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Tuesday, 17 April 2012

NiQuitin Clear 7mg

1. Name Of The Medicinal Product

NiQuitin Clear 7 mg

2. Qualitative And Quantitative Composition

NiQuitin Clear is a transdermal delivery system for topical application available in systems of 7 cm² containing 36 mg nicotine, equivalent to 5.1 mg/cm² of nicotine and delivering 7 mg over 24 hours.

3. Pharmaceutical Form

Transdermal patch.

4. Clinical Particulars

4.1 Therapeutic Indications

NiQuitin Clear relieves and/or prevents craving and nicotine withdrawal symptoms associated with tobacco dependence. It is indicated to aid smokers wishing to quit or reduce prior to quitting, to assist smokers who are unwilling or unable to smoke, and as a safer alternative to smoking for smokers and those around them.

NiQuitin Clear is indicated in pregnant and lactating women making a quit attempt.

If possible, when stopping smoking, NiQuitin Clear should be used in conjunction with a behavioural support programme.

4.2 Posology And Method Of Administration

NiQuitin Clear patches should be applied once a day, at the same time each day and preferably soon after waking, to a non-hairy, clean, dry skin site and worn continuously for 24 hours. The NiQuitin Clear patch should be applied promptly on removal from its protective sachet.

Avoid applying to any skin which is broken, red or irritated. After 24 hours the used patch should be removed and a new patch applied to a fresh skin site. The patch should not be left on for longer than 24 hours. Skin sites should not be reused for at least seven days. Only one patch should be worn at a time.

Patches may be removed before going to bed if desired. However use for 24 hours is recommended to optimise the effect against morning cravings.

Concurrent behavioural support is recommended, as such programmes have been shown to be beneficial for smoking cessation.

Adults (18 years and over)

Abrupt cessation of smoking:

During a quit attempt every effort should be made to stop smoking with NiQuitin Clear.

NiQuitin Clear therapy should usually begin with NiQuitin Clear 21 mg and be reduced according to the following dosing schedule:-

Dose	Duration
Step 1	NiQuitin Clear 21 mg	First 6 weeks
Step 2	NiQuitin Clear 14 mg	Next 2 weeks
Step 3	NiQuitin Clear 7 mg	Last 2 weeks

Light smokers (e.g. those who smoke less than 10 cigarettes per day) are recommended to start at Step 2 (14 mg) for 6 weeks and decrease the dose to NiQuitin Clear 7 mg for the final 2 weeks.

Patients on NiQuitin Clear 21 mg who experience excessive side-effects (please refer to precautions), which do not resolve within a few days, should change to NiQuitin Clear 14mg. This strength should then be continued for the remainder of the 6 week course before stepping down to NiQuitin Clear 7mg for two weeks. If the symptoms persist the patient should be advised to seek the advice of a healthcare professional.

For optimum results, the 10 week treatment course (8 weeks for light smokers or patients who have reduced strength as above), should be completed in full. Treatment with NiQuitin Clear patch may be continued beyond 10 weeks if you need it to stay cigarette free, however those who have quit smoking but have difficulty discontinuing using the patches are recommended to seek additional help and advice from a healthcare professional.

Further courses may be used at a later time, for NiQuitin Clear patch users who continue or resume smoking.

Gradual Cessation:

For smokers who are unwilling or unable to quit abruptly.

The 21 mg patch can be used daily for 2-4 weeks while the user continues to smoke as needed. At the end of the 2-4 weeks the user should quit completely and continue using Step 1 21 mg patch for 6 weeks daily without smoking. Thereafter following the Step 2 and 3 directions for abrupt cessation above. Should the patient feel able to quit completely before their designated quit date they can do so.

Reduction in smoking:

For smokers who wish to cut down with no immediate plans to quit.

A patch can be used while the user continues to smoke as needed. The user should reduce the number of cigarettes smoked as far as possible and to refrain from smoking as long as possible. Users should be encouraged to stop smoking completely as soon as possible.

If users are still feeling the need to use the patches on a regular basis 6 months after the start of treatment and have still been unable to undertake a permanent quit attempt, then it is recommended to seek additional help and advice from a healthcare professional.

Temporary Abstinence

Apply a patch to control troublesome withdrawal symptoms including craving during the period when smoking is being avoided. Users should be encouraged to stop smoking completely as soon as possible.

Adolescents and children

Adolescents (12 to 17 years) should follow the schedule of treatment for abrupt cessation of smoking as given above. Where adolescents are not ready or not able to stop smoking abruptly, advice from a healthcare professional should be sought.

Safety and effectiveness in children who smoke has not been evaluated. NiQuitin Clear is not recommended for use in children under 12 years of age.

4.3 Contraindications

NiQuitin Clear is contraindicated in patients with hypersensitivity to the system, the active substance, or any of the excipients.

NiQuitin Clear patches should not be used by non-smokers, occasional smokers or children under 12.

4.4 Special Warnings And Precautions For Use

The risks associated with the use of NRT are substantially outweighed in virtually all circumstances by the well established dangers of continued smoking.

Patients hospitalised for MI, severe dysrhythmia or CVA who are considered to be haemodynamically unstable should be encouraged to stop smoking with non-pharmacological interventions. If this fails, NiQuitin Clear patches may be considered, but as data on safety in this patient group are limited, initiation should only be under medical supervision. Once patients are discharged from hospital they can use NRT as normal.

Diabetes Mellitus: Patients with diabetes mellitus should be advised to monitor their blood sugar levels more closely than usual when NRT is initiated as catecholamines released by nicotine can affect carbohydrate metabolism.

Allergic reactions: Susceptibility to angioedema and urticaria.

