Fiber in Your Diet

Why do I need fiber in my diet?

Dietary fiber is the part of plants that cannot be digested. There are 2 kinds of dietary fiber. Insoluble fiber adds bulk to keep foods moving through the digestive system. Soluble fiber holds water which, in turn, softens the stool for easy bowel movements. Fiber is an important part of your diet even though it passes through your body. A high-fiber diet can:

• reduce cholesterol levels
• promote regular bowel movements
• improve blood sugar levels in diabetics
• treat diverticular disease (inflammation of part of the intestine) and irritable bowel syndrome (abdominal pain, diarrhea, and constipation that come and go).

A high-fiber diet may help prevent some cancers, such as colon and breast.

If you do not have enough fiber in your diet, you may have constipation. Your bowel movements may be small, hard, and dry.

What foods contain fiber?

Breads, cereals, and pasta made with whole-grain flour and brown rice are high-fiber foods. Many breakfast cereals list the bran or fiber content, so it's easy to know which products are high in fiber.

All fruits and vegetables also contain fiber. Dried beans, leafy vegetables, peas, raisins, prunes, apples, and citrus fruits are all especially good sources of fiber.

How much fiber do I need in my diet?

You should have at least 14 grams of fiber for every 1000 calories that you eat every day. Read the label on food packages to find out how much fiber a serving of a food will provide. Foods containing more than 20% of the daily value of fiber per serving are considered high in fiber.

What can I do to increase fiber?

When increasing the fiber in your diet, it is best to do so slowly, because large, sudden increases can cause discomfort, gas, and bloating. Start with small changes, like switching to whole-grain bread, and add a new source of fiber each week or two. You may have some gas or bloating at first, but your body will adjust in time.

• Start your day with a high-fiber breakfast cereal.
• Buy more fruits and vegetables. If you buy them, you'll probably eat them. Use carrot sticks or apple slices for snacks. Include fruits or vegetables with every meal. Cooked fiber is just as effective as raw fiber.
• Eat whole-grain breads.
• Add whole grains and dried beans to casseroles.
• Serve fruit-based desserts.
• If you have constipation even though you have added high-fiber foods to your diet, talk to your health care provider about fiber laxatives. Psyllium is a soluble fiber that is often used for this purpose. It can be taken as a pill or as a powder that is mixed in a glass of water. Always read and follow the directions on the label carefully.

Adding fiber to your diet is easy, and a high-fiber diet can provide long-term health benefits.

Developed by Ann Carter, MD, for McKesson Provider Technologies

Transform in the British Medical Journal: 'An Alternative to the War onDrugs'

Transform in the British Medical Journal: 'An Alternative to the War onDrugs'

The British Medical Journal this week publishes a special edition on drug titled: 'Drug users and HIV: treat don't punish'. the cover feature includes a special commentary section on drugs, HIV/AIDS and harm reduction to coincide with the huge AIDS 2010 conference in Vienna that kicks off this Sunday (see this blog for details and Transform's involvement in the Global Village's Drug Policy Networking Zone).

The special edition of the BMJ features five commissioned commentaries, including; 'Alternatives to the war on drugs' by Transform's Steve Rolles, one of the first detailed explorations in a mainsteam medical journal of legal regulatory models as alternatives to existing unregulated criminal drug markets, specifically from a public health perspective. The full text (also available on the BMJ site here, with rapid responses here) is copied below as it appears online.

The issue also includes Professor Tim Rhodes, Anya Sarang, Peter Vickerman, and Professor Matthew Hickman, on ‘Policy resistance to harm reduction for drug users and potential effect of change’; Richard Hurley on ‘How Ukraine is tackling Europe’s worst HIV epidemic’ and an editorial on ‘Evidence based policy for illicit drugs’ by Prof Evan Wood (who was on BBC R4's Today program this Friday discussing these issues and talking about the Vienna Declaration). These are all now available in full online.

In a significant endorsement, the editor of the BMJ Fiona Godlee, in an editorial titled 'Ideology in the ascendant' , concludes by noting that:

"In a beautifully argued essay Stephen Rolles calls on us to envisage an alternative to the hopelessly failed war on drugs. He says, and I agree, that we must regulate drug use, not criminalise it."

