Q) People on this forum have mentioned Clonidine and
have said Moxonidine has less side effects. Will someone please tell me
what the side effects of Clonidine and/or Moxonidine are? Which is
better or worse, and why?
A) Moxonidine is a more selective imidazoline I1
receptor agonist with only low affinity for alpha2-adrenoceptors; it is
the alpha2-adrenoceptor agonistic properties of the older centrally
acting antihypertensives (clonidine) that cause many of their adverse
effects.
These are generally dry mouth & drowsiness. Moxonidine does cause
less of these but has a shorter half-life. The drowsiness tends to subside even more than any
dry mouth over several weeks of treatment.
The tested dose range for clonidine is much broader & has a longer
half-life however so if one
does not find moxonidine effective at 0.6 mg, clonidine has been taken
up to 2.4mg/day although most find relief from clonidine at 0.1 - 0.6mg
/day, rarely employed beyond 1.2mg..
Q) uhhh...thanks for the info but it was kinda
technical. So are you saying that Moxonidine is better to try first? Do
you know which one is more effective for HH/FB?
A) Yeah it had some technical info for your doc, etc..
but since it does have a lower side effect profile it makes sense to try
it first but clonidine has been around much longer with a record of
efficacy and its effects should last longer.
Both Moxonidine & Clonidine lower sympathetic output hence less FB/FF/HH
(& Blood pressure-pulse significantly more so in hypertensive
people).
If Moxonidine 0.6 mg (max rec. dose) does not cut it, then it makes
sense to switch over to clonidine which has a much broader tested dose
range.
My Personal Experience: Q & A
1Q) How did the testing of Monoxidine vs. Clonidine go?
1A) I would roughly equate 0.4mg of Moxonidine to 0.1mg
of Clonidine for FB/FF/HH on myself with significantly less dry mouth
& drowsiness. YMMV (Your Mileage May Vary). I do agree
with reports that clonidine's effect can last longer which is in accord
with its longer half-life.
2Q. Why don't you take Clonidine or Monoxidine everyday?
Do they lose their effectiveness over time like someone has just posted?
2A) No shame in taking it everyday (most with hypertension do) but I try
to encourage myself now when possible that I can do it without it (of
course knowing I got it in case for backup helps!) Some do find some
tolerance but it's more the exception & the dose range is very broad
for clonidine. If you find tolerance developing & increasing
the dose causes undesirable side effects then cutting down on the dose
when less needed may be a better approach. Also when used daily,
knowing the peak effect is 2-5 hours may help in its effective use.
3Q) When you take or took Clonidine, what dose did you
use..
3A) I take 0.05 mg for mild stressors (at least 45-60 minutes before), 0.1mg for
moderate stressors and for major stressors will increase to 0.2mg or occasionally
add up to 50 mg of atenolol (since I do get dose dependent dry mouth
from clonidine) & schedule in accordance to peak effects of 2-5
hours. A pill cutter from your pharmacy or Health
Maintenance Organization can come in handy when fine-tuning doses.
I established my BP/pulse reaction.
* "Precaution listed for hypertensive use: If therapy is to be discontinued in patients receiving a beta-blocker like atenolol and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual (2-4 day) discontinuation of
clonidine."
4Q) I weigh over 200lbs. With my bigger size, in your
opinion, would I require a larger dosage of clonidine than say a 100lb
female.
4) Likely, either way the studied dose range for clonidine is very broad
as mentioned above although I would recommend establishing your BP &
pulse response.. Your risk for hypertension increases if overweight
& FB/FF/HH as well as you strain your heart & sympathetic
nervous system.
Moxonidine and the sympathetic nervous system
What is the role of sympathetic nervous system overactivity in
hypertension?
Do you know of any centrally-acting antihypertensives?
What is moxonidine?
One of the roles of the autonomic nervous system is the regulation of
vascular tone, and activation of the sympathetic nervous system leads to
vasoconstriction directly and also adrenal catecholamine release.
Vascular sympathetic tone is governed by neurones originating from a
nucleus within the rostroventral medulla. Thus, increased sympathetic
nervous activity is a feature of hypertension and is found in
association with insulin resistance (Reaven GM, NEJM, 1996; 334:
374-381). Older anti-hypertensives such as clonidine and alpha-methyl
dopa are thought to attenuate centrally mediated sympathetic tone
through activation of medullary alpha 2-adrenoceptors. Other
non-vascular effects may be mediated by these receptors which may
explain the unwanted effects such as sedation, dry mouth and impotence.
Rebound hypertension is a more serious side effect associated with the
abrupt discontinuation of Clonidine.
Moxonidine is a newer class of centrally-acting antihypertensive, being
an agonist of Imidazoline I1 Receptors, again located within the
rostroventral medulla, and produces a reduction in central sympathetic
tone. Moxonidine is better tolerated than other centrally acting agents,
with a comparable side effect profile and similar efficacy to other
anti-hypertensives agents (ACEI, beta-blockers, diuretics and calcium
channel blockers).
Moxonidine a Better Tolerated Centrally Acting Antihypertensive?
Adverse events with moxonidine are seldom so troublesome that patients
need to stop treatment. Approximately 2.5 to 4% of patients treated with
moxonidine were withdrawn from clinical trials because of adverse
events.[1] This rate was slightly higher than that with placebo (2% with
placebo vs 4% with moxonidine in placebo-controlled trials). The vast
majority of adverse events were of mild to moderate severity, which may
help patients to be compliant.
Dry Mouthed, Sleepy and Dizzy?
Dry mouth, somnolence, headache and dizziness were the most frequently
reported adverse event in clinical trials of moxonidine in
hypertension.[1] Dry mouth was the most common adverse event, being
spontaneously reported by 8 to 15% of patients. The other 3 events were
spontaneously reported by 5 to 8% of moxonidine recipients.
Both dry mouth and somnolence appeared to be dose related in the dosage
range tested (0.1 to 1 mg/day), and dizziness was considered to be
possibly related to the pharmacology of moxonidine.[1] The incidence and
severity of these effects may lessen over time with continued treatment.
