she also developed shingles not long after finishing the course
of fluvoxamine.
- High flow oxygen
patient recovered and will be going home soon
- The other 2 outpatients
on flu day 2-3 recovered 100%
Steve Kirsch arranged for 3 people to get fluvoxamine prescriptions
- Barbara L. (Wife’s
friend): 50mg BID for 7 days: never developed any symptoms
- Chris E. (Decorator’s
husband): 50mg BID. Sick in bed for a week. O2sat =92. Four days after
50mg BID treatment he wanted to run on the treadmill. He’s fully recovered. Never
needed to be hospitalized.
- Micaela M.
(Housekeeper): 50mg QD. Wrote: “Yesterday I felt back pain headache sore
throat muscle pain and my right ear swollen. Today, one day after
starting the medication, I feel much better. Pain significantly reduced.
Please see the Fluvoxamine reporting form to report your results.
Fluvoxamine prescribing information
There is a consumer and doctor aversion to taking any psychotropic drug.
Dosing
See Fluvoxamine Dosing Guidelines
Caffeine interaction
Warn
patients about using caffeine while on the drug! This is not
in the FDA guidelines. The WashU trial warns patients about this.
From https://www.crazyboards.org/topic/14354-luvox/:
"Your one
cup of joe will suddenly become like five cups, and the effects will last six
times as long. These effects have been confirmed by subsequent studies,
including one that shows these effects with just 10mg of fluvoxamine. Don't mix
coffee and fluvoxamine!”
Studies: one study. another and another.:
The half-life of caffeine is increased from 5 to 31 hours.
Standard cautions
Adverse Effects:
▪ Restlessness, agitation, insomnia, nausea,
diarrhea, headache, dizziness, fatigue,
sexual dysfunction, hyponatremia
▪ SSRIs can increase the risk of bleeding by
inhibiting serotonin uptake by platelets
▪ QT interval prolongation has been
reported with all SSRIs; the risk appears to
be greatest with citalopram and
escitalopram
Drug Interactions:
▪ Increased risk of serotonin syndrome
when used with other serotonergic drugs
▪ Use of SSRIs and monoamine oxidase
inhibitors (MAOIs) concurrently or within
2 weeks of each other is contraindicated
▪ Use with antiplatelet or anticoagulant
drugs may increase the risk of bleeding
▪ Use with other QT-interval prolonging
drugs could result in additive effects and
an increased risk of torsades de pointes
▪ Fluvoxamine is a strong inhibitor of
CYP1A2 and moderate inhibitor of
CYP2C19 and can increase serum
concentrations of drugs metabolized by
these pathways
▪ SSRI often used for treatment of OCD
▪ Effects on the sigma-1 receptor may
down-regulate cytokine release
Pregnancy:
▪ Limited data are available on use of
fluvoxamine in pregnancy compared to
other SSRIs
▪ Risk of congenital malformations after
taking an SSRI during pregnancy appears
to be very low, and no increase in
perinatal mortality has been
demonstrated
▪ Increased risk of cardiovascular and other
malformations has been reported in
infants born to mothers who took
paroxetine in the first trimester
1. EJ
WashU dispensing guidelines
See https://healthymind.wustl.edu/
Three safety issues are
important:
- First, fluvoxamine affects the metabolism of some drugs. In
particular, people taking theophylline, clozapine, olanzapine, or
tizanidine should either avoid fluvoxamine or talk to their doctor about
how to avoid a dangerous drug interaction. Also, people using
caffeine (like in coffee or tea) should greatly cut down on it.
- Second, fluvoxamine has psychiatric effects. We did not see
any untoward effects from it (such as anxiety or loss of concentration),
but people with psychiatric conditions such as bipolar disorder or who
already take psychiatric medications such as antidepressants or mood
stabilizers, should talk carefully with their doctor before adding
fluvoxamine.
- Third,
patients taking drugs that promote bleeding such as coumadin may be at
higher risk because fluvoxamine can also increase bleeding risk. We
don’t know how important this effect is, given how short is the course of
fluvoxamine.
FDA dispensing guidelines for use in OCD
Note the warnings:
1.
Coadministration of tizanidine, thioridazine, alosetron, pimozide
2.
Use of MAOI’s concomitantly with or within 14 days of treatment
with Luvox Tablets (4)
Fluvoxamine for COVID 8 mechanisms of action
There is a restricted access directory with
information on the mechanisms of action that we don't have the rights to
publicly disclose thas significant data on mechanisms of action. There are two
presentations (one by Angela Reiersen and the other is the prezo given to the
KOL meeting attendees on Jan 22). In particular, if you don’t watch Farid
Jalali’s 1.5 hour video on SSRIs, serotonin, platelets, and the virus, you are
missing out on a huge part of how and why SSRIs are so effective.