Also of note is that two other leading journals, the Lancet and Science, are running special editions on drugs and harm reduction this week. The Lancet is due to lead with the publication ofthe Vienna Declaration calling for science based drug policy and the decriminalisation of drug use. It is the declaration being adopted by the AIDS 2010 conference and supported by a growing list of public figures from political and scientific establishments.

The BMJ has also produced this excellent short film (below) by Martin Freeth, titled 'HIV shoots up', to go with its special edition. It features Alex Stevens, Tim Rhodes, Gerry Stimson, Steve Rolles and Elzabeth Pisani.

Published 13 July 2010, doi:10.1136/bmj.c3360
Cite this as: BMJ 2010;341:c3360

Analysis

An alternative to the war on drugs

Stephen Rolles, senior policy analyst

¹ Transform Drug Policy Foundation, Bristol BS5 0HE

steve@tdpf.org.uk

Stephen Rolles argues that we need to end the criminalisation of drugs and instead set up regulatory models that will control drug markets and reduce the health and social harms caused by current policy

Consensus is growing within the drugs field and beyond that the prohibition on production, supply, and use of certain drugs has not only failed to deliver its intended goals but has beencounterproductive. Evidence is mounting that this policy has not only exacerbated many public health problems, such as adulterated drugs¹ and the spread of HIV and hepatitis B and C infectionamong injecting drug users, but has created a much larger set of secondary harms associated with the criminal market. These now include vast networks of organised crime, endemic violence related to the drug market,² corruption of law enforcement and governments, militarised crop eradication programmes (environmental damage, food insecurity, and human displacement), and funding for terrorism and insurgency.^{3 4}

These conclusions have been reached by a succession of committees and reports including, in the United Kingdom alone, the Police Foundation,⁵ the Home Affairs Select Committee,⁶ The prime minister’s Strategy Unit,⁷ the Royal Society of Arts,⁸ and the UK Drug Policy Consortium.⁹ The United Nations Office of Drugs and Crime has also acknowledged the many "unintended negative consequences" of drug enforcement,¹⁰ increasingly shifting its public rhetoric away from its former aspirational goals of a "drug free world," towards "containment" of the problem at current levels.

Problems of prohibition

Despite this emerging consensus on the nature of the problem, the debate about how policy can evolve to respond to it remains driven more by populist politics and tabloid headlines than by rational analysis or public health principles.


The criminalisation of drugs has, historically, been presented as an emergency response to an imminent threat rather than an evidence based health or social policy intervention.¹¹ Prohibitionistrhetoric frames drugs as menacing not just to health but also to our children, national security, and the moral fabric of society itself. The prohibition model is positioned as a response to such threats,^{12 13} and is often misappropriated into populist political narratives such as "crackdowns" on crime, immigration, and, more recently, the war on terror.


This conceptualisation has resulted in the punitive enforcement of drug policy becoming largely immune from meaningful scrutiny.¹⁴ A curiously self justifying logic now prevails in which the harms of prohibition—such as drug related organised crime and deaths from contaminated heroin—are conflated with the harms of drug use. These policy related harms then bolster the apparent menace of drugs and justify the continuation, or intensification, of prohibition. This has helped create a high level policy environment that routinely ignores or actively suppresses critical scientific engagement and is uniquely divorced from most public health and social policy norms, such as evaluation of interventions using established indicators of health and wellbeing.

Emerging change

Despite this hostile ideological environment, two distinct policy trends have emerged in recent decades: harm reduction¹⁵ and decriminalisation of personal possession and use. Although both are nominally permitted within existing international legal frameworks, they pose serious practical and intellectual challenges to the overarching status quo. Both have been driven by pragmaticnecessity: harm reduction emerging in the mid-1980s in response to the epidemic of HIV among injecting drug users, and decriminalisation in response to resource pressures on overburdened criminal justice systems (and, to a lesser extent, concerns over the rights of users). Both policies have proved their effectiveness. Harm reduction is now used in policy or practice in 93 countries,¹⁶and several countries in mainland Europe,^{17 18} and central and Latin America have decriminalised all drugs, with others, including states in Australia and the United States, decriminalisingcannabis.¹⁹


Decriminalisation has shown that less punitive approaches do not necessarily lead to increased use. In Portugal, for example, use among school age young people has fallen since all drugs were decriminalised in 2001.²⁰ More broadly, an extensive World Health Organization study concluded:"Globally, drug use is not distributed evenly and is not simply related to drug policy, since countries with stringent user-level illegal drug policies did not have lower levels of use than countries with liberal ones."²¹

Similarly US states that have decriminalised cannabis do not have higher levels of use than those without. More importantly, the Netherlands, where cannabis is available from licensed premises,does not have significantly different levels of use from its prohibitionist neighbours.¹⁹

New approach

Although these emerging policy trends are important, they can be seen primarily as symptomatic responses to mitigate the harms created by the prohibitionist policy environment. Neither directlytackles the public health or wider social harms created or exacerbated by the illegal production and supply of drugs.