Whether reported headache is caused by the drug is uncertain because
headache occurred with similar frequency in moxonidine and placebo
recipients in placebo-controlled trials.[1]
Analysis of tolerability of moxonidine in hypertension[1]
A Large Body Of Data
A clear picture of the tolerability of moxonidine in patients with
hypertension is now able to be formed, with more than 3000 patients
treated in clinical trials and an estimated 370 000 patient-years of
worldwide exposure to moxonidine available (see table 1).[1] This
article focuses on data pooled from phase II to IV clinical trials in
patients with hypertension and periodic drug safety update reports (PDSURs).
Tolerability information for moxonidine in the treatment of hypertension
was obtained from clinical trials and periodic drug safety update
reports (PDSURs) for the period 1989 to 1997.
Data from clinical trials included >3000 patients treated with the
drug in 9 countries. Data were pooled for 20 phase I trials [302
moxonidine recipients (mainly healthy volunteers)], 8 placebo-controlled
phase II/III trials (742 moxonidine recipients, 399 placebo recipients),
22 active-drug-controlled phase III/IV trials (957 moxonidine
recipients, 888 controls) and 24 uncontrolled trials (1058 moxonidine
recipients). Patients in phase II to IV trials had hypertension and the
mean age was approximately 56 years. Moxonidine was most commonly
administered orally at a dosage of 0.4 mg/day (range: oral 0.1 to 1
mg/day, intravenous 0.2 to 1 mg/day). Most trials were of 1 to 3 months'
treatment (maximum 24 months).
The PDSURs covered adverse events of moxonidine reported spontaneously
from the market, reports from health authorities, published case reports
and serious drug-related adverse events from clinical trials.
Introduction
Traditionally, centrally acting antihypertensives are associated with a
variety of adverse effects that limit their usefulness. Moxonidine†,
one of a new generation of these agents, may have overcome some of these
problems. A large amount of accumulated data suggest that the drug is
generally well tolerated in patients with hypertension. The most common
adverse events are dry mouth, somnolence and dizziness, which seldom
necessitate treatment discontinuation. Furthermore, moxonidine may be
particularly useful in certain patient groups with hypertension and
concomitant conditions, such as those with asthma and diabetes mellitus.
Moxonidine is a selective imidazoline I1 receptor agonist with only low
affinity for alpha2-adrenoceptors;[1] it is the alpha2-adrenoceptor
agonistic properties of the older centrally acting antihypertensives
that cause many of their adverse effects.
How Does it Compare With Other Agents?
The overall incidence of adverse effects with moxonidine suggest that
this drug is at least as well tolerated as other antihypertensives when
considered as a group (see figure 2). What cannot be determined from
these data are how moxonidine compares to individual agents or classes
of agents. The drugs to which moxonidine has been compared include the
alpha2-adrenoceptor agonist clonidine, the imidazoline receptor agonist
rilmenidine, the beta-blocker atenolol, the diuretic hydrochlorothiazide,
and various ACE inhibitors and calcium antagonists. These drugs have
diverse tolerability profiles, and thus consideration as a group may be
misleading. Nevertheless, the overall favourable tolerability profile of
moxonidine bodes well and there are some characteristics of the
tolerability profile that suggest that this drug could be useful in
specific circumstances.
Although somnolence was one of the most commonly reported adverse events
with moxonidine, the drug is less sedating than the older centrally
acting antihypertensive clonidine.[2,3] Importantly, moxonidine does not
impair the ability to drive.[4]
Moxonidine does not cause clinically significant changes in laboratory
parameters, and does not appear to have adverse effects on glucose and
lipid metabolism.[1] This could be an advantage over agents like some
beta-blockers and thiazide diuretics.
Pulmonary function in patients with chronic obstructive pulmonary
disorder and hypertension was not impaired by moxonidine treatment.[5]
Thus, the drug may be a better choice for patients with asthma than
beta-blockers, as these agents have the potential to cause bronchospasm
Moxonidine Does not Result in Rebound Hypertension After Drug
Withdrawal.
Cardiovascular Drugs and Therapy 1996; 10(suppl. 1): 251-262
To examine the antihypertensive action of the centrally acting
antiadrenergic drugs moxonidine and clonidine, systolic and diastolic
blood pressure as well as heart rate were monitored by radio telemetry
in spontaneously hypertensive rats (SHR) with established high blood
pressure. Increasing doses were administered with regular rat chow for
6-8 day periods. Moxonidine reduced (p<0.05) diastolic blood pressure
at a dose of 8 mg/kg/day and systolic blood pressure at 13 mg/kg/day.
Heart rate was reduced during high activity of rats corresponding to an
antitachycardic action. After withdrawal of 18 mg/kg administered for
only one day, blood pressure returned to pretreatment values within 8
days.
Clonidine reduced systolic and diastolic blood pressure at 0.3
mg/kg/day. At 0.8 and 1.3 mg/kg/day, systolic blood pressure reduction
was less pronounced although heart rate was reduced further, reaching
values which were below those of untreated sleeping rats. When 1.3
mg/kg/day clonidine was discontinued, systolic as well as diastolic
blood pressure increased above pretreatment values within one day. A
rebound was observed also in heart rate which increased by 150 BPM. A
comparable rebound in blood pressure was observed after withdrawal of
0.3 mg/kg/day. Since a blood pressure rebound occurred also after
withdrawal of 0.3 mg/kg/day clonidine in normotensive rats, the rebound
phenomenon was independent of the presence of high blood pressure. No
blood pressure rebound was observed when moxonidine (8 mg/kg/day) was
administered (chow or gavage) in normotensive rats.
These findings in unanesthetized undisturbed rats demonstrate distinct
differences in the mode of action of moxonidine and clonidine which can
be accounted for by specific interactions of moxonidine with imidazoline
(I1)-receptors, whereas clonidine would interact not only with
I1-receptors but also with a2-adrenoceptors and most probably also with
the vagal activity.
Since a hypercaloric diet intake was associated with a raised
sympathetic outflow of the brain, the selective I1-receptor agonist
moxonidine appears particularly appropriate treating hypertension in
patients with overweight.
Of importance is in this respect that a moxonidine-induced reduction in
sympathetic outflow was not associated with a gain in body weight but
resulted in a reduced caloric intake.
