Section 1 - CHEMICAL PRODUCT AND COMPANY IDENTIFICATION

PRODUCT NAME

VARDENAFIL

NFPA

PRODUCT USE

A phosphodiesterase inhibitor. The parasympathetic nervous system, when stimulated,
induces smooth muscle relaxation, resulting in a larger artery. Upon certain types of
stimulation (for example, allergic or sexual) the terminal of the axons of the
parasympathetic nerves release mononitrogen monoxide (NO) which diffuses into the smooth
muscles which line the arteries. This, in turn, binds to adenine and guanylate cyclase,
enzymes which thus activated, convert the nucleotides adenine and guanosine triphosphate
(ATP and GTP respectively) to their cyclic monophosphate counterparts, cAMP and cGMP.
These cyclic nucleotides induce the relaxation of smooth muscle cells, producing dilation.
A super- family of enzymes, described as phosphodiesterases, cleave cyclic nucleotides
(cAMP and cGMP) thus reversing smooth muscle relaxation; these enzymes occur in multiple
forms (isozymes) which catalyze the same chemical reaction. The so- called PDEIs
(phosphodiesterase inhibitors) generally produce arterial dilation (and bronchodilation)
and some are used in the treatment of certain respiratory disease (such as asthma). In
general, isozyme- specific inhibitors are referred to as second- generation inhibitors.
They are represented by a variety of synthetic drugs as well as naturally occurring agents
such as the xanthines (found in coffee and tea) and the alkaloid, papaverine. PDEs are
divided into two major classes, I and II which have no recognizable sequence similarity.
Class I includes all known mammalian PDEs. Some PDEs are highly specific for hydrolysis of
cAMP (PDE- IV , PDE- VII, PDE- VIII, also described as PDE4 etc.), some are highly cGMP-
specific (PDE- V, PDE- VI, PDE- IX) and some have mixed specificity (PDE- I, PDE- II, PDE-
III, PDE- X). All mammalian PDEs are dimeric. Activators of PDEs appear to relieve the
influence of autoinhibitory domains located within the enzyme structure. Side- effects of
treatment with PDEIs, often are specific to the nature of inhibition. For example, the use
of PDE- III- specific agents have a tendency to produce tachycardia (elevated heart-
rates, typically exceeding 100 beats per minute). PDE- IV, the primary isozyme located in
inflammatory cells associated with bronchial asthma have been targeted by PDE- IV-
specific inhibitors; atopic dermatitis is also treated with this family of inhibitors.
Some PDE- IV- specific agents (such as rolipram) produce central nervous system side-
effects. Type- V inhibitors (typically dipyridamole) have been used as vasodilators of the
coronary circulation, increasing blood flow to a weakened heart, in part, because they
inhibit thrombo- embolism (it has been shown that increased cAMP and cGMP levels reduce
platelet aggregation, reducing the size of clots). cGMP- PDE- specific agents (those
mimicking the action of cGMP and thus acting as substrates for several isozymes, in a
specific manner) are generally targeted towards angina, hypertension, congestive heart
failure, atherosclerosis, peripheral vascular disease, stroke, bronchitis, asthma,
glaucoma and irritable bowel syndrome. One of these, a synthetic vasodilator, Sildenafil
(Viagra) was found to produce unexpected side- effects, namely formation and maintenance
of penile erection. The effect of this drug on the corpus cavernosal smooth muscle of the
penis is now established; PDE- V has been identified as the primary isoenzyme associated
with relaxation of the arteries of the this muscle. A side- effect of Viagra treatment
involves substrate binding to PDE- VI, the predominant PDE found in the retina. Patients
occasionally complain about altered colour perception and/or increased sensitivity to
light (photophobia). This " blue haze" showed a dose- related effect, probably restricted
to the blue- green part of the spectrum. Cardiovascular effects have also been noted with
Viagra especially amongst patients receiving nitric oxide donators (e.g nitroglycerin,
isosorbide mononitrate and pentaerythritol) for hypertension and heart disease. These
drugs produce a synergistic effect resulting in unexpectedly high levels of cGMP; this
often results in a catastrophic drop in systemic blood pressure (due to vasodilation)
producing a continuum of symptoms ranging from mild dizziness or light- headedness,
fainting upon standing, or even a heart attack or stroke. Vasodilator; an oral therapy for
erectile dysfunction. Drug

SYNONYMS

C23-H32-N6-O4-S, 4-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonyl-phenyl]-, 4-[2-ethoxy-5-(4-
ethylpiperazin-1-yl)sulfonyl-phenyl]-, "9-methyl-7-propyl- 3, 5, 6, 8-
tetrazabicyclo[4.3.0]", "9-methyl-7-propyl- 3, 5, 6, 8-tetrazabicyclo[4.3.0]", "nona-3, 7,
9-trien-2-one", "nona-3, 7, 9-trien-2-one", Levitra, "vasodilator/ erectile dysfunction
treatment", "phosphodiesterase inhibitor", (PDEI-V), "PDE-5 inhibitor"