The logic of both, however, ultimately leads us to confront the inevitable choice: non-medicaldrug markets can remain in the hands of unregulated criminal profiteers or they can be controlled and regulated by appropriate government authorities. There is no third option under which drugsdo not exist. The choice needs to be based on an evaluation of which option will deliver the best outcomes in terms of minimising the harms, both domestic and international, associated with drug production, supply, and use. This does not preclude reducing demand as a legitimate long term policy goal, rather it accepts that policy must also deal with the reality of current high levels of demand.


A historical stumbling block in this debate has been that the eloquent and detailed critiques of the drug war have not been matched by a vision for its replacement. Unless a credible public health led model of drug market regulation is proposed, myths and misrepresentations will inevitably fill the void. So what would such a model look like?


Transform’s blueprint for regulation²² attempts to answer this question by offering different options for controls over products (dose, preparation, price, and packaging), vendors (licensing, vetting and training requirements, marketing and promotions), outlets (location, outlet density, appearance), who has access (age controls, licensed buyers, club membership schemes), and where and when drugs can be consumed. It then explores options for different drugs in different populations and suggests the regulatory models that may deliver the best outcomes (box). Lessons are drawn from successes and failings with alcohol and tobacco regulation in the UK and beyond, as well as controls over medicinal drugs and other risky products and activities that are regulated by government.

Five basic models for regulating drug availability22 Medical prescription model or supervised venues—For highest risk drugs (injected drugs including heroin and more potent stimulants such as methamphetamine) and problematic users Specialist pharmacist retail model—combined with named/licensed user access and rationing of volume of sales for moderate risk drugs such as amphetamine, powder cocaine, and methylenedioxymethamphetamine (ecstasy) Licensed retailing—including tiers of regulationappropriate to product risk and local needs. Used for lower risk drugs and preparations such as lower strength stimulant based drinks Licensed premises for sale and consumption—similarto licensed alcohol venues and Dutch cannabis "coffee shops," potentially also for smoking opium or poppy tea Unlicensed sales—minimal regulation for the least risky products, such as caffeine drinks and coca tea.

Such a risk guided regulatory approach is the norm for almost all other arenas of public policy, and in this respect it is prohibition, not regulation, that can be viewed as the anomalous and radical policy option.


Moves towards legal regulation of drug markets depend on negotiating the substantial institutional and political obstacles presented by the international drug control system (the UN drug conventions). They would also need to be phased in cautiously over several years, with close evaluation and monitoring of effects and any unintended negative consequences.

Rather than a universal model, a flexible range of regulatory tools would be available with the more restrictive controls used for more risky products and less restrictive controls for lower risk products. Such differential application of regulatory controls could additionally help create a risk-availability gradient. This holds the potential to not only reduce harms associated with illicit supply and current patterns of consumption but, in the longer term, to progressively encourage use of safer products, behaviours, and environments. Understanding of such processes is emerging from "route transition" interventions aimed at encouraging injecting users to move to lower risk non-injecting modes of administration by, for example, providing foil for smoking.²³ This process is the opposite of what has happened under prohibition, where a profit driven dynamic has tended to tilt the market towards ever more potent (but profitable) drugs and drug preparations, as well as encouraging riskier behaviours in high risk environments.


The oversight and enforcement of new regulations would largely fall within the remit of existing public health, regulatory, and enforcement agencies. Activities that take place outside the regulatory framework would naturally remain prohibited and subject to civil or criminal sanctions.


Regulation is no silver bullet. In the short term it can only seek to reduce the problems that stem from prohibition and the illicit trade it has created. It cannot tackle the underlying drivers of problematic drug use such as inequality and social deprivation. But by promoting a more pragmatic public health model and freeing up resources for evidence based social policy and public health based interventions it would create a more conducive environment for doing so. The costs of developing and implementing a new regulatory infrastructure would represent only a fraction of the ever increasing resources currently directed into efforts to control supply. There would also be potential for translating a proportion of existing criminal profits into legitimate tax revenue.