-
- PHYSIOTENS® (moxonidine)
- Treating hypertension, not in the blood vessels, but at its
source. This is possible with PHYSIOTENS® (moxonidine). This
antihypertensive re-sets the blood pressure control system
centrally, while maintaining the patient's ability to lead an active
life without the troublesome side effects like impotence, cold hands
and feet, and the possible triggering of attacks of asthma or gout.
Moreover, PHYSIOTENS® has additional benefits in metabolic
syndrome, a whole cluster of symptoms of which hypertension is one.
People with metabolic syndrome often share some common traits. Many
are easily stressed smokers, with a sedentary lifestyle. Often they
are overweight, prone to non-insulin dependent diabetes (Type 2
diabetes) and high triglyceride levels. These symptoms are typical
for someone whose sympathetic system is in permanent 'overdrive'.
This is called Metabolic Syndrome. Most drugs lower blood pressure
by reducing the resistance in the blood vessels, and not by acting
on the control centers higher up in the brain. PHYSIOTENS® reduces
hypertension by its selective action through the sympathetic system.
Because it works through the sympathetic system it is possible that
PHYSIOTENS® also has beneficial effects on other components of the
metabolic syndrome, such as insulin resistance. Preliminary data
have supported this. Solvay Pharmaceuticals licensed PHYSIOTENS®
from Beyersdorf in 1987, and has since worked on further clinical
development of this unique molecule.
generic name
moxonidine
brandnames
PHYSIOTENS®, FISIOTENS®, NORMATENS® and MOXON®
product description
PHYSIOTENS® is a so-called selective imidazoline receptor
agonist (SIRA), part of a new class of antihypertensive agents that
modulate sympathetic activity. PHYSIOTENS® (moxonidine) is an
antihypertensive that stops the chain of reactions that leads to
high blood pressure. PHYSIOTENS® works in the brain, where blood
pressure is regulated.
indications
Essential hypertension.
description of indications
Essential hypertension
Hypertension is high blood pressure or a pressure higher than 140/90
mmHg . Essential hypertension is the most common cardiovascular
disorder. In general about 20-25% of the population have high blood
pressure, of which only about one in five are receiving adequate
treatment. High blood pressure is a 'silent disease' and usually has
no clear symptoms. Many people have high blood pressure for years
without knowing it. Untreated high blood pressure can cause damage
to the heart, brain, kidney, and arteries. It also increases the
risk of heart attack, heart failure, kidney failure and stroke.
worldwide availability
PHYSIOTENS® (moxonidine) is available in more than 20 countries
world-wide.
date and country of first launch
1991 in Germany
maintenance dosages
PHYSIOTENS® (moxonidine) is available as tablets containing
0.2; 0.3; and 0.4 mg. The normal maintenance dose is 0.4 mg once
daily. The maximum recommended dosage is 0.6 mg in divided dosages.
-
J***, what you may be experiencing is a gustatory FB
similar to GS. I'm not sure how long you've been on clonidine but the
dry mouth & sedation does generally improve with time although don't
necessarily expect its total absence. Sugarless gum & fluids (&
proper dental care) obviously help. BUT***for those in the Europe/Where
Available you may want to try Moxonidine (not available in the US
unfortunately) which has less of the typical side effets of clonidine.
Above is some research on it & your doctor should have to sense to
rx it for you before opting for ETS. For those who try it please report
back to the forum your experiences with both Moxonidine & Clonidine.
is it safe?!
I encourage all to educate themselves on what they
consume & visit many credible scientific sites (beyond that clearly
sensationalistic one).
That was a different formulation tested in "severely ill congestive
heart-failure who normally would have a death rate of between 10% and
50% a year, regardless". If you have any heart condition, any med
should be highly supervised but it has a large body of safety data.
There's even more up to date Study
shows moxonidine helps patients with congestive heart failure:
I did find this one obscure warning:
Moxonidine-induced cholestatic hepatitis.(Research Letters)
Author/s: Michael Tamm
Issue: Dec 20, 1997
An 83-year-old man was treated with 0a2 mg moxonidine daily because
of moderate hypertension. No other medication was given. The patient's
past history was uneventful. A routine laboratory check before treatment
with moxonidine showed normal values for leucocytes, platelets,
haemoglobin, creatinine, bilirubin, and liver enzymes. 9 months after
the start of moxonidine, he developed itching and nausea. Painless
jaundice then occurred, accompanied by a maculopapular rash.
Ultrasound examination showed a normal-sized liver with a 2 cm
diameter cyst in the left lobe, but no dilatation of the biliary ducts
and no stones. Bilirubin rose to 173 mol/L and transaminases were higher
than 1000 U/L, whereas there was only a slight elevation of gamma-glutamyl
transpeptidase and alkaline phosphatase (table). Hepatitis B surface
antigen and hepatitis B and C antibodies were negative. Hepatitis A IgG
antibodies were positive but IgM antibodies negative. Because of rising
bilirubin (up to 412 mol/L), a coagulation disorder, and
hypoalbuminaemia (17 g/L) with generalised oedema the patient was
admitted to the hospital 10 days after discontinuation of moxonidine.
Abnormal ultrasound confirmed previous results with no dilatation of the
bile ducts and no other pathological findings. Liver biopsy showed
severe localised intralobular and intraportal lymphoplasmocellular
infiltrates, including some neutrophils and intracytoplasmatic
intracanalicular cholestasis. There was only mild proliferation of the
small bile ducts but considerable localised pericellular fibrosis.
Antinuclear, antimitochondrial, and antineutrophil antibodies in the
serum were negative and a-1-antitrypsin, caeruloplasmin, and copper
levels were normal. A skin biopsy showed parakeratosis.
Treatment was supportive including vitamin K, albumin, and diuretics
for a few days. Within 4 weeks, he was discharged from hospital. 8 weeks
after the end of treatment with moxonidine, laboratory indices were
normal (table). 1 year after discontinuation he is in good health and
liver indices remain normal. His arterial hypertension is controlled
with an ACE inhibitor and diuretics.