Section 2 - HAZARDS IDENTIFICATION

CANADIAN WHMIS SYMBOLS

None

EMERGENCY OVERVIEW

RISK

POTENTIAL HEALTH EFFECTS

ACUTE HEALTH EFFECTS

SWALLOWED

  Accidental ingestion of the material may be damaging to the health of the individual.  The material may produce biochemical inhibition of the enzyme, phosphodiesterase. Several families of drug (including xanthines, papaverine, bipyridines, imidazolines, imidazolones, dihydropyridazinones, dihydroquinilones, pyrrolidinones) produce this effect. Synthetic inhibitors of these types, (PDEIs), may produce a wide range of adverse effects in a clinical setting. These include tachycardia (elevated pulse rate), decreased blood pressure (hypotension), central nervous system effects, altered colour perception (a blue-green haze persists), an increased sensitivity to light (photophobia), dizziness, light-headedness, fainting, nausea, vomiting and diarrhoea, dyspepsia (upset stomach), facial flushing, nasal congestion, urinary tract infection, skin rash, muscle aches in the pelvic area and, rarely, heart attack or even stroke. Other reported effects include hepatotoxicity, especially in long-term treatment, dose-dependent thrombocytopenia, cardiac arrhythmia, headache, fever, chest pain and hypersensitivity reactions.  .  Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Certain drugs such as sildenafil, tadalafil, vardenafil inhibit PDE5 and are used in the treatment of erectile dysfunction.. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by these drugs has no effect in the absence of sexual stimulation.  The most common side effects when using these drugs are headache, indigestion, back pain, muscle aches, flushing, and stuffy or runny nose. These side effects reflect the ability of PDE5 inhibition to vasodilate (cause blood vessels to widen) and usually go away after a few hours. Back pain and muscle aches can occur 12 to 24 hours after taking the drugs, and the symptom usually disappears after 48 hours.  Other symptoms include tinnitus, vertigo and dizziness.  Since PDE5 inhibitors may cause transiently low blood pressure (hypotension), organic nitrates should not be taken for at least 48 hours after taking the last dosel. Using organic nitrites (such as the sex drug amyl nitrite) within this timeframe may increase the risk of life-threatening hypotension.  Since people who have taken PDE5 inhibitors within the past 48 hours cannot take organic nitrates to relieve angina (such as glyceryl trinitrate spray), these patients should seek immediate medical attention if they experience anginal chest pain.[5] In the event of a medical emergency, paramedics and medical personnel should be notified of any recent doses of the drug.  PDE5 inhibitors are associated with vision impairment related to NAION (non-arteritic anterior ischemic optic neuropathy) in certain patients taking these drugs in the post-  marketing (outside of clinical trials) setting. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION unrelated to PDE5 use, including: low cup to disc ratio (鎻穜owded disc?, age over 50, diabetes, hypertension,  coronary artery disease, hyperlipidemia and smoking. Given the small number of NAION events with PDE5 use (less than 1 in 1 million), the large number of users of PDE5 inhibitors (millions) and the fact that this event occurs in a similar population to those who do not take these medicines, the FDA concluded that they were not able to draw a cause and effect relationship, given these patients underlying vascular risk factors or anatomical defects.  The FDA also announced that the labeling for all PDE5 inhibitors requires a more prominent warning of the potential risk of sudden hearing loss as the result of postmarketing reports of deafness associated with use of PDE5 inhibitors. In most cases hearing loss involved one ear and about a third of the time it is temporary.  In patients with pulmonary arterial hypertension, it is believed that there is an imablance of the PDE5/NO system in the pulmonary vasculature that favors selective vasoconstriction of the pulmonary artery. The use of PDE5 inhibitors in this disease assumes that PDE5 inhibition will result in pulmonary artery vasodilation, thus lowering pulmonary artery pressure and pulmonary vascular resistance. These physiologic changes may then reduce the workload of the right ventricle of the heart. Right heart failure is the main consequence of pulmonary arterial hypertension.  PDE5 inhibitors are primarily metabolised by the cytochrome P450 enzyme CYP3A4. The potential exists for adverse drug interactions with other drugs which inhibit or induce CYP3A4, including HIV protease inhibitors, ketoconazole, itraconazole, and other anti-  hypertensive drugs such as Nitro-spray (due to its capacity to diminish blood pressure).  When given by mouth or by injection, in therapeutic doses, vasodilators may produce transient flushing of the face, a sensation of heat, a pounding in the head, peripheral oedema, headache, hypotension, palpitations, dizziness and fatigue. Most reactions are dose dependent and transient. High doses may cause flushing and dryness of the skin, skin lesions, abdominal cramps, diarrhoea, nausea, vomiting, malaise, anorexia, activation of peptic ulcer, jaundice and impairment of liver function, decrease in glucose tolerance, mild diabetes and hyperuricaemia. Most of these effects subside with withdrawal of the drug.  

EYE

  Although the material is not thought to be an irritant, direct contact with the eye may cause transient discomfort characterized by tearing or conjunctival redness (as with windburn). Slight abrasive damage may also result. The material may produce foreign body irritation in certain individuals.  

SKIN

  The material is not thought to be a skin irritant (as classified using animal models). Abrasive damage however, may result from prolonged exposures. Good hygiene practice requires that exposure be kept to a minimum and that suitable gloves be used in an occupational setting.  Skin contact with the material may damage the health of the individual; systemic effects may result following absorption.  Entry into the blood-stream, through, for example, cuts, abrasions or lesions, may produce systemic injury with harmful effects. Examine the skin prior to the use of the material and ensure that any external damage is suitably protected.  

INHALED

  The material is not thought to produce either adverse health effects or irritation of the respiratory tract following inhalation (as classified using animal models). Nevertheless, adverse effects have been produced following exposure of animals by at least one other route and good hygiene practice requires that exposure be kept to a minimum and that suitable control measures be used in an occupational setting.  

CHRONIC HEALTH EFFECTS

  Long-term exposure to the product is not thought to produce chronic effects adverse to the health (as classified using animal models); nevertheless exposure by all routes should be minimized as a matter of course.  Long term exposure to high dust concentrations may cause changes in lung function i.e. pneumoconiosis; caused by particles less than 0.5 micron penetrating and remaining in the lung. Prime symptom is breathlessness; lung shadows show on X-ray.