Different social environments will require different approaches in response to the specific challenges they face. Transform’s blueprint does not seek to provide all the answers but to movethe debate beyond whether we should end the war on drugs to what the world could look like after the war on drugs. It is a debate that the medical and public health sectors have failed to engage with for far too long.

---

Contributors and sources: SR is the author of After the War on Drugs: Blueprint for Regulation.The book is published by Transform Drug Policy Foundation, which actively campaigns for drug policy and law reform, and is available free online (www.tdpf.org.uk/Transform_Drugs_Blueprint.pdf).


Competing interests: The author has completed the unified competing interest form atwww.icmje.org/coi_disclosure.pdf (available on request from him) and declares (1) the writing and production of SR’s book, including a contribution to his salary, were funded by the J Paul Getty Jr Charitable Trust and the Glass House Trust; (2) no financial relationships with commercial entities that might have an interest in the submitted work; (3) no spouses, partners, or children with relationships with commercial entities that might have an interest in the submitted work; and (4) no non-financial interests that may be relevant to the submitted work.
Provenance and peer review: Commissioned; externally peer reviewed.

References

1. Cole C, Jones L, McVeigh J, Kicman A, Qutub Syed Q, Bellis M. A guide to the adulterants, bulking agents and other contaminants found in illicit drugs. Centre for Public Health, John Moores University, 2010.
2. Werb D, Rowell G, Kerr T, Guyatt G, Montaner J, Wood E. Effect of drug law enforcement on drug-related violence: evidence from a scientific review. International Centre for Science in Drug Policy, 2010.
3. Felbab-Brown V. Shooting up: counter-insurgency and the war on drugs. Brookings Institution Press, 2009.
4. Barrett D, Lines L, Schleifer R, Elliot R, Bewley-Taylor D. Recalibrating the regime. Beckley Foundation. International Harm Reduction Association, 2008.
5. Police Foundation. Drugs and the law: report of the independent inquiry into the Misuse of Drugs Act 1971. Police Foundation, 1999.
6. Home Affairs Select Committee. The government’s drugs policy: is it working? Stationery Office, 2002.
7. Prime Minister’s Strategy Unit. Strategy Unit drugs report. 2003.www.cabinetoffice.gov.uk/media/cabinetoffice/strategy/assets/drugs_report.pdf..
8. Royal Society of Arts Commission on Illegal Drugs, Communities and Public Policy. Drugs—facing facts. RSA, 2007.
9. Reuter P, Stevens A. An analysis of UK drug policy. UK Drug Policy Commission, 2007.
10. Costa A. Making drug control "fit for purpose": Building on the UNGASS decade. UN Office on Drugs and Crime, 2008.
11. Barrett D. Security, development and human rights: Normative, legal and policy challenges for the international drug control system. Int J Drug Policy 2010;21:140-4.[CrossRef][Web of Science][Medline]
12. United Nations. United Nations convention against illicit traffic in narcotic drugs and psychotropic substances. 1988. www.unodc.org/pdf/convention_1988_en.pdf.
13. Brown G. Prime minister’s questions. Hansard 2010 Mar 24.www.publications.parliament.uk/pa/cm200910/cmhansrd/cm100324/debtext/100324-0003.htm#10032434000735.
14. Committee on Data and Research for Policy on Illegal Drugs. Informing America’s policy on illegal drugs: what we don’t know keeps hurting us. National Research Council, National Academy Press, 2001.
15. International Harm Reduction Association. What is harm reduction? A position statement. 2010.www.ihra.net/Whatisharmreduction.
16. Cook C, ed. The global state of harm reduction 2010: key issues for broadening the response.www.ihra.net/Assets/2522/1/GlobalState2010_Web.pdf.
17. European Monitoring Centre for Drugs and Drug Addiction. Illicit drug use in the EU: legislative approaches. EU, 2005.
18. Blickman T, Jelsma M. Drug policy reform in practice. Transnational Institute, 2009.
19. Room R, Hall W, Reuter P, Fischer B, Lenton S. Global cannabis commission report. Beckley Foundation, 2009.
20. Hughes C, Stevens A . What can we learn from the Portuguese decriminalisation of illicit drugs?. Br J Criminology (forthcoming).
21. Degenhard L, Chiu W-T, Sampson N, Kessler RC, Anthony JC, Angermeyer M, et al. Toward a global view of alcohol, tobacco, cannabis, and cocaine use: findings from the WHO World Mental Health Surveys. PLoS Med2008;5:e141.[CrossRef][Medline]
22. Rolles S. After the war on drugs: blueprint for regulation. Transform Drug Policy Foundation, 2009.www.tdpf.org.uk/Transform_Drugs_Blueprint.pdf.
23. Bridge J. Route transition interventions: Potential public health gains from reducing or preventing injecting. Int J Drug Policy 2010;21:125-8.[CrossRef][Web of Science][Medline]