Cholestatic hepatitis is a frequent complication of drugs, and
hepatitis is a known side-effect of centrally acting antihypertensive
drugs such as clonidine.1 To our knowledge no case of cholestatic
hepatitis during treatment with moxonidine has been reported. Moxonidine
is increasingly used for the treatment of hypertension. Frequent
side-effects include dryness of the mouth, headache, tiredness,
disturbance of sleep, and gastric symptoms. In a postmarketing
surveillance programme by the manufacturer none of more than 20000
patients observed has developed cholestatic hepatitis. There is
convincing evidence of a causative role of moxonidine in this case. No
other drug was given to this previously healthy patient and he denied
taking any non-prescription drugs; a liver biopsy specimen showed
features compatible with drug-induced inflammatory intrahepatic
cholestasis;2 other diseases of the liver and bile ducts were excluded;
and the patient recovered after stopping the drug.
Latest Controversy
More Info With
Precautions
Intl Suppliers
-
Moxonidine: some controversy.
Doggrell SA.
Doggrell Biomedical Communications, 47 Caronia Crescent, Lynfield,
Auckland, New Zealand.
Initially it was considered that moxonidine, like clonidine, acted
at central (2)-adrenoceptors to reduce blood pressure. With the
characterisation of imidazoline binding sites distinct from
(2)-adrenoceptors, the consensus became that moxonidine was acting
predominantly at imidazoline I(1) receptors in the rostral
ventrolateral medulla to lower blood pressure. Moxonidine acts at
prejunctional (2)-adrenoceptors on sympathetic nerve endings to
decrease noradrenaline release and this may contribute to its
ability to lower blood pressure. The predominant site of action of
moxonidine may also depend on route of administration, with
imidazoline I(1) receptors being predominant after central, and
(2)-adrenoceptors predominant after systemic administration. The
controversy over the mechanism and site of action with moxonidine is
ongoing. In animal models, moxonidine lowers blood pressure, reduces
cardiac hypertrophy and remodelling, reduces cardiac arrhythmias and
increases blood flow in cerebral ischaemia. Moxonidine also has
beneficial effects in animal models of diabetes and kidney disease.
Moxonidine increases sodium and water excretion in rats, but not
humans. Animal studies indicate that moxonidine may be useful in the
treatment of glaucoma by reducing intra-ocular pressure. Animal
studies show that moxonidine may also be effective in pain and in
ethanol withdrawal. In humans, the pharmacokinetics of moxonidine
are of the one-compartment model with first-order absorption. Renal
elimination is the major route of elimination and individual
titration of moxonidine is needed in patients with renal impairment.
There is overwhelming evidence that moxonidine is a safe and
effective antihypertensive. A large clinical trial of moxonidine
in heart failure, MOXCON, was stopped because
of excessive deaths in the moxonidine group. Moxonidine should
not be used in patients with heart failure, but there are no obvious
reasons to stop its use as an antihypertensive, or its development
for other clinical uses.
PMID: 11336590 [PubMed - in process]
-
| 1: J Cardiovasc Pharmacol 2000;35(7 Suppl 4):S1-7 |
Books |
Sympathetic nervous system activation in
essential hypertension, cardiac failure and psychosomatic heart
disease.
Esler M, Kaye D.
Baker Medical Research Institute Melbourne, Australia.
Regional sympathetic activity can be studied in humans using
electrophysiological methods measuring sympathetic nerve firing
rates and neurochemical techniques providing quantification of
noradrenaline spillover to plasma from sympathetic nerves in
individual organs. Essential hypertension: Such measurements in
patients with essential hypertension disclose activation of the
sympathetic outflows to skeletal muscle blood vessels, the heart
and kidneys, particularly in younger patients. This sympathetic
activation, in addition to underpinning the blood pressure
elevation, most likely also contributes to left ventricular
hypertrophy, and to the commonly associated metabolic
abnormalities of insulin resistance and hyperlipidaemia. Antihypertensive
drugs, such as moxonidine, which act primarily by inhibiting the
sympathetic nervous system, should have additional clinical
benefits beyond those attributable to blood pressure reduction, in
protecting against hypertensive complications. Obesity-related
hypertension: Understanding the neural pathophysiology of
hypertension in the obese has been difficult. In normotensive
obesity, renal sympathetic tone is doubled, but cardiac
noradrenaline spillover (a measure of sympathetic activity in the
heart) is only 50% of normal. In obesity-related hypertension,
there is a comparable elevation of renal noradrenaline spillover,
but without suppression of cardiac sympathetics (cardiac
sympathetic activity being more than double that of normotensive
obese and 25% higher than in healthy volunteers). Increased renal
sympathetic activity in obesity may be a 'necessary' cause for the
development of hypertension (and predisposes to hypertension
development), but apparently is not a 'sufficient' cause. The
discriminating feature of the obese who develop hypertension is
the absence of the adaptive suppression of cardiac sympathetic
tone seen in the normotensive obese. Heart failure: In cardiac
failure, the sympathetic nerves of the heart are preferentially
stimulated. Noradrenaline release from the failing heart at rest
in untreated patients is increased as much as 50-fold, similar to
the level seen in the healthy heart during near-maximal exercise.
Activation of the cardiac sympathetic outflow provides adrenergic
support to the failing myocardium, but at a cost of arrhythmia
development and progressive myocardial deterioration.
Psychosomatic heart disease: No more than 50% of clinical coronary
heart disease is explicable in terms of classical cardiac risk
factors. There is gathering evidence that psychological
abnormalities, particularly depressive illness, anxiety states,
including panic disorder and mental stress, are involved here,
'triggering' clinical cardiovascular events, and possibly also
contributing to atherosclerosis development. The mechanisms of
increased cardiac risk attributable to mental stress and
psychiatric illness are not entirely clear, but activation of the
sympathetic nervous system seems to be of prime importance.
PMID: 11346214 [PubMed - in process]
-
SOURCE: The Indianapolis Newspapers
SUPPLIER: Lexis-Nexis
DATE: 09/08/1999
TIME: 00:00
HEADLINE: Drug-test deaths may remain a mystery; Now that Lilly has
ended trial use of moxonidine, questions about its safety may never be
answered.