Atopic or eczematous dermatitis (due to localised patch sensitivity): In the case of severe or persistent local reactions at the site of application (e.g. severe erythema, pruritus or oedema) or a generalised skin reaction (e.g. urticaria, hives or generalised skin rashes), users should be instructed to discontinue use of NiQuitin Clear and contact their physician.

Contact sensitisation: Patients with contact sensitisation should be cautioned that a serious reaction could occur from exposure to other nicotine-containing products or smoking.

A risk benefit assessment should be made by an appropriate healthcare professional for patients with the following conditions:

• Renal and hepatic impairment: Use with caution in patients with moderate to severe hepatic impairment and/or severe renal impairment as the clearance of nicotine or its metabolites may be decreased with the potential for increased adverse effects.

• Phaeochromocytoma and uncontrolled hyperthyroidism: Use with caution in patients with uncontrolled hyperthyroidism or phaeochromocytoma as nicotine causes release of catecholamines.

Danger in small children: Doses of nicotine tolerated by adult and adolescent smokers can produce severe toxicity in small children that may be fatal. Products containing nicotine should not be left where they may be misused, handled or ingested by children. The patches should be folded in half with the adhesive side innermost and disposed of with care.

Stopping smoking: Polycyclic aromatic hydrocarbons in tobacco smoke induce the metabolism of drugs catalysed by CYP 1A2 (and possibly by CYP 1A1). When a smoker stops this may result in a slower metabolism and a consequent rise in blood levels of such drugs.

Transferred dependence: Transferred dependence is rare and is both less harmful and easier to break than smoking dependence.

Safety on handling: NiQuitin Clear is potentially a dermal irritant and can cause contact sensitisation. Care should be taken during handling and in particular contact with the eyes and nose avoided. After handling, wash hands with water alone as soap may increase nicotine absorption.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically relevant interactions between nicotine replacement therapy and other drugs have definitely been established, however nicotine may possibly enhance the haemodynamic effects of adenosine.

4.6 Pregnancy And Lactation

Pregnancy

Stopping smoking is the single most effective intervention for improving the health of both the pregnant smoker and her baby, and the earlier abstinence is achieved the better. However, if the mother cannot (or is considered unlikely to) quit without pharmacological support, NRT may be used as the risk to the foetus is lower than that expected with smoking tobacco. Stopping completely is by far the best option but NRT may be used in pregnancy as a safer alternative to smoking. Because of the potential for nicotine-free periods, intermittent dose forms are preferable, but patches may be necessary if there is significant nausea and/or vomiting. If patches are used they should, if possible, be removed at night when the foetus would not normally be exposed to nicotine.

Lactation

The relatively small amounts of nicotine found in breast milk during NRT use are less hazardous to the infant than second-hand smoke. Intermittent dose forms would minimize the amount of nicotine in breast milk and permit feeding when levels were at their lowest.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

NRT may cause adverse reactions similar to those associated with nicotine administered by other means, including smoking. These may be attributable to the pharmacological effects of nicotine, some of which are dose dependent. At recommended doses NiQuitin Clear patches have not been found to cause any serious adverse effects. Excessive use of NiQuitin Clear patches by those who have not been in the habit of inhaling tobacco smoke could possibly lead to nausea, faintness or headaches.

Subjects quitting smoking by any means could expect to suffer from asthenia, headache, dizziness, sleep disturbance, coughing or influenza-like illness. Certain symptoms which have been reported such as depression, irritability, nervousness, restlessness, mood lability, anxiety, drowsiness, impaired concentration and insomnia may be related to withdrawal symptoms associated with smoking cessation.

The following undesirable effects have been reported in clinical trials or spontaneously post-marketing.

Immune System Disorders

Uncommon>1/1000; <1/100: hypersensitivity NOS*

Very rare <1/10000: anaphylactic reactions

Psychiatric

Very common>1/10: sleep disorders including abnormal dreams and insomnia

Common>1/100; <1/10: nervousness

Nervous system disorders

Very Common>1/10: headache, dizziness

Common>1/100; <1/10: tremor

Cardiac Disorders

Common>1/100; <1/10: palpitations

Uncommon>1/1000; <1/100: tachycardia NOS

Respiratory, Thoracic and Mediastinal Disorders

Common>1/100; <1/10: dyspnoea, pharyngitis, cough

Gastrointestinal Disorders

Very Common>1/10: nausea, vomiting

Common>1/100; <1/10: dyspepsia, abdominal pain upper, diarrhoea NOS, dry mouth, constipation

Skin and Subcutaneous Tissue Disorders

Common>1/100; <1/10: sweating increased

Very rare>1/100000; <1/10000: dermatitis allergic*, dermatitis contact*, photosensitivity

Musculoskeletal and Connective Tissue Disorders

Common>1/100; <1/10: arthralgia, myalgia

General Disorders and Administration Site Conditions

Very common>1/10: application site reactions NOS*

Common>1/100; <1/10: chest pain, pain in limb, pain NOS, asthenia, fatigue

Uncommon>1/1000; <1/100: malaise, influenza-like illness

*see below

Application site reactions, including transient rash, itching, burning, tingling, numbness, swelling, pain and urticaria are the most frequent undesirable effects of NiQuitin patch. The majority of these topical reactions are minor and resolve quickly following removal of the patch. Pain or sensation of heaviness in the limb or area around which the patch is applied (e.g. chest) may be reported.

Hypersensitivity reactions, including contact dermatitis and allergic dermatitis have also been reported. In the case of severe or persistent local reactions at the application site (e.g. severe erythema, pruritus or oedema) or a generalised skin reaction (e.g. urticaria, hives or generalised skin rashes) users should be instructed to discontinue use of NiQuitin and contact their physician.

If there is a clinically significant increase in cardiovascular or other effects attributable to nicotine, the NiQuitin dose should be reduced or discontinued.