CARDIZEM

CARDIZEM^®
(diltiazem hydrochloride)
Direct Compression Tablets

DESCRIPTION

CARDIZEM^® (diltiazem hydrochloride) is a calcium ion influx inhibitor (slow channel blocker or calcium antagonist). Chemically, diltiazem hydrochloride is 1, 5-Benzothiazepin-4(5H)one,3-(acetyloxy)-5-[2-(dimethyl-amino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride,(+)-cis-. The chemical structure is:

Diltiazem hydrochloride is a white to off-white crystalline powder with a bitter taste. It is soluble in water, methanol, and chloroform. It has a molecular weight of 450.98. Each tablet of CARDIZEM contains 30 mg, 60 mg, 90 mg, or 120 mg diltiazem hydrochloride.

Also contains: D&C Yellow #10 Aluminum Lake, FD&C Yellow #6 Aluminum Lake (60 mg and 120 mg), FD&C Blue #1 Aluminum Lake (30 mg and 90 mg), hypromellose, lactose, magnesium stearate, methylparaben, microcrystalline cellulose, silicon dioxide and other ingredients.

For oral administration.

CLINICAL PHARMACOLOGY

The therapeutic benefits achieved with CARDIZEM are believed to be related to its ability to inhibit the influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.

Mechanisms of Action

Although precise mechanisms of its antianginal action are still being delineated, CARDIZEM is believed to act in the following ways:

• 1.Angina Due to Coronary Artery Spasm. CARDIZEM has been shown to be a potent dilator of coronary arteries both epicardial and subendocardial. Spontaneous and ergonovine-induced coronary artery spasm are inhibited by CARDIZEM.
• 2.Exertional Angina. CARDIZEM has been shown to produce increases in exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart rate and systemic blood pressure at submaximal and maximal exercise workloads.

In animal models, diltiazem interferes with the slow inward (depolarizing) current in excitable tissue. It causes excitation-contraction uncoupling in various myocardial tissues without changes in the configuration of the action potential. Diltiazem produces relaxation of coronary vascular smooth muscle and dilation of both large and small coronary arteries at drug levels which cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischemic and nonischemic models and are accompanied by dose-dependent decreases in systemic blood pressure and decreases in peripheral resistance.

Hemodynamic and Electrophysiologic Effects

Like other calcium antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses.

In man, diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure and, in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product for any given workload. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end-diastolic pressure have not been affected. There are as yet few data on the interaction of diltiazem and beta-blockers. Resting heart rate is usually unchanged or slightly reduced by diltiazem.

Intravenous diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods approximately 20%. In a study involving single oral doses of 300 mg of CARDIZEM in six normal volunteers, the average maximum PR prolongation was 14% with no instances of greater than first-degree AV block. Diltiazem-associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases).

Chronic oral administration of CARDIZEM in doses of up to 240 mg/day has resulted in small increases in PR interval, but has not usually produced abnormal prolongation.

Pharmacokinetics and Metabolism

Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous dosing) of about 40%. CARDIZEM undergoes extensive metabolism in which 2% to 4% of the unchanged drug appears in the urine. In vitro binding studies show CARDIZEM is 70% to 80% bound to plasma proteins. Competitive in vitro ligand binding studies have also shown CARDIZEM binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin. The plasma elimination half-life following single or multiple drug administration is approximately 3.0 to 4.5 hours. Desacetyl diltiazem is also present in the plasma at levels of 10% to 20% of the parent drug and is 25% to 50% as potent as a coronary vasodilator as diltiazem. Minimum therapeutic plasma levels of CARDIZEM appear to be in the range of 50-200 ng/mL. There is a departure from linearity when dose strengths are increased. A study that compared patients with normal hepatic function to patients with cirrhosis found an increase in half-life and a 69% increase in AUC (area-under-the-plasma concentration vs time curve) in the hepatically impaired patients. A single study in nine patients with severely impaired renal functions showed no difference in the pharmacokinetic profile of diltiazem as compared to patients with normal renal function.