HIGHLIGHTS: University\of Minnesota,Medical School
The date field represents that of the printing. The electronic
version was distributed on 09-08-99.
Intranet Tracker: Document Copyright 1999 The Indianapolis
Newspapers, Inc.
THE INDIANAPOLIS NEWS
September 4, 1999 Saturday ALL EDITION
BUSINESS; Pg. C01; 798 words
JEFF SWIATEK; STAFF WRITER
An unexpected rash of sudden deaths that caused Eli Lilly and Co. and
its partner to abort a global heart drug study in March has left
scientists baffled, a lead investigator says.
"It mystifies us; we can't explain it. It probably never will be
explained," Dr. Jay N. Cohn, professor of medicine at the University
of Minnesota Medical School, said Friday.
Cohn's comments came two days after the first scientific presentation
about the aborted study. The talk occurred at a meeting of the
European Society of Cardiologists in Spain.
The halting of the study, dubbed MOXCON, comes as a disappointment to
Lilly, as well as sufferers of congestive heart failure. It's been 10
years since a new drug to treat the often-deadly heart condition has
been introduced in the United States, Lilly said.
Lilly had hoped that its drug moxonidine, in a formulation designed
to be released slowly into the bloodstream, would prove effective in
slowing down the revved-up nervous system condition that's linked to
congestive heart failure.
But just seven months into a planned multi-year test of the drug, an
alarming trend popped up:
Patients taking moxonidine and getting standard care were dying at
twice the rate of those receiving standard care only.
Of the first 1,933 patients who had enrolled in the study from August
1998 to March 1999, 53 deaths had occurred among the half who were
taking the drug, while 29 people died among the other half receiving
standard care.
The sheer numbers of deaths weren't surprising, since many patients
in the study were gravely ill, but "we were hoping thetrend would be
the opposite" among the two groups, Cohn said.
After the disturbing data were compiled March 2, worried officials at
Lilly and the Belgian drug company Solvay SA decided to cancel the
huge study, which was planned for a total of 4,500 patients on four
continents.
The companies' decision came March 12, after what Cohn described as
10 "very intense days" of discussion and analysis of study data.
Urged to continue study
Lead investigators and an independent safety monitoring board both
urged Lilly and Solvay to let the study go on, with modifications.
Suggested changes included reducing the dose of moxonidine given to
patients, Cohn said.
Those who wanted to proceed noted that moxonidine seemed to be
causing "remarkable" drops in the overstimulated nervous system
activity, Cohn said. And there was no clear evidence the drug was
causing the deaths, which might have been occurring because of "luck
of the draw, happenstance," he said.
The two drug companies were urged to "hang on a little longer" and
see if more data provided answers, Cohn said.
"But we did not get the opportunity to explore that," said Cohn, who
nonetheless said he can understand the companies' wish to end the
study.
"It was not a clear-cut decision," said Dr. Holger Schilske, aLilly
physician who headed the global clinical development program for
moxonidine.
He said Lilly and Solvay decided to shut down the study because "we
cannot stand behind it in case
it is going in the wrong direction and we end up with more deaths. "
It's typical for heart-failure drugs to cause health disruptions in
patients when they first take the drug and their bodies are getting
used to it.
Whether that was the case for moxonidine, and whether a lower dose
would have avoided the deaths, "we don't know, and that's the
complexity of it," said Dr. Theressa Wright, the primary Lilly
physician in the study.
The study was the last of three steps of human testing that a drug
must go through before the manufacturer applies for marketing
approval.
Congestive heart failure is the leading cause of hospitalization for
Americans older than 65. The five-year mortality rate for those
diagnosed with the condition is 10 percent to 50 percent, depending
on how advanced the condition is, according to Lilly.
So much demand exists for a cure that sales for a new treatment could
quickly hit $ 1 billion annually, health industry analysts have said.
The failure of the MOXCON study won't mean the end of moxonidine.
Lilly licenses the drug to Solvay to sell as a hypertension
medication in many countries, although not in the United States.
But the drug's future as a heart-failure medicine is undoubtedly
over, Schilske said.
"From an ethical standpoint, it would be very, very difficult to do
another study," he said.
Cohn said he made his MOXCON presentation to cardiologists with
Lilly's blessing. "Sometimes bad news is squashed, but in this case
we felt there was much to be learned. "
One thing to learn from the case, he said: how to end a clinical
trial fast if the test drug seems to be unsafe.
Enterprise Products About LEXIS-NEXIS Copyright (c) 1997 LEXIS-NEXIS,
a division of Reed Elsevier Inc. All rights reserved.
---
Hi,
Google has about 800+ results on Moxonidine, some of which look
interesting:
http://www.google.com/search?q=moxonidine
Medline also has around 200 artciles on Moxonidine (note to everyone:
the following links may be split on more than one line in which case
you will have to copy and paste both lines).
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
CMD=&DB=PubMed&term=moxonidine
These are specifically about Moxonidine safety:
Moxonidine: a review of safety and tolerability after seven years of
clinical experience.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
cmd=Retrieve&db=PubMed&list_uids=10489097&dopt=Abstract
I1-imidazoline-receptor agonists in the treatment of hypertension: an
appraisal of clinical experience.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
cmd=Retrieve&db=PubMed&list_uids=7533226&dopt=Abstract
There are a number of aricles that refer to the study that R* (?)
highlighted pointed to from Google. However, I think that it's fair
to say that I don't believe that the information will have gone un-
noticed in the UK and Europe where the drug is used. If there was
any evidence for increased risk in normal-risk groups I don't think
the drug would have been given clearance or remain cleared.
Netdoctor.co.uk has a good summary of the warnings and contra-
indications which some may find useful: There are many related to
heart problems:
http://www.netdoctor.co.uk/medicines/showpreparation.asp?id=3271
Thoughts anyone?
---
The US Drug market is highly protectionistic of itself & just because
a drug is not approved here does not mean it is not safe. There are
many drugs available in Europe that may take decades before being
approved here (Pharms protecting the SSRI drug cycle for example).
Even FDA approval is no guarantee of safety (recent diet & diabetes
drugs anyone?) & some safety experts even suggest waiting a few years
for the post-marketing data to come in.