4.9 Overdose

Symptoms: The minimum lethal dose of nicotine in a non-tolerant man has been estimated to be 40 to 60mg. Symptoms of acute nicotine poisoning include nausea, salivation, abdominal pain, diarrhoea, sweating, headache, dizziness, disturbed hearing and marked weakness. In extreme cases, these symptoms may be followed by hypotension, rapid or weak or irregular pulse, breathing difficulties, prostration, circulatory collapse and terminal convulsions.

Management of an overdose: All nicotine intake should stop immediately and the patient should be treated symptomatically. Artificial respiration with oxygen should be instituted if necessary. Activated charcoal reduces the gastro-intestinal absorption of nicotine.

Overdose from topical exposure: The NiQuitin Clear system should be removed immediately if the patient shows signs of overdosage and the patient should seek immediate medical care. The skin surface may be flushed with water and dried. No soap should be used since it may increase nicotine absorption. Nicotine will continue to be delivered into the bloodstream for several hours after removal of the system because of a depot of nicotine in the skin.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic classification: N07BA01

(Anti-smoking agents: N07BA, Nicotine 01)

Nicotine, the chief alkaloid in tobacco products and a naturally occurring autonomic drug, is an agonist at nicotine receptors in the peripheral and central nervous system and has pronounced CNS and cardiovascular effects. Withdrawal from nicotine in addicted individuals is characterised by craving, nervousness, restlessness, irritability, mood lability, anxiety, drowsiness, sleep disturbances, impaired concentration, increased appetite, minor somatic complaints (headache, myalgia, constipation, fatigue) and weight gain. Withdrawal symptoms, such as cigarette craving, may be controlled in some individuals by steady-state plasma levels lower than those for smoking.

In clinically controlled trials, nicotine withdrawal symptoms were alleviated as well as craving. The severity of craving was reduced by at least 35% at all times of day during the first two weeks of abstinence, compared to placebo (p<0.05).

5.2 Pharmacokinetic Properties

Absorption

Following transdermal application, the skin rapidly absorbs nicotine released initially from the patch adhesive. The plasma concentrations of nicotine reach a plateau within 2-4 hours after initial application of NiQuitin Clear with relatively constant plasma concentrations persisting for 24 hours or until the patch is removed. Approximately 68% of the nicotine released from the patch enters systemic circulation and the remainder of the released nicotine is lost via vaporisation from the edge of the patch.

With continuous daily application of NiQuitin Clear (worn for 24 hours), dose-dependent steady state plasma nicotine concentrations are achieved following the second NiQuitin Clear application and are maintained throughout the day. These steady state maximum concentrations are approximately 30% higher than those following a single application of NiQuitin Clear.

Plasma concentrations of nicotine are proportional to dose for the three dosage forms of NiQuitin Clear. The mean plasma steady state concentrations of nicotine are approximately 17 ng/ml for the 21 mg/day patch, 12 ng/ml for the 14 mg /day patch and 6 ng/ml for the 7 mg/day patch. For comparison, half-hourly smoking of cigarettes produces average plasma concentrations of approximately 44 ng/ml.

The pronounced early peak in nicotine blood levels seen with inhalation of cigarette smoke is not observed with NiQuitin Clear.

Distribution

Following removal of NiQuitin Clear, plasma nicotine concentrations decline with an apparent mean half-life of 3 hours, compared with 2 hours for IV administration due to continued absorption of nicotine from the skin depot. If NiQuitin Clear is removed most non-smoking patients will have non-detectable nicotine concentrations in 10 to 12 hours.

A dose of radio-labelled nicotine given intravenously showed a distribution of radioactivity corresponding to the blood supply with no organ selectively taking up nicotine. The volume of distribution of nicotine is approximately 2.5 l/kg.

Metabolism

The major elimination organ is the liver and average plasma clearance is about 1.2 l/min; the kidney and the lung also metabolise nicotine. More than 20 metabolites of nicotine have been identified, all of which are believed to be pharmacologically inactive. The principal metabolites are cotinine and trans

Excretion

Both nicotine and its metabolites are excreted through the kidneys and about 10% of nicotine is excreted unchanged in the urine. As much as 30% may be excreted in the urine with maximum flow rates and extreme urine acidification (pH

There were no differences in nicotine kinetics between men and women using nicotine patches. Obese men using nicotine patch had significantly lower AUC and Cmax values compared with normal weight men. Linear regression of AUC vs total body weight showed the expected inverse relationship (AUC decreases as weight increases). Nicotine kinetics were similar for all sites of application on the upper body and upper outer arm.

5.3 Preclinical Safety Data

The general toxicity of nicotine is well known and taken into account in the recommended posology. Nicotine was not mutagenic in appropriate assays. The results of carcinogenicity assays did not provide any clear evidence of a tumorigenic effect of nicotine. In studies in pregnant animals, nicotine showed maternal toxicity, and consequential mild fetal toxicity. Additional effects included pre- and postnatal growth retardation and delays and changes in postnatal CNS development.

Effects were only noted following exposure to nicotine at levels in excess of those which will result from recommended use of NiQuitin Clear. Effects on fertility have not been established.

Comparison of the systemic exposure necessary to elicit these adverse responses from preclinical test systems with that associated with the recommended use of NiQuitin Clear indicate that the potential risk is low and outweighed by the demonstrable benefit of nicotine therapy in smoking cessation. However, NiQuitin Clear should only be used by pregnant women on medical advice if other forms of treatment have failed.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Drug Reservoir:	Ethylene Vinyl Acetate Copolymer
Occlusive Backing:	Polyethylene Terephthalate/ Ethylene vinyl acetate
Rate Controlling Membrane:	Polyethylene Film
Contact Adhesive:	Polyisobutylene B100 and B12 SFN
Protective Layer:	Siliconised Polyester Film
Printing Ink:	White ink

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

None stated.