CARDIZEM Tablets. Diltiazem is absorbed from the tablet formulation to about 98% of a reference solution. Single oral doses of 30 to 120 mg of CARDIZEM tablets result in detectable plasma levels within 30 to 60 minutes and peak plasma levels 2 to 4 hours after drug administration. As the dose of CARDIZEM tablets is increased from a daily dose of 120 mg (30 mg qid) to 240 mg (60 mg qid) daily, there is an increase in area-under-the-curve of 2.3 times. When the dose is increased from 240 mg to 360 mg, daily, there is an increase in area-under-the-curve of 1.8 times.

INDICATIONS AND USAGE

CARDIZEM is indicated for the management of chronic stable angina and angina due to coronary artery spasm.

CONTRAINDICATIONS

CARDIZEM is contraindicated in (1) patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker, (2) patients with second- or third-degree AV block except in the presence of a functioning ventricular pacemaker, (3) patients with hypotension (less than 90 mm Hg systolic), (4) patients who have demonstrated hypersensitivity to the drug, and (5) patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission.

WARNINGS

1. Cardiac Conduction. CARDIZEM prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block (six of 1243 patients for 0.48%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction. A patient with Prinzmetal's angina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg of diltiazem. (See ADVERSE REACTIONS section.)

2. Congestive Heart Failure. Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index nor consistent negative effects on contractility (dp/dt). Experience with the use of CARDIZEM alone or in combination with beta-blockers in patients with impaired ventricular function is very limited. Caution should be exercised when using the drug in such patients.

3. Hypotension. Decreases in blood pressure associated with CARDIZEM therapy may occasionally result in symptomatic hypotension.

4. Acute Hepatic Injury. In rare instances, significant elevations in enzymes such as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted. These reactions have been reversible upon discontinuation of drug therapy. The relationship to CARDIZEM is uncertain in most cases, but probable in some. (See PRECAUTIONS.)

PRECAUTIONS

General

CARDIZEM (diltiazem hydrochloride) is extensively metabolized by the liver and excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters of renal and hepatic function should be monitored at regular intervals. The drug should be used with caution in patients with impaired renal or hepatic function. In subacute and chronic dog and rat studies designed to produce toxicity, high doses of diltiazem were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liver, which were reversible when the drug was discontinued, in dogs, doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing. Dermatological events (see ADVERSE REACTIONS section) may be transient and may disappear despite continued use of CARDIZEM. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis have also been infrequently reported. Should a dermatologic reaction persist, the drug should be discontinued.

Drug Interactions

Due to the potential for additive effects, caution and careful titration are warranted in patients receiving CARDIZEM concomitantly with any agents known to affect cardiac contractility and/or conduction. (See WARNINGS.)

Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with CARDIZEM. (See WARNINGS.)

As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem is both a substrate and an inhibitor of the cytochrome P-450 3A4 enzyme system. Other drugs that are specific substrates, inhibitors, or inducers of this enzyme system may have a significant impact on the efficacy and side effect profile of diltiazem. Patients taking other drugs that are substrates of CYP450 3A4, especially patients with renal and/or hepatic impairment, may require dosage adjustment when starting or stopping concomitantly administered diltiazem in order to maintain optimum therapeutic blood levels.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 24-month study in rats and a 21-month study in mice showed no evidence of carcinogenicity. There was also no mutagenic response in in vitro bacterial tests. No intrinsic effect on fertility was observed in rats.

Pregnancy

Nursing Mothers

Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of CARDIZEM is deemed essential, an alternative method of infant feeding should be instituted.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of diltiazem did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

Serious adverse reactions have been rare in studies carried out to date, but it should be recognized that patients with impaired ventricular function and cardiac conduction abnormalities usually have been excluded.

In domestic placebo-controlled angina trials, the incidence of adverse reactions reported during CARDIZEM therapy was not greater than that reported during placebo therapy.