I think it is critical to understand that any drug can be very
indication-dependent. They even said they were going for CHF market
since it's been 10 years that a new drug was introduced for that
market instead of the very populated general hypertension market.
Moxonidine even clonidine has no to much less blood pressure effects
on normotensives than hypertensives. Moxonidine does not affect my
BP-pulse at all just lower FB/FF & clonidine does lower it a bit but
still well within normal range.
With all that said I have shared my experience with moxonidine vs.
clonidine with some group members and this may be a good time to
share it with the whole group. I have used it for about 4 months &
should be getting more next month. I'm new to this group but my page
has been up for many months.
The site page states toward the bottom:
"is it safe?!
I encourage all to educate themselves on what they
consume & visit many credible scientific sites.
That was a different formulation tested in "severely ill congestive
heart-failure who normally would have a death rate of between 10% and
50% a year, regardless". If you have any heart condition, any med
should be highly supervised but it has a large body of safety data.
There's even more up to date Study
shows moxonidine helps patients with congestive heart failure:
"
It has been on the European market for a decade with over 500,000
patient-years of use now & I'm am comfortable with its safety data &
will continue to use it but for those who don't share the same
comfort from the available info, it really is not significantly more
effective than clonidine for FB/FF/HH IMHO just has less noticeable side
effects...
Other antihypertensives
Moxonidine - Physiotens 0.2, 0.3 & 0.4mg
PHARMACOLOGY
PHARMACOKINETICS
DOSAGE
PRECAUTIONS & CONTRA-INDICATIONS
ADVERSE EFFECTS
PLACE IN THERAPY
PHARMACOLOGY
Although moxonidine has a chemical structure similar to clonidine, its pharmacological profile is different.
Moxonidine is a centrally acting imidazoline-I-1 and alpha-2 receptor agonist. Moxonidine has up to a 600-fold greater selectivity at imidazole receptor sites than at alpha-2 receptors. The imidazoline I-1 subtype is located in the rostral ventrolateral medulla oblongata in the brainstem. It is a major site for the depressor action of moxonidine, resulting in sympathetic inhibition of the heart, gastrointestinal tract and kidneys, and a reduction in peripheral resistance and blood pressure. The antihypertensive activity of moxonidine has been shown to correlate with binding at these receptors. Moxonidine is a full alpha-2 agonist in vitro but with a low affinity at pre- and postsynaptic alpha-2 receptors, resulting in fewer central side effects such as dry mouth and sedation than with clonidine. Its antihypertensive activity did not correlate significantly with alpha-2 binding. Moxonidine does not affect heart rate, cardiac output and stroke volume. It reverses left ventricular hypertrophy and does not appear to adversely affect lipid or glucose metabolism.
Moxonidine reduces central adrenergic tone as demonstrated by 25% to 35% reductions in serum noradrenalin and serum renin levels 4 to 6 hours after dosing in hypertensive patients, with later reductions in serum adrenalin. Moxonidine also increases urine flow rates and natruresis at subtherapeutic doses. This may represent an additional antihypertensive mechanism.
PHARMACOKINETICS
ONSET AND DURATION
ONSET
A. INITIAL RESPONSE:
1. Hypertension, oral: 1 hour
B. PEAK RESPONSE:
1. Hypertension, oral: 1.5 hours to 4 hours
DURATION
A. MULTIPLE DOSE:
1. Hypertension, oral: 2 to 3 days
DRUG CONCENTRATION LEVELS - THERAPEUTIC
A. TIME TO PEAK CONCENTRATION:
1. Oral, 30 to 180 minutes
Maximum plasma concentrations of 1291 to 1330 picograms/milliliter (pg/mL) were reached after administration of single and multiple (every 12 hours) oral doses of moxonidine 0.2 milligrams (mg) to healthy volunteers. Maximum plasma levels of 2319 pg/mL resulted after 0.4 mg oral doses in hypertensive patients.
2. Intravenous, end of infusion
Concentrations of 3965 pg/mL were reached 0.17 hours after the start of an intravenous infusion of 0.2 mg over 10 minutes
ADME
ABSORPTION
A. BIOAVAILABILITY:
1. ORAL, 80% to 90%
The average absorption half-life is 0.353 hours
B. EFFECTS OF FOOD: None
Concurrent food intake 30 minutes prior to a single oral 0.2 milligram dose does not influence the pharmacokinetics of moxonidine
DISTRIBUTION
TOTAL PROTEIN BINDING: 5.8% to 7.9%
DISTRIBUTION HALF-LIFE: 0.099 hours (oral); 0.074 hours (IV)
VOLUME OF DISTRIBUTION (Vd): 3 L/kg
MODERATE TO SEVERE RENAL IMPAIRMENT: 2.2 to 2.4 L/kg
Normal volunteers: 1.79 L/kg
METABOLISM SITES AND KINETICS
Liver, 10% to 20%
METABOLITES
4,5-dehydromoxonidine (active)
One-tenth as active as the parent compound
Guanidine derivative (active)
One-hundredth as active as the parent compound
EXCRETION
BREASTFEEDING: UNKNOWN
Moxonidine crosses into the breast milk. After moxonidine 0.2 milligram/day for 4 days, breast milk concentrations were 50% to 100% higher than plasma concentrations in 4 of 5 lactating women. The nursing mother should avoid breastfeeding until more information with moxonidine is available.