My personal guess is that 50% of the effect is
explained in Farid’s prezo since all SSRIs have this level of effect or more.
Also, smokers don’t get COVID symptoms. Again, this points to platelets and
serotonin. And depression is the only comorbidity that is protective.
The other 50% is due to sigma1 activation, this is why
some SSRIs are more effective than others. They line up perfectly based on
their sigma1 activation.
Other mechanisms like the FIASMA antiviral effect
are present as well, but likely not as significant. So serotonin vacuuming and
the sigma1 activation are really the big 2.
Contact stk@treatearly.org for access
permission.
The “serotonin related” directory has data
regarding platelets and serotonin, the use of cyproheptadine for COVID
patients, and why amitriptyline might be very useful for long haul patients
(and SSRIs may make things worse for those patients).
Sigma1 activation
Is sigma1 basically in the mitochondria of every
cell? do we understand how it works to regulate the inflammatory storm?
A: S1R is NOT in the mitochondria. It is located at
the membrane of the endoplasmic reticulum (ER), and especially at the portions
of the ER membrane that are NEAR mitochondria. S1R regulates activity of
another ER protein called IRE1 (see additional information about IRE1 below).
S1R also regulates some other ER proteins.
For example, is it mast cells that would be the
most important that would be regulated here or are all cells involved?
A: S1R is in many types of cells.
I think SSRIs in general inhibit mast cell activity
(not sure how relevant S1R is to effects on the mast cells).
The article says the receptor acts as a
“chaperone”…. so activating it is “enabling” some sort of activity here that is
helpful. what is a good way to describe to a lay person what is going on? it’s
not really like a fire sprinkler turning on, is it?
A: The endoplasmic reticulum is somewhat like a
factory for building proteins into their final form. In general, chaperone
proteins can assist in proper folding and maturation of other proteins that are
being produced in the endoplasmic reticulum. one S1R function is to act
as a chaperone to facilitate the maturation of certain proteins. But it also
has other functions, such as regulating the actions of other ER proteins
(including a protein called IREI that that is involved with the ER stress
response and inflammatory responses). IRE1 is a protein that can activate
another protein called XBP1 which can then promote the production of cytokines.
In the presence of a S1R agonist, S1R can essentially turn off IRE1, so IRE1
will not activate XBP1, so that the cytokine production will
decrease.
Summary of mechanisms
Dr. Angela Reiersen who led the Wash U study writes the following:
I have counted about 7-8 plausible mechanisms. I think at least 2 of
them are likely to have very substantial effects. In approximate order of my
current guess on which are most important:
- Anti-inflammatory
effect SIR-IRE1 pathway (reduction of the amount of cytokines produced in
response to the infection).
- Inhibition
of platelet activation.
- Inhibition of mast
cell activation.
- Functional inhibition
of acid sphingomyelinase activity(FIASMA).
- Lysosomotropism, which
is characteristic of cationic amphiphilic drugs (CAD) in general. This is also related to #4.
- Direct interaction of
S1R with viral proteins (which could be modified by various S1R ligands).
- Inhibition of
melatonin metabolism, which leads to increased melatonin levels (melatonin
had its own anti-inflammatory effects).
- Reduction of G9a histone methyltransferase
(this is an interesting mechanism which seems to be affected by some
antidepressants, but I don’t know yet whether fluvoxamine acts on this
pathway).
I could certainly be wrong about the order of importance. All the
potential mechanisms need further study.
1 applies to SSRIs (and other drugs) only if they
are S1R agonists (as far as SSRIS, probably applies at least to fluvoxamine and
fluoxetine, maybe to escitalopram and citalopram also).
2&3 probably apply to all SSRIs.
4&5 probably apply to most or all SSRIs (and
probably quite a few other drugs).
6 might apply to SSRIs (and other drugs) if they
are S1R ligands (might include agonists & antagonists), but each would need
to be tested individually to confirm.
7 applies only to fluvoxamine.
8 may apply to some antidepressants and some other
drugs, but each would need to be tested individually to determine this. I have
read that this applies to amitriptyline, imipramine and paroxetine, but not venlafaxine,
carbamazepine, or valproic acid. The only SSRI on this list is paroxetine, but
I don’t know if other SSRIs have been tested.