The following represent occurrences observed in clinical studies of angina patients. In many cases, the relationship to CARDIZEM has not been established. The most common occurrences from these studies, as well their frequency of presentation, are edema (2.4%), headache (2.1%), nausea (1.9%), dizziness (1.5%), rash (1.3%), and asthenia (1.2%). In addition, the following events were reported infrequently (less than 1 %):

Cardiovascular: Angina, arrhythmia, AV block (first degree), AV block (second or third degree – see conduction warning), bradycardia bundle branch block, congestive heart failure, ECG abnormality, flushing, hypotension, palpitations, syncope, tachycardia, ventricular extrasystoles.

Nervous System: Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, somnolence, tremor

Gastrointestinal: Anorexia, constipation, diarrhea, dysgeusia, dyspepsia, mild elevations of alkaline phosphatase, SGOT, SGPT, and LDH (see hepatic warnings), thirst, vomiting, weight increase

Dermatological: Petechiae, photosensitivity, pruritus, urticaria

Other: Amblyopia, CPK elevation, dry mouth, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain, polyuria, sexual difficulties, tinnitus

The following postmarketing events have been reported infrequently in patients receiving CARDIZEM: allergic reactions, alopecia, angloedema (including facial or periorbital edema), asystole, erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal necrolysis), extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, leukopenia, purpura, retinopathy, myopathy, and thrombocytopenia. There have been observed cases of a generalized rash, some characterized as leukocytoclastic vasculitis. In addition, events such as myocardial infarction have been observed, which are not readily distinguishable from the natural history of the disease in these patients. A definitive cause and effect relationship between these events and CARDIZEM therapy cannot yet be established. Exfoliative dermatitis (proven by rechallenge) has also been reported.

OVERDOSAGE OR EXAGGERATED RESPONSE

The oral LD₅₀s in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD₅₀s in these species were 60 and 38 mg/kg, respectively. The oral LD₅₀ in dogs is considered to be in excess of 50 mg/kg, while lethality was seen in monkeys at 360 mg/kg.

The toxic dose in man is not known. Due to extensive metabolism, blood levels after a standard dose of diltiazem can vary over tenfold, limiting the usefulness of blood levels in overdose cases.

There have been reports of diltiazem overdose in amounts ranging from <1>

Events observed following diltiazem overdose included bradycardia, hypotension, heart block, and cardiac failure. Most reports of overdose described some supportive medical measure and/or drug treatment. Bradycardia frequently responded favorably to atropine, as did heart block, although cardiac pacing was also frequently utilized to treat heart block. Fluids and vasopressors were used to maintain blood pressure and in cases of cardiac failure inotropic agents were administered. In addition, some patients received treatment with ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium.

The effectiveness of intravenous calcium administration to reverse the pharmacological effects of diltiazem overdose has been inconsistent. In a few reported cases, overdose with calcium channel blockers associated with hypotension and bradycardia that was initially refractory to atropine became more responsive to after the patients received intravenous calcium. In some cases intravenous calcium has been administered (1 g calcium chloride or 3 g calcium gluconate) over 5 minutes, and repeated every 10-20 minutes as necessary. Calcium gluconate has also been administered as a continuous infusion at a rate of 2 g per hour for 10 hours. Infusions of calcium for 24 hours or more may be required. Patients should be monitored for signs of hypercalcemia.

In the event of overdose or exaggerated response, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. Diltiazem does not appear to be removed by peritoneal or hemodialysis. Limited data suggest that plasmapheresis or charcoal hemoperfusion may hasten diltiazem elimination following overdose. Based on the known pharmacological effects of diltiazem and/or reported clinical experiences, the following measures may be considered:

Bradycardia: Administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockade, administer isoproterenol cautiously.

High-Degree AV Block: Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing.

Cardiac Failure: Administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics.

Hypotension: Vasopressors (eg, dopamine or levarterenol bitartrate).

Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.

DOSAGE AND ADMINISTRATION

Exertional Angina Pectoris Due to Atherosclerotic Coronary Artery Disease or Angina Pectoris at Rest Due to Coronary Artery Spasm

Dosage must be adjusted to each patient's needs. Starting with 30 mg four times daily, before meals, and at bedtime, dosage should be increased gradually (given in divided doses three or four times daily) at 1- to 2-day intervals until optimum response is obtained. Although individual patients may respond to any dosage level, the average optimum dosage range appears to be 180 to 360 mg/day. There are no available data concerning dosage requirements in patients with impaired renal or hepatic function. If the drug must be used in such patients, titration should be carried out with particular caution.

