Moxonidine Vs. Clonidine & Adrenergic Agents

- Moxonidine Vs. Clonidine Q & A / Moxonidine Info -

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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

1: Expert Opin Pharmacother 2001 Feb;2(2):337-50 Related Articles, Books: 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]

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.
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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.

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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