Articles
on antidepressants that inhibit G9a:
https://pubmed.ncbi.nlm.nih.gov/29417943/
https://pubmed.ncbi.nlm.nih.gov/22880885/
IL-6 and IL-10 ratio
FLV is known to reduce IL-6 and increase IL-10.
Adverse
reactions
This is from
FDA and applies to use in treating OCD. See Full Prescribing Information.
Because the
dosing required for COVID is modest and the treatment is only for 14 days, the
side effects we’ve seen dosing at 50mg BID for 14 days produced mild nausea in
one patient.
Patients should avoid caffeine while on the drug.
Adverse Reactions
The following adverse drug reactions and incidences are derived from
product labeling unless otherwise specified. Frequency varies by dosage form
and indication. Adverse reactions reported as a composite of all indications.
>10%:
Central nervous system: Headache (22% to 35%), insomnia (21% to 35%),
drowsiness (22% to 27%), dizziness (11% to 15%), nervousness (10% to 12%)
Gastrointestinal: Nausea (34% to 40%), diarrhea (11% to 18%), xerostomia
(10% to 14%), anorexia (6% to 14%)
Genitourinary: Ejaculatory disorder (8% to 11%)
Neuromuscular & skeletal: Weakness (14% to 26%)
1% to 10%:
Cardiovascular: Chest pain (3%), palpitations (3%), vasodilation (2% to
3%), hypertension (1% to 2%), edema (≥1%), hypotension (≥1%), syncope (≥1%)
Central nervous system: Pain (10%), anxiety (5% to 8%), anorgasmia (2%
to 5%), yawning (2% to 5%), abnormal dreams (3%), abnormality in thinking (3%),
paresthesia (3%), agitation (2% to 3%), apathy (≥1% to 3%), central nervous
system stimulation (2%), chills (2%), depression (2%), hypertonia (2%),
psychoneurosis (2%), twitching (2%), amnesia (≥1%), manic reaction (≥1%),
myoclonus (≥1%), psychotic reaction (≥1%), malaise (≤1%)
Dermatologic: Diaphoresis (6% to 7%), ecchymoses (4%), acne vulgaris
(2%)
Endocrine & metabolic: Decreased libido (2% to 10%; incidence higher
in males), hypermenorrhea (3%), weight loss (≥1% to 2%), weight gain (≥1%)
Gastrointestinal: Dyspepsia (8% to 10%), constipation (4% to 10%),
vomiting (5% to 6%), abdominal pain (5%), flatulence (4%), dental caries (≤3%),
tooth loss (≤3%), toothache (≤3%), dysgeusia (2% to 3%), dysphagia (2%),
gingivitis (2%)
Genitourinary: Urinary frequency (3%), sexual disorder (2% to 3%),
impotence (2%), urinary tract infection (2%), urinary retention (1%)
Hepatic: Abnormal hepatic function tests (2%)
Infection: Tooth abscess (≤3%), viral infection (2%)
Neuromuscular & skeletal: Tremor (5% to 8%), myalgia (5%),
hyperkinesia (≥1%), hypokinesia (≥1%)
Ophthalmic: Amblyopia (2% to 3%)
Renal: Polyuria (2%)
Respiratory: Upper respiratory tract infection (9%), pharyngitis (6%),
flu-like symptoms (3%), laryngitis (3%), bronchitis (2%), dyspnea (2%),
epistaxis (2%), increased cough (≥1%), sinusitis (≥1%)
<1%, postmarketing, and/or case reports: Abnormal gait, activation
syndrome, acute renal failure, aggressive behavior, agranulocytosis, akinesia,
amenorrhea, anaphylaxis, anemia, angina pectoris, angioedema, angle-closure
glaucoma, anuria, aplastic anemia, apnea, asthma, ataxia, blurred vision,
bradycardia, bruxism, bullous skin disease, cardiac conduction delay,
cardiomyopathy, cardiorespiratory arrest, cerebrovascular accident,
cholecystitis, cholelithiasis, colitis, crying, decreased white blood cell
count, delirium, diplopia, drowsiness (neonatal), dysarthria, dyskinesia, dystonia,
extrapyramidal reaction, fatigue, fever, first degree atrioventricular block,
gastroesophageal reflux disease, gastrointestinal hemorrhage, glossalgia,
goiter, hallucination, hematemesis, hematuria, hemoptysis, hepatitis, homicidal
ideation, hypercholesterolemia, hyperglycemia, hypersensitivity reaction,
hypoglycemia, hypokalemia, hyponatremia, hypothyroidism, IgA vasculitis,
impulsivity, interstitial pulmonary disease, intestinal obstruction,
intoxicated feeling, irritability, jaundice, jitteriness, laryngismus,
lethargy, leukocytosis, leukopenia, loss of consciousness, lymphadenopathy,
melena, myasthenia, myocardial infarction, myopathy, neuroleptic malignant
syndrome (Stevens 2008), outbursts of anger, pancreatitis, paralysis,
Parkinsonian-like syndrome, pericarditis, porphyria, priapism, prolonged QT
interval on ECG, purpura, Raynaud's phenomenon (Khouri 2016; Peiró 2007), renal
insufficiency, rhabdomyolysis, seizure, serotonin syndrome, shock, SIADH, ST
segment changes on ECG, Stevens-Johnson syndrome, suicidal tendencies,
supraventricular extrasystole, tachycardia, tardive dyskinesia,
thrombocytopenia, thromboembolism, toxic epidermal necrolysis, vasculitis,
ventricular arrhythmia, ventricular tachycardia (including torsades de pointes)
Contraindications
Concurrent use with alosetron, pimozide, thioridazine, or tizanidine;
use of MAO inhibitors intended to treat psychiatric disorders (concurrently or
within 14 days of discontinuing either fluvoxamine or the MAO inhibitor);
initiation of fluvoxamine in a patient receiving linezolid or intravenous
methylene blue.