6.5 Nature And Contents Of Container

7 or 14 patches in a carton. Each patch is rectangular and is comprised of clear backing and a protective liner which is removed prior to use. Each patch is contained in a laminate sachet.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Beecham Group PLC

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

T/A GlaxoSmithKline Consumer Healthcare

Brentford

TW8 9GS

8. Marketing Authorisation Number(S)

PL 00079/ 0354

9. Date Of First Authorisation/Renewal Of The Authorisation

23^rd June 2000

10. Date Of Revision Of The Text

11/10/2010

Monday, 16 April 2012

Promethazine with Dextromethorphan

Generic Name: dextromethorphan and promethazine (dex troe me THOR fan and pro METH a zeen)

Brand Names: Promethazine with Dextromethorphan, Promethazine with DM

What is Promethazine with Dextromethorphan (dextromethorphan and promethazine)?

Dextromethorphan is a cough suppressant. It affects the signals in the brain that trigger cough reflex.

Promethazine is an antihistamine. It blocks the effects of the naturally occurring chemical histamine in your body.

The combination of dextromethorphan and promethazine used to treat cough, itching, runny nose, sneezing, and itchy or watery eyes caused by colds or allergies.

Dextromethorphan will not treat a cough that is caused by smoking, asthma, or emphysema.

Dextromethorphan and promethazine may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about dextromethorphan?

Call your doctor immediately if you experience uncontrollable movements of your eyes, lips, tongue, face, arms, or legs. These could be early signs of dangerous side effects. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Do not use dextromethorphan and promethazine if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take dextromethorphan and promethazine before the MAO inhibitor has cleared from your body. Do not use any other over-the-counter cough, cold, or allergy medication without first asking your doctor or pharmacist. If you take certain products together you may accidentally take too much of one or more types of medicine. Read the label of any other medicine you are using to see if it contains dextromethorphan. Dextromethorphan will not treat a cough that is caused by smoking, asthma, or emphysema.

What should I discuss with my healthcare provider before taking Promethazine with Dextromethorphan (dextromethorphan and promethazine)?

Do not use dextromethorphan and promethazine if you have asthma or other lung disease. Do not use a cough or cold medicine if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take a cough or cold medicine before the MAO inhibitor has cleared from your body.

Before taking dextromethorphan and promethazine, tell your doctor if you are allergic to any drugs, or if you have emphysema or chronic bronchitis. You may not be able to use this medication, or you may need a dosage adjustment or special tests during treatment.

Before taking dextromethorphan and promethazine, tell your doctor if you have:

epilepsy or another seizure disorder;

emphysema or chronic bronchitis;

sleep apnea (breathing stops during sleep);

glaucoma;

a stomach ulcer or digestive obstruction;

bone marrow disorder;

problems with urination;

high blood pressure or heart disease; or

liver disease.

If you have any of these conditions, you may not be able to use dextromethorphan and promethazine, or you may need a dosage adjustment or special tests during treatment.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether this medication passes into breast milk or if it could harm an unborn baby. Do not use dextromethorphan and promethazine without telling your doctor if you are breast-feeding a baby.

How should I take Promethazine with Dextromethorphan (dextromethorphan and promethazine)?

Take this medication exactly as it has been prescribed by your doctor. Do not use the medication in larger amounts, or use it for longer than recommended. Follow the directions on your prescription label. Cough or cold medicine is usually taken only for a short time until your symptoms clear up.

Always ask a doctor before giving cough or cold medicine to a child. Death can occur from the misuse of cough or cold medicine in very young children.

Measure the liquid form of this medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Talk with your doctor if your symptoms do not improve after 7 days of treatment, or if you have a fever with a headache, cough, or skin rash.

If you need to have any type of surgery, tell the surgeon ahead of time if you have taken a cough medicine within the past few days.

Store dextromethorphan and promethazine at room temperature, away from heat, light, and moisture.

What happens if I miss a dose?

Since cough and cold medicine is usually taken only as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Symptoms of a dextromethorphan and promethazine overdose may include feeling restless or nervous, severe drowsiness, dizziness, dry mouth, large pupils, flushing, nausea, vomiting, shallow breathing, and fainting.

What should I avoid while taking Promethazine with Dextromethorphan (dextromethorphan and promethazine)?

This medication can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Avoid drinking alcohol. It can increase some of the side effects of dextromethorphan and promethazine.

Avoid taking diet pills, caffeine pills, or other stimulants (such as ADHD medications) without your doctor's advice. Taking a stimulant together with cough medicine can increase your risk of unpleasant side effects.

Avoid using other drugs that make you sleepy (such as cold medicine, sleeping pills, pain medication, muscle relaxers, and medicine for seizures, depression or anxiety).

Do not use any other over-the-counter cough, cold, or allergy medication without first asking your doctor or pharmacist. Dextromethorphan is contained in many medicines available over the counter. If you take certain products together you may accidentally take too much of this medicine. Read the label of any other medicine you are using to see if it contains dextromethorphan.

Promethazine with Dextromethorphan (dextromethorphan and promethazine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using dextromethorphan and promethazine and call your doctor at once if you have any of these serious side effects:

uncontrollable movements of your eyes, lips, tongue, face, arms, or legs;

tremors, twitching, or uncontrolled muscle movements in your face, arms, or legs.

severe dizziness, anxiety, restless feeling, or nervousness;

hallucinations (seeing or hearing things);

confusion, hallucinations; or

slow, shallow breathing, weak pulse;

nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

fever, muscle stiffness, confusion, fast or uneven heartbeat, sweating, fainting.

Keep taking dextromethorphan and promethazine and talk with your doctor if you have any of these less serious side effects:

dizziness, drowsiness, sleepiness, or confusion;

blurred vision, dry mouth;

ringing in your ears;

nausea or vomiting; or

increased sensitivity to sunlight.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Promethazine with Dextromethorphan (dextromethorphan and promethazine)?