KIDNEY
RENAL CLEARANCE: 809 mL/minute
Moderate renal impairment: 569 mL/minute
Severe renal impairment: 387 mL/minute
RENAL EXCRETION: 80% to 90%
Excreted within 24 hours; 51% of a dose is excreted unchanged
OTHER
TOTAL BODY CLEARANCE: 12.5 mL/minute/kg
OTHER EXCRETION:
FAECES, 1%
HALF-LIFE
ELIMINATION HALF-LIFE: 2 TO 3 hours
RENAL IMPAIRMENT: 3.46 hours in patients with moderate renal impairment and 6.89 hours in patients with severe renal impairment
METABOLITES
ELIMINATION HALF-LIFE: 5 hours
DOSING INFORMATION
ADULT DOSAGE - NORMAL DOSE - ORAL
HYPERTENSION - ESSENTIAL
For the treatment of ESSENTIAL HYPERTENSION, the starting dose is 0.2 to 0.4 milligram/day in the morning. The dose may be increased after 3 weeks to 0.2 to 0.3 milligram twice daily in the morning and evening, and may be taken with or after meals. The maximum single dose is 0.4 milligram, and maximum daily dose 0.6 milligram. Although rebound hypertension has not occurred in clinical studies to date, therapy should be discontinued gradually
DOSAGE IN RENAL FAILURE
Moxonidine should be used with caution and under close medical supervision in patients with moderate renal insufficiency (glomerular filtration rate 30 to 60 milliliters (mL)/minute, serum creatinine 1.2 to 1.8 milligrams/deciliter (mg/dL)). Single doses of 0.2 milligram and maximum daily doses of 0.4 milligram should not be exceeded. Moxonidine is not expected to accumulate during renal insufficiency
DOSAGE IN GERIATRIC PATIENTS
No dosage adjustment is necessary in elderly patients. The apparent clearance of moxonidine was 30% lower when compared to young patients. However the differences were not considered clinically significant
PRECAUTIONS AND CONTRAINDICATIONS
CONTRAINDICATIONS
Hypersensitivity to moxonidine
PRECAUTIONS
A. Sick sinus syndrome
B. Atrioventricular or sinoatrial conduction defects
C. Resting bradycardia (less than 50 beats per minute)
D. Malignant arrhythmias
E. Congestive heart failure New York Heart Association Class IV
F. Severe coronary insufficiency
G. Unstable angina pectoris
H. Severe renal insufficiency (serum creatinine greater than 1.8 milligrams/deciliter, glomerular filtration rate less than 30 milliliters/minute)
I. Angioedema
J. Intermittent claudication
K. Raynaud's syndrome
L. Parkinson's disease
M. Epilepsy
N. Glaucoma
O. Depression
P. Pregnancy
Q. Lactation
R. Children under 16-years-old
S. Moderate renal insufficiency (glomerular filtration rate 30 to 60 milliliters/minute, serum creatinine 1.2 to 1.8 milligrams/deciliter)
T. Moxonidine should not be abruptly discontinued.
ADVERSE REACTIONS
CARDIOVASCULAR EFFECTS
ORTHOSTATIC DYSREGULATION and OEDEMA occurred in 1 of 122 patients receiving moxonidine. Rebound HYPERTENSION has not occurred in clinical studies to date, although no trials have been designed to specifically address this question.
Although considered unlikely to be treatment-related, CARDIAC FAILURE, SYNCOPE, and UNSTABLE ANGINA were reported in 3 of 970 patients in controlled clinical trials
CENTRAL NERVOUS SYSTEM EFFECTS
In a large clinical (n=5142) and postmarketing surveillance (n=62820) data set, side effects associated with moxonidine include SOMNOLENCE (less than 1% to 8%), HEADAHCES (1 to 7%), DIZZINESS (1 to 5%), and INSOMNIA (less than 1% to 2%). The incidence and severity of somnolence decreased over a period of up to 2 years.
Moxonidine may increase reaction time, especially if alcohol is consumed. Cognitive dysfunction following combined lorazepam and moxonidine was enhanced over the effects induced by lorazepam alone.
Headache, VERTIGO, and NERVOUSNESS occurred in 0.8% to 1.6% of 122 patients receiving 0.2 to 1 milligrams (mg)/day. Moderate-to-severe tiredness was reported by 3 of 20 patients receiving moxonidine 0.2 mg/day.
In both single-dose and multiple-dose comparative studies, moxonidine 0.2 milligrams caused significantly less SEDATION than clonidine 0.2 mg
Although considered only possibly related to treatment, transient CEREBRAL ISCHAEMIA was reported in 1 of 99 patients in uncontrolled clinical trials.
In both single-dose and long-term 4-week studies, moxonidine has not adversely affected performance of hypertensive patients in a number of psychomotor skill tests, including driving. Attention and concentration scores have improved slightly in some. Cognitive dysfunction induced by single-dose lorazepam 1 milligram was enhanced by the addition of 0.4 milligrams moxonidine
Following accidental overdose (unspecified quantity) in a 2-year-old, COMA, sedation, and hypotension were noted.
ENDOCRINE/METABOLIC EFFECTS
No evidence of alterations in carbohydrate or lipid metabolism have been noted in controlled or uncontrolled clinical trials involving nearly 2000 moxonidine-treated patients.
Moxonidine doses of 0.2 milligrams (mg) twice daily exhibited an approximately 20% blood-sugar lowering effect in patients with fasting blood sugars greater than 115 milligrams/deciliter, although the effect was not present at 0.4 mg twice daily, suggesting a peripheral alpha-2-agonist activity at higher dose levels
ENDOCRINE EFFECTS
During moxonidine treatment, serum levels of epinephrine and norepinephrine are reduced, along with renin levels. Angiotensin II, aldosterone, and atrial naturetic factor are essentially unchanged
Transient increases in growth hormone are reported. Thyroid-stimulating hormone, prolactin, gonadotropins, and adrenocorticotrophic hormone levels are unchanged
GASTROINTESTINAL EFFECTS
Adverse effects associated with moxonidine include DRY MOUTH and rarely GASTROINTESTINAL UPSET. Dry mouth occurred in 19.7% and DIARRHOEA in 1 of 122 patients receiving moxonidine 0.2 to 1 milligrams/day
In a large clinical (n=5142) and postmarketing surveillance (n=62820) data set, DRY MOUTH (2 to 14%) was reported as the most frequent adverse events and appeared to be dose-related. The incidence and severity of dry mouth decreased over a period of up to 2 year.
In a comparative study, clonidine 0.2 milligrams (mg) produced a marked decrease in salivary flow while the fall in salivary flow associated with moxonidine was not statistically significant compared to placebo and was only about half the magnitude of effect produced by clonidine. An incidence of approximately 45% for clonidine compared to 20% for moxonidine is cited
KIDNEY/GENITOURINARY
RENAL EFFECTS
DIURESIS occurred in 2 of 122 patients receiving moxonidine 0.2 to 1 milligrams/day
No change in renal function has been reported
URINARY EFFECTS
MICTURITION DIFFICULTIES occurred in 1 of 122 patients receiving moxonidine.