Canadian labeling: Additional
contraindications (not in US labeling): Hypersensitivity to fluvoxamine or any
component of the formulation; concurrent use with astemizole, cisapride,
mesoridazine, ramelteon, or terfenadine.
Warnings/Precautions
Major psychiatric warnings:
• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants
increase the risk of suicidal thinking and behavior in children, adolescents,
and young adults (18 to 24 years of age) with major depressive disorder (MDD)
and other psychiatric disorders; consider risk prior to prescribing.
Short-term studies did not show an increased risk in patients >24 years of
age and showed a decreased risk in patients ≥65 years. Closely monitor patients
for clinical worsening, suicidality, or unusual changes in behavior,
particularly during the initial 1 to 2 months of therapy or during periods of
dosage adjustments (increases or decreases); the patient's family or caregiver
should be instructed to closely observe the patient and communicate condition
with healthcare provider. A medication guide concerning the use of
antidepressants should be dispensed with each prescription. Fluvoxamine is
FDA approved for the treatment of OCD in children ≥8 years of age.
- The possibility of a suicide attempt is inherent in major depression
and may persist until remission occurs. Worsening depression and severe abrupt
suicidality that are not part of the presenting symptoms may require
discontinuation or modification of drug therapy. Use caution in high-risk
patients during initiation of therapy.
- Prescriptions should be written for the smallest quantity consistent
with good patient care. The patient's family or caregiver should be alerted to
monitor patients for the emergence of suicidality and associated behaviors such
as anxiety, agitation, panic attacks, insomnia, irritability, hostility,
impulsivity, akathisia, hypomania, and mania; patients should be instructed to
notify their health care provider if any of these symptoms or worsening
depression occur.
Concerns related to adverse effects:
• Bleeding risk: May impair platelet aggregation resulting in increased
risk of bleeding events, particularly if used concomitantly with aspirin,
NSAIDs, warfarin or other anticoagulants. Bleeding related to SSRI use has been
reported to range from relatively minor bruising and epistaxis to
life-threatening hemorrhage.
• CNS depression: Has a low potential to impair cognitive or motor
performance; caution operating hazardous machinery or driving.
• Fractures: Bone fractures have been associated with antidepressant
treatment. Consider the possibility of a fragility fracture if an
antidepressant-treated patient presents with unexplained bone pain, point
tenderness, swelling, or bruising (Rabenda 2013; Rizzoli 2012).
• Impaired glucose control: Impaired glucose control (eg, hyperglycemia,
hypoglycemia) has been reported; monitor for signs/symptoms of loss of glucose
control particularly in diabetic patients.
• Ocular effects: May cause mild pupillary dilation which in susceptible
individuals can lead to an episode of narrow-angle glaucoma. Consider
evaluating patients who have not had an iridectomy for narrow-angle glaucoma
risk factors.
• Serotonin syndrome: Potentially life-threatening serotonin syndrome
(SS) has occurred with serotonergic agents (eg, SSRIs, SNRIs), particularly
when used in combination with other serotonergic agents (eg, triptans, TCAs,
fentanyl, lithium, tramadol, buspirone, St John's wort, tryptophan) or agents
that impair metabolism of serotonin (eg, MAO inhibitors intended to treat
psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous
methylene blue]). Monitor patients closely for signs of SS such as mental
status changes (eg, agitation, hallucinations, delirium, coma); autonomic
instability (eg, tachycardia, labile blood pressure, diaphoresis);
neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg,
nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any
concomitant serotonergic agent) immediately if signs/symptoms arise.