Before taking dextromethorphan and promethazine, tell your doctor if you are using any of the following drugs:

celecoxib (Celebrex);

cinacalcet (Sensipar);

darifenacin (Enablex);

imatinib (Gleevec);

quinidine (Quinaglute, Quinidex);

ranolazine (Ranexa)

ritonavir (Norvir);

sibutramine (Meridia);

terbinafine (Lamisil);

medicines to treat high blood pressure;

antidepressant medications such as amitriptyline (Elavil, Etrafon), bupropion (Wellbutrin, Zyban), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), imipramine (Janimine, Tofranil), paroxetine (Paxil), sertraline (Zoloft), and others.

sedatives or anxiety medicines such as alprazolam (Xanax), diazepam (Valium), chlordiazepoxide (Librium), temazepam (Restoril), or triazolam (Halcion);

phenobarbital (Luminal), amobarbital (Amytal) and secobarbital (Seconal); or

atropine (Donnatal, and others), belladonna, clidinium (Quarzan), dicyclomine (Bentyl), glycopyrrolate (Robinul), hyoscyamine (Anaspaz, Cystospaz, Levsin, and others), methscopolamine (Pamine), and scopolamine (Transderm-Scop).

If you are using any of these drugs, you may not be able to use dextromethorphan and promethazine, or you may need dosage adjustments or special tests during treatment.

There may be other drugs not listed that can affect dextromethorphan and promethazine. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Promethazine with Dextromethorphan resources

Promethazine with Dextromethorphan Side Effects (in more detail)
Promethazine with Dextromethorphan Use in Pregnancy & Breastfeeding
Promethazine with Dextromethorphan Drug Interactions
0 Reviews for Promethazine with Dextromethorphan - Add your own review/rating

Promethazine DM Prescribing Information (FDA)

Compare Promethazine with Dextromethorphan with other medications

Cold Symptoms
Cough
Hay Fever

Where can I get more information?

Your pharmacist has information about dextromethorphan and promethazine written for health professionals that you may read.

See also: Promethazine with Dextromethorphan side effects (in more detail)

Saturday, 14 April 2012

Triamterene

Class: Potassium-sparing Diuretics
VA Class: CV704
CAS Number: 396-01-0
Brands: Dyazide, Dyrenium, Maxzide

Hyperkalemia (i.e., serum potassium concentrations ≥5.5 mEq/L) may occur with all potassium-sparing agents, including triamterene.^b ^c ^d More likely to occur in patients with renal impairment and diabetes (even without evidence of renal impairment), and in geriatric or severely ill patients or those receiving prolonged therapy with large doses.^a ^b ^c ^d

Uncorrected hyperkalemia may be fatal; monitor serum potassium concentrations at frequent intervals especially during initial therapy, after dosage adjustment, or in patients with concurrent illness that may affect renal function.^b ^c ^d

Introduction

Potassium-sparing diuretic; pteridine derivative.^b

Uses for Triamterene

Edema

Management of edema associated with CHF, cirrhosis of the liver, or nephrotic syndrome.^b

Management of steroid-induced edema, idiopathic edema, and edema caused by secondary hyperaldosteronism.^b

May be used alone but most valuable when used in combination with other diuretics to promote diuresis and/or decrease potassium excretion caused by kaliuretic diuretics.^b

May be particularly useful in patients excreting excessive amounts of potassium (especially those who cannot tolerate potassium supplements) and for those in whom potassium loss could be detrimental, such as patients receiving digitalis glycosides or those with myasthenia gravis.^a ^b

Promotes increased diuresis in patients resistant or only partially responsive to thiazides or other diuretics because of secondary hyperaldosteronism.^b

May be effective in some patients unresponsive to spironolactone; unlike spironolactone, diuretic effect of triamterene is independent of aldosterone concentrations.^a

Used in fixed combination with hydrochlorothiazide for treatment of edema in patients who require a thiazide diuretic and in whom the development of hypokalemia cannot be risked.^c ^d

Used in fixed combination with hydrochlorothiazide for treatment of edema in patients who develop hypokalemia during hydrochlorothiazide monotherapy.^c ^d

Do not use for routine therapy in pregnant women with mild edema who are otherwise healthy.^b ^c ^d

CHF

In the management of edema associated with CHF, generally used in conjunction with other more effective, rapidly acting diuretics (e.g., thiazides, chlorthalidone, loop diuretics).^a Some patients resistant to triamterene monotherapy may respond to such combined therapy.^a

Most experts state that all patients with symptomatic CHF who have evidence or a prior history of fluid retention generally should receive diuretic therapy in conjunction with moderate sodium restriction (≤3 g of sodium daily), an ACE inhibitor, and usually a β-adrenergic blocking agent, with or without a cardiac glycoside.¹¹² ¹¹³

Most experts state that the diuretics of choice for most patients with CHF are loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, torsemide).^a

Do not use diuretics as monotherapy in CHF even if symptoms (e.g., peripheral edema, pulmonary congestion) are well controlled; diuretics alone do not prevent progression of heart failure.

Once fluid retention in CHF has resolved, diuretic therapy should be maintained to prevent its recurrence. Ideally, diuretic therapy should be adjusted according to changes in body weight (as an indicator of fluid retention) rather than maintained at a fixed dosage.

Diuretics should be continued in CHF and comorbid conditions (e.g., hypertension) where ongoing therapy with the drugs is indicated.