Concomitant Use With Other Cardiovascular Agents

• 1.Sublingual NTG may be taken as required to abort acute anginal attacks during CARDIZEM (diltiazem hydrochloride) therapy.
• 2.Prophylactic Nitrate Therapy. CARDIZEM may be safely coadministered with short- and long-acting nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination.
• 3.Beta-blockers. (See WARNINGS and PRECAUTIONS.)

HOW SUPPLIED

CARDIZEM 30-mg tablets are supplied in bottles of 100 (NDC 64455-771-47) and 500 (NDC 64455-771-55). Each green tablet is engraved with MARION on one side and 1771 on the other.

CARDIZEM 60-mg scored tablets are supplied in bottles of 100 (NDC 64455-772-47) and 500 (NDC 64455-772-55). Each yellow tablet is engraved with MARION on one side and 1772 on the other.

CARDIZEM 90-mg scored tablets are supplied in bottles of 100 (NDC 64455-791-47). Each green oblong tablet is engraved with CARDIZEM on one side and 90 mg on the other.

CARDIZEM 120-mg scored tablets are supplied in bottles of 100 (NDC 64455-792-47). Each yellow oblong tablet is engraved with CARDIZEM on one side and 120 mg on the other.

Store at 25°C (77°); excursions permitted to 15-30°C (59-86°) [see USP Controlled Room Temperature].

Avoid excessive humidity.

Prescribing Information as of August 2001

®Cardizem is a registered trademark of Biovail Laboratories Incorporated

Manufactured by:
Aventis Pharmaceuticals Inc.
Kansas City, MO, 64137, USA

Distributed by:
Biovail Pharmaceuticals, Inc.
Bridgewater, NJ, 08807, USA

50070671

HYDROCORTISONE LOTION

HYDROCORTISONE LOTION
USP, 2.5%

Rx only
FOR EXTERNAL USE ONLY
AVOID CONTACT WITH EYES

DESCRIPTION:

Each mL of Hydrocortisone Lotion USP, 2.5% contains 25 mg of hydrocortisone in a vehicle consisting of carbomer 940, propylene glycol, polysorbate 40, propylene glycol stearate, cholesterol and related sterols, isopropyl myristate, sorbitan palmitate, cetyl alcohol, triethanolamine, sorbic acid, simethicone, and purified water.

Chemically, hydrocortisone is pregn-4-ene-3,20-dione, 11,17,21-trihydroxy-, (11β)- and is represented by the following structural formula:

Hydrocortisone has the molecular formula C₂₁H₃₀O₅ and a molecular weight of 362.47. The topical corticosteroids, including hydrocortisone, constitute a class of primarily synthetic steroids used as anti-inflammatory and antipruritic agents.

CLINICAL PHARMACOLOGY:

Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man.

Pharmacokinetics

The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings.

Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase the percutaneous absorption of topical corticosteroids. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses. (See DOSAGE AND ADMINISTRATION.)

Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.

INDICATIONS AND USAGE:

Topical corticosteroids are indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.

CONTRAINDICATIONS:

Topical corticosteroids are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.

PRECAUTIONS:

ADVERSE REACTIONS:

The following local adverse reactions are reported infrequently with topical corticosteroids, but may occur more frequently with the use of occlusive dressings. These reactions are uled in an approximate decreasing order of occurrence:

	Burning	Perioral dermatitis
	Itching	Allergic contact dermatitis
	Irritation	Maceration of the skin
	Dryness	Secondary infection
	Folliculitis	Skin atrophy
	Hypertrichosis	Striae
	Acneiform eruptions	Miliaria
	Hypopigmentation

OVERDOSAGE:

Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects (See PRECAUTIONS).

DOSAGE AND ADMINISTRATION:

Topical corticosteroids are generally applied to the affected area as a thin film from two to four times daily depending on the severity of the condition. Occlusive dressings may be used for the management of psoriasis or recalcitrant conditions.

If an infection develops, the use of occlusive dressings should be discontinued and appropriate antimicrobial therapy instituted.

HOW SUPPLIED:

Hydrocortisone Lotion USP, 2.5% is supplied in a 59 mL (2 Fl Oz) bottle.

• NDC 0168-0288-02

Shake well before using. Store at controlled room temperature 15°- 30°C (59°- 86°F).

Keep out of the reach of children.

E. FOUGERA & CO.
a division of Altana Inc.
MELVILLE, NEW YORK 11747