• Sexual dysfunction: May cause or exacerbate sexual dysfunction.
• SIADH and hyponatremia: SSRIs and SNRIs have been associated with the
development of SIADH; hyponatremia has been reported rarely (including severe
cases with serum sodium <110 mmol/L), predominately in the elderly. Volume
depletion and/or concurrent use of diuretics likely increases risk. Consider
discontinuation if symptomatic hyponatremia occurs.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with
cardiovascular disease; fluvoxamine has not been systemically evaluated in
patients with a recent history of MI or unstable heart disease.
• Hepatic impairment: Use with caution in patients with hepatic impairment;
clearance is decreased and half-life and plasma concentrations are increased; a
lower dosage may be needed. However, selective serotonin reuptake inhibitors
such as fluvoxamine are considered the safest antidepressants to use in chronic
liver disease because of their relative lack of side effects and high
therapeutic index (Mullish 2014).
• May precipitate a shift to mania or hypomania in patients with bipolar
disorder. Monotherapy in patients with bipolar disorder should be avoided.
Combination therapy with an antidepressant and a mood stabilizer may be
effective for acute treatment of bipolar major depressive episodes, but should
be avoided in acute mania or mixed episodes, as well as maintenance treatment
in bipolar disorder due to the mood-destabilizing effects of antidepressants
(CANMAT [Yatham 2018]; WFSBP [Grunze 2018]). Patients presenting with
depressive symptoms should be screened for bipolar disorder. Fluvoxamine is
not FDA approved for the treatment of bipolar depression.
• Seizure disorder: Use with caution in patients with a previous seizure
disorder and avoid use with unstable seizure disorder. Discontinue use if
seizures occur or if seizure frequency increases.
Concurrent drug therapy issues:
• Smokers: Fluvoxamine levels may be lower in patients who smoke.
Other
warnings/precautions:
• Discontinuation syndrome: Abrupt discontinuation or interruption of
antidepressant therapy has been associated with a discontinuation syndrome.
Symptoms arising may vary with antidepressant however commonly include nausea,
vomiting, diarrhea, headaches, light-headedness, dizziness, diminished
appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and
sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include
electric shock-like sensations, cardiac arrhythmias (more common with tricyclic
antidepressants), myalgias, parkinsonism, arthralgias, and balance
difficulties. Psychological symptoms may also emerge such as agitation,
anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of
mood, dysphoria, mood lability, hyperactivity, mania/hypomania,
depersonalization, decreased concentration, slowed thinking, confusion, and
memory or concentration difficulties. Greater risks for developing a
discontinuation syndrome have been associated with antidepressants with shorter
half-lives, longer durations of treatment, and abrupt discontinuation. For
antidepressants of short or intermediate half-lives, symptoms may emerge within
2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010;
Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).
• Electroconvulsive therapy: Risk:benefits of combined therapy with
electroconvulsive therapy have not been established.
Warnings: Additional Pediatric
Considerations
SSRI-associated behavioral activation (ie,
restlessness, hyperkinesis, hyperactivity, agitation) is two- to threefold more
prevalent in children compared to adolescents; it is more prevalent in
adolescents compared to adults. Somnolence (including sedation and drowsiness)
is more common in adults compared to children and adolescents (Safer 2006). May
impair cognitive or motor performance. SSRI-associated vomiting is two- to
threefold more prevalent in children compared to adolescents and is more
prevalent in adolescents compared to adults (Safer 2006). A recent report (Lake
2000) describes five children (age 8 to 15 years) who developed epistaxis (n=4)
or bruising (n=1) while receiving sertraline therapy. Another recent report
describes the SSRI discontinuation syndrome in six children; the syndrome was
similar to that reported in adults (Diler 2002). Due to limited long-term
studies, the clinical usefulness of fluvoxamine should be periodically
reevaluated in patients receiving the drug for extended intervals; effects of
long-term use of fluvoxamine on pediatric growth, development, and maturation
have not been directly assessed. Note: Case reports of decreased growth
in children receiving fluoxetine or fluvoxamine (n=4; age: 11.6 to 13.7 years)
for 6 months to 5 years suggest a suppression of growth hormone secretion
during SSRI therapy (Weintrob 2002).
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