Hypertension

Triamterene alone has little if any hypotensive effect; however, it may be used with another diuretic (e.g., hydrochlorothiazide) or a hypotensive agent in the management of mild to moderate hypertension.^a However, JNC 7 recommends that thiazides be used as initial therapy for the treatment of uncomplicated hypertension in most patients, either alone or combined with other classes of antihypertensive drugs that have demonstrated benefit (e.g., ACE inhibitors, angiotensin II receptor antagonists, β-blockers, calcium-channel blockers).¹¹⁹

Used principally in patients with diuretic-induced hypokalemia or to prevent hypokalemia in patients receiving diuretics who are at risk of this adverse effect.^a

Used in fixed combination with hydrochlorothiazide for treatment of hypertension in patients who require a thiazide diuretic and in whom the development of hypokalemia cannot be risked.^c ^d

Used in fixed combination with hydrochlorothiazide for treatment of hypertension in patients who develop hypokalemia during hydrochlorothiazide monotherapy.^c ^d

Used in fixed combination with hydrochlorothiazide for treatment of hypertension as an adjunct to other antihypertensive drugs (e.g., β-blockers).^c ^d

Triamterene Dosage and Administration

General

Monitor serum potassium concentrations following changes in dosage or with concurrent illness or drug therapy.^b ^d (See Hyperkalemia under Cautions and also see Interactions.)

Avoid use of potassium-sparing diuretics, including triamterene, in patients with renal insufficiency, in those with hyperkalemia who have serum potassium concentrations >5 mEq/L while not receiving drug therapy, and in those who develop hyperkalemia during therapy.¹⁰⁹ ¹¹⁹ ^b ^c ^d

Do not use concurrent potassium supplementation or potassium-containing salt substitutes.^b Discontinue potassium supplementation when triamterene is added to other diuretic therapy or when patients are switched to triamterene from other diuretics.^b

Do not use fixed-combination triamterene/hydrochlorothiazide tablets or capsules for initial therapy of edema or hypertension, except in patients in whom the clinical consequences of hypokalemia represent an important risk (e.g., patients receiving cardiac glycosides or patients with cardiac arrhythmias).^a ^c ^d

Do not use as initial monotherapy in severe CHF since bowel edema or intestinal hypoperfusion may delay absorption and subsequent therapeutic effect.^a

Careful etiologic diagnosis should precede the use of any diuretic.^a

Administration

Oral Administration

Capsules: Administer orally twice daily after meals.^b

Fixed-combination triamterene/hydrochlorothiazide tablets or capsules: Administer orally once daily.^c ^d

Twice-daily administration of the fixed combination of triamterene and hydrochlorothiazide may increase risk of electrolyte imbalance and renal dysfunction.^d

Dosage

Individualize dosage according to patient’s requirements and response.^b

If added to an existing antihypertensive regimen, initially reduce dosage of each antihypertensive agent and then individualize dosage according to patient’s requirements and response.^b

Abrupt discontinuance may result in rebound kaliuresis; taper dosage gradually.^b

Different commercially available fixed-combination triamterene/hydrochlorothiazide preparations may not be therapeutic equivalents.^a The oral bioavailabilities of the individual drugs and the amounts and ratios of these drugs in various commercially available fixed-combination preparations may differ.^a

Pediatric Patients

Usual Dosage†

Oral

Initially, 2–4 mg/kg daily or 115 mg/m² daily, given in a single dose or 2 divided doses after meals.^a ^e

If necessary, increase dosage to 6 mg/kg daily.^a Do not exceed 300 mg daily.^b ^e

Hypertension†

Oral

Initially, 1–2 mg/kg daily given in 2 divided doses after meals.¹²⁰ Increase dosage as necessary up to 3–4 mg/kg daily given in 2 divided doses.¹²⁰ Do not exceed 300 mg daily.¹²⁰

Adults

Edema

Monotherapy

Oral

Initially, 100 mg twice daily after meals.^b After edema is controlled, usual maintenance dosage is 100 mg daily or every other day.^a Do not exceed 300 mg daily.^b

Combination Therapy

Oral

When Dyazide, Maxzide or Maxzide-25 mg, or therapeutically equivalent formulations of these combinations are used, the usual dosage in terms of triamterene is 37.5–75 mg once daily.^c ^d

Patients receiving 25 mg of hydrochlorothiazide who become hypokalemic may be switched to Maxzide-25 mg (37.5 mg triamterene/25 mg hydrochlorothiazide).^d

Patients receiving 50 mg of hydrochlorothiazide who become hypokalemic may be switched to Maxzide (75 mg triamterene/50 mg hydrochlorothiazide).^d

Hypertension

Monotherapy

Oral

Usual dosage recommended by JNC 7 as monotherapy: 50–100 mg daily.¹¹⁹ Some patients may benefit from dividing the daily dosage into 2 doses.¹¹⁹

Combination Therapy

Oral

Usually combined with a kaliuretic diuretic.^a

In conjunction with a kaliuretic diuretic, an initial triamterene dosage of 25 mg once daily has been recommended.¹⁰⁹ Titrate dosage upward as needed and tolerated to a suggested maximum triamterene dosage of 100 mg daily.¹⁰⁹ ¹¹⁹

Initially, administer each drug separately to adjust dosage.^a

May use in fixed combination with hydrochlorothiazide if optimum maintenance dosage corresponds to drug ratio in combination preparation.^a

Administer each drug separately whenever dosage adjustment is necessary.^a

When Dyazide, Maxzide or Maxzide-25 mg, or therapeutically equivalent formulations of these combinations are used, the usual dosage in terms of triamterene is 37.5–75 mg once daily.^d

Patients receiving 25 mg of hydrochlorothiazide who become hypokalemic may be switched to Maxzide-25 mg (37.5 mg triamterene/25 mg hydrochlorothiazide).^d

Patients receiving 50 mg of hydrochlorothiazide who become hypokalemic may be switched to Maxzide (75 mg triamterene/50 mg hydrochlorothiazide).^d

If BP is not adequately controlled by use of 75 mg once daily (of triamterene in the fixed combination of triamterene/hydrochlorothiazide), another antihypertensive agent may be added.^d

Prescribing Limits

Pediatric Patients

Oral

Maximum 300 mg daily.¹²⁰

Adults

Oral

Maximum 300 mg daily.^b

The manufacturer states there is no clinical experience to date with dosages of fixed-combination Maxzide or Maxzide-25 mg exceeding 75 mg of triamterene and 50 mg of hydrochlorothiazide daily.^d

Special Populations

Hepatic Impairment

No specific dosage recommendations for hepatic impairment; caution if using fixed combination with hydrochlorothiazide because of risk of precipitating hepatic coma.^c ^d (See Contraindications under Cautions.)