LIVER
CHOLESTATIC HEPATITIS
INCIDENCE is RARE (incidence less than 0.1%), with this case the first known report; no previous occurrence among 20,000 patients surveyed in post-marketing surveillance. OUTCOME was SEVERE, with hospitalization necessary 10 days after drug withdrawal due to worsening clinical condition. This 83-year-old male presented 9 months after beginning 0.2 mg moxonidine as monotherapy for hypertension. Presenting signs and symptoms included painless jaundice, itching, nausea, and a maculopapular rash. Bilirubin (173 micromoles/L) and transaminases (1000-1500 units/L for ASAT and ALAT, respectively) were elevated. Despite immediate moxonidine withdrawal, the clinical condition deteriorated leading to hospitalization 10 days later; bilirubin at admission was 413 micromole/L, while ASAT and ALAT remained elevated at 257 to 338 u/L. Symptomatic support for a coagulation disorder (vitamin K) and hypoalbuminemia were required. Liver function returned to normal over 8 weeks. Rechallenge was considered unethical. One year later, the patient was in good health, liver function was normal, and his hypertension was controlled on ACE inhibitors and diuretics.
DERMATOLOGIC EFFECTS
ALLERGIC SKIN REACTIONS have rarely been reported
Facial FLUSHING occurred in 1 of 122 patients receiving moxonidine
HAEMATOMA
Although considered only possibly related to treatment, haematoma of the arm was judged a serious reaction in 1 of 999 patients in uncontrolled clinical trials
MUSCULOSKELETAL EFFECTS
WEAKNESS of the legs occurred in 1 of 122 patients receiving moxonidine
OTHER
WITHDRAWAL
A symptomatic withdrawal syndrome characteristic of that following clonidine (headache, restlessness, apprehension, sweating, tremor, palpitation, flushing, vomiting) has not been described for moxonidine. Blood pressure generally returns to pre-treatment values slowly over 2 to 3 days.
PLACE IN THERAPY
Data compiled from reviews of controlled clinical trials show moxonidine to produce the combination response of a 5 millimeters of mercury (mmHg) or greater reduction in blood pressure during treatment accompanied by a subsequent rise of 5 mmHg or more in blood pressure above baseline values in 1.8% to 2% during either placebo-controlled or reference-drug studies.
Clinical trials have shown the efficacy and tolerability of moxonidine to be equivalent to drugs from other major antihypertensive drug classes. While most of these trials have been small and of short duration, a post-market survey of over 9000 patients on doses ranging between 0.2 to 0.6 milligrams daily rated efficacy and tolerability good in 89%, with adverse effects present in only 7%.
Moxonidine has a unique mechanism of action which allows for blood pressure control without significant central adverse effects. The rebound hypertension that occurs with discontinuation of clonidine does not appear to be a problem with moxonidine. Preliminary study results indicate that moxonidine reverses left ventricular hypertrophy and does not appear to adversely affect lipid or glucose metabolism. Moxonidine reduces sympathetic nervous activity and may be beneficial in coronary risks reduction. Further clinical trials are needed to establish its efficacy and safety compared to other first choice antihypertensives.
---
Here is a website for a
Swiss pharmacy that will supply moxonidine: http://www.pharmaworld.com/
Although they don't have a list of available medications, there is
contact info at the site. They'll send you info on the price, shipping
charges, and dosages available. Since moxonidine is a prescription med,
if you place an order with them, you'll also need to send or fax a
prescription from your doctor.
---
Dear Pete,
thank you for your request. Moxonidine is available upon medical
prescription by the name of Physiotens the following:
Physiotens Filmtabl
Antihypertensivum, zentrales Antiadrenergikum
----------------------------------------------------------------------------
Indikationen
essentielle Hypertonie;
Prices
Physiotens 0.2 Tabletten 0.2 mg
28 Stk
sFr. 28.75 = approx. $ 17.40+
98 Stk
sFr. 86.55 = approx. $ 52.45+
Physiotens 0.3 Tabletten 0.3 mg
28 Stk
sFr. 37.75 = approx. $ 22.85+
98 Stk
sFr. 113.60 = approx. $ 68.85
Physiotens 0.4 Tabletten 0.4 mg *
28 Stk
sFr. 43.25 = approx. $ 26.20+
98 Stk
sFr. 130.30 = approx. $ 78.95
price for shipping and handling will be added and is dependent on weight
of
the parcel.
(up to 500g by airmail: sFr. 37.00 = approx. $ 22.40: delivery time
approx.
10-14 days)
Kind regards
IMPORTANT NOTICE:
IF PRESCRIPTION DRUG IS ORDERED, DUE TO NEW LEGAL REGULATION WE
ALWAYS WILL
NEED ORIGINAL MEDICAL PRESCRIPTION TO BE SENT BY MAIL ALONG WITH YOUR
ORDER!
Pharmaworld is registered trade mark of
VICTORIA APOTHEKE ZUERICH
Professional's International Pharmacy
Dr. C.Egloff, Ph.D.
Bahnhofstrasse 71, CH - 8021 Zurich, Switzerland
Phone: 011 411 211 24 32 ; FAX: 011 411 221 23 22
Web-site: http://www.pharmaworld.com
e-mail: pharmaworld@access.ch
Pharmacy #2 in Germany (seems to be less expensive):
Thank you for your Email.
Here are the two medications they contain moxonidine as an active
substance:
Physiotens 0.4 mg * :
28 tabs = DEM 47.59 =
approx . $ 21.90
98 tabs = DM 142.09 =
approx . $ 65.40
Shipping cost to the U.S. via airmail DM 36 = approx. $ 16.50
If you need more information, don't hesitate to contact us.
Pharmacy International:
Web-site: http://www.pharmacy-international.de/html/intro.html
e-mail : mail@pharmacy-international.de
http://www.xe.com/ucc/
- Universal Currency Converter