Renal Impairment

No specific dosage recommendations for renal impairment; do not use in patients with renal impairment and elevated serum potassium; discontinue in patients who develop hyperkalemia while on the drug.^b (See Contraindications under Cautions and also see Hyperkalemia under Cautions.)

Cautions for Triamterene

Contraindications

Anuria, severe or progressive renal disease or dysfunction (except possibly nephrosis), acute or chronic renal insufficiency, substantial renal impairment.^b ^c ^d

Preexisting hyperkalemia (≥5.5 mEq/L).^b ^d

History of triamterene-induced hyperkalemia.^b ^c ^d

Concurrent potassium supplementation, including potassium salts or potassium-containing salt substitutes.^b (See Interactions.)

Concurrent therapy with potassium-sparing agents (e.g., spironolactone, amiloride hydrochloride, or fixed-combination formulations containing triamterene).^b (See Interactions.)

Severe hepatic disease.^b

Known hypersensitivity to triamterene or any ingredient in the formulation.^b ^c ^d

Warnings/Precautions

Warnings

Hyperkalemia

Hyperkalemia (i.e., serum potassium concentrations ≥5.5 mEq/L) may occur with all potassium-sparing agents, including triamterene.^b ^c ^d (See Boxed Warning.) Serum potassium concentrations persistently >6 mEq/L require careful observation and treatment.^b

If hyperkalemia occurs, discontinue triamterene; if using a triamterene/hydrochlorothiazide fixed combination, switch to a thiazide alone.^b ^c ^d

Evaluate BUN and serum potassium concentrations regularly, especially in patients with suspected or confirmed renal insufficiency.^b Monitor serum potassium concentrations closely in geriatric and diabetic patients.^b

Warning signs of hyperkalemia include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, and shock.^c ^d

Hyperkalemia has been associated with cardiac irregularities.^b Obtain ECG if hyperkalemia present or suspected.^b If ECG does not show widening of QRS or arrhythmia in the presence of hyperkalemia, usually sufficient to discontinue triamterene and any potassium supplementation and switch to a thiazide alone.^b May administer sodium polystyrene sulfonate to enhance excretion of excess potassium.^b

Presence of widened QRS complex or arrhythmia in association with hyperkalemia requires prompt additional therapy.^b For tachyarrhythmia, infuse 44 mEq of sodium bicarbonate or 10 mL of 10% calcium gluconate or calcium chloride over several minutes.^b For asystole, bradycardia, or AV block, transvenous pacing also is recommended.^b The effect of calcium and sodium bicarbonate is transient and repeated administration may be required.^b When indicated by the clinical situation, excess potassium may be removed by dialysis or oral or rectal administration of sodium polystyrene sulfonate.^b Infusion of glucose and insulin has also been used to treat hyperkalemia.^b

Potassium Supplementation

Do not use potassium supplementation (e.g., potassium salts, high potassium diet, salt substitutes) in patients receiving triamterene alone.^b Discontinue potassium supplements when triamterene is added to existing diuretic therapy or when patients are switched to triamterene from other diuretics.^b

Do not use potassium supplementation with fixed-combination triamterene/hydrochlorothiazide except in severe cases of hypokalemia or if dietary intake of potassium is markedly impaired.^a ^c Such concomitant therapy may be associated with rapid increases in serum potassium concentrations.^c Monitor serum potassium concentrations frequently if potassium supplementation is used, especially in patients receiving digitalis or with a history of cardiac arrhythmias.^c (See Interactions.)

If serious hypokalemia (serum potassium <3.0 mEq/L demonstrated by repeat serum potassium determinations) occurs in a patient receiving fixed-combination triamterene/hydrochlorothiazide, discontinue fixed combination and initiate potassium supplementation.^c

If hyperkalemia occurs in a patient receiving fixed-combination triamterene/hydrochlorothiazide and supplemental potassium therapy, discontinue supplementation and substitute a thiazide diuretic alone for fixed-combination triamterene/hydrochlorothiazide until potassium concentrations return to normal.^c

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, rash, photosensitivity) reported; monitor for blood dyscrasias, liver damage or other idiosyncratic reactions.^b

General Precautions

Use of Fixed Combinations

When triamterene is used in fixed combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with hydrochlorothiazide.^d

Use during Pregnancy

Routine use of diuretics, including triamterene, in otherwise healthy women exposes mother and fetus to unnecessary risk and is not generally indicated.^b ^c ^d Diuretics do not prevent development of toxemia of pregnancy and do not appear to be beneficial in the treatment of toxemia.^b ^c ^d

Edema may develop during pregnancy due to comorbid pathology or the physiologic and mechanical consequences of pregnancy.^b ^c ^d Diuretic therapy may be appropiate in the management of edema due to a pathologic cause manifesting during pregnancy.^b ^c ^d However, dependent edema in pregnancy resulting from restriction of venous return by the gravid uterus may be treated by elevating the lower extremities and using support hose; diuretic therapy to lower intravascular volume is not appropriate in such cases.^b ^c ^d

Hypervolemia and associated edema, including generalized edema, occurs in the majority of pregnant women and is not harmful to fetus or mother.^b ^c ^d Increased recumbency will generally provide relief; however, edema may cause extreme discomfort which is not relieved by rest.^b ^c ^d Rarely, in such cases, a short course of diuretic therapy may be appropriate to provide relief.^b ^c ^d

Electrolyte Imbalance

Electrolyte imbalance may worsen or develop during diuretic therapy, including triamterene.^b Risk of electrolyte imbalance is increased in patients with CHF, renal disease, or cirrhosis.^b Full-dose diuretic therapy in patients on restricted salt intake may cause a low-salt syndrome.^b

Monitor serum electrolytes regularly.^d

Renal Effects

Elevations in BUN and/or S_cr may occur, possibly secondary to a reversible reduction of GFR or a depletion of the intravascular fluid volume.^d May occur more frequently in patients receiving twice-daily dosing with fixed combination of triamterene and hydrochlorothiazide.^d

Monitor BUN and S_cr, especially in geriatric patients and those with suspected or confirmed hepatic or renal disease.^d If azotemia increases, discontinue fixed-combination triamterene/hydrochlorothiazide preparation.^d

Nitrogen Retention

May cause mild nitrogen retention, which is reversible upon drug discontinuance; seldom observed with intermittent (every-other-day) therapy.^b

Metabolic Acidosis

May cause a decreasing alkali reserve with the possibility of metabolic acidosis.^b

Avoid use of potassium-sparing diuretics in severely ill patients in whom respiratory or metabolic acidosis may occur; acidosis may result in rapid increases in serum potassium concentrations.^c ^d Perform frequent assessments of acid-base balance and serum electrolytes.^c ^d

Megaloblastosis

Triamterene is a weak folic acid antagonist and may contribute to the appearance of megaloblastosis, especially in patients with depleted folic acid stores (e.g., pregnant women, alcoholics).^a ^b Patients with cirrhosis and splenomegaly may have marked hematologic abnormalities; these patients should have periodic blood studies and be observed for exacerbations of underlying liver disease.^b

Hyperuricemia

May cause elevations in serum uric acid concentrations, especially in patients predisposed to gouty arthritis.^b

Renal Calculi

Has been reported in renal calcluli associated with usual calculus components.^b ^c ^d Manufacturers state that triamterene may be used with caution in patients with histories of renal calcluli;^b ^c ^d however, some clinicians recommend that the drug not be used in these patients because of the risk of triamterene nephrolithiasis.^a

If a patient passes a urinary calculus during triamterene therapy, the drug should be discontinued and the calculus analyzed for the presence of triamterene and/or its metabolites.^a

Rebound Kaliuresis

Because triamterene conserves potassium, it has been suggested that patients who have received intensive therapy or have been given the drug for prolonged periods may develop a rebound kaliuresis if such therapy is discontinued abruptly.^b Discontinue drug gradually in such patients.^b

Specific Populations

Pregnancy

Category C.^b ^c ^d

Lactation

Distributed into milk in animals and is likely to distribute into human milk.^b Discontinue nursing or the drug.^b

Pediatric Use

Safety and efficacy in pediatric patients remain to be fully established for triamterene or triamterene in fixed combination with hydrochlorothiazide;^b ^c however, some experts have suggested a triamterene dosage for hypertension based on limited clinical experience.¹²⁰

Geriatric Use

Reduced clearance and increased risk of hyperkalemia; monitor serum potassium concentrations frequently.^b ^c ^d (See Hyperkalemia under Cautions.)

Hepatic Impairment

Use with caution in patients with impaired hepatic function.^a Do not use in patients with severe hepatic disease.^a Diuretic therapy in such patients should be initiated while the patient is hospitalized, because rapid alterations in fluid and electrolyte balance may precipitate hepatic coma.^a Monitor serum potassium concentrations closely in patients with hepatic cirrhosis and administer potassium supplementation if required.^a (See Contraindications under Cautions.)

Potassium loss has been reported during triamterene therapy in some patients with hepatic cirrhosis and may result in signs and symptoms of hepatic coma or precoma.^a

Patients with cirrhosis and splenomegaly may have marked hematologic abnormalities; these patients should have periodic blood studies and be observed for exacerbations of underlying liver disease.^b (See Megablastosis under Cautions.)

Renal Impairment

Use with caution; increased risk of hyperkalemia.^b Monitor serum potassium concentrations closely.^b Do not use in patients with renal impairment and elevated serum potassium; discontinue in patients who develop hyperkalemia while on the drug.^b (See Contraindications under Cautions and also see Hyperkalemia under Cautions.)

Common Adverse Effects

Hyperkalemia, azotemia, increased BUN and creatinine, renal calculi, jaundice and/or liver enzyme abnormalities, nausea and vomiting, diarrhea, thrombocytopenia, megaloblastic anemia, weakness, fatigue, dizziness, headache, dry mouth.^b

Interactions for Triamterene

Specific Drugs, Foods, and Laboratory Tests

Drug, Food, or Test	Interaction	Comments
ACE inhibitor	Increased risk of hyperkalemia^b ^c ^d	Use caution with concomitant ACE inhibitor therapy; monitor serum potassium concentrations frequently^a ^b ^d Use potassium-sparing diuretics with great caution, if at all, in patients receiving an ACE inhibitor (e.g., enalapril) for CHF^a Discontinue or reduce dosage of potassium-sparing diuretics as necessary in patients receiving an ACE inhibitor^a
Anesthetic agents	Possible potentiation of anesthetic effects^b
Antidiabetic agents (e.g., insulin, oral agents)	Possible increase in blood glucose concentration^b	Adjust dosage of antidiabetic agent during triamterene therapy and after discontinuance^b
Antihypertensive agents	Possible additive antihypertensive effects^b
Blood products	Increased risk of hyperkalemia^b May promote potassium accumulation; plasma from blood bank may contain up to 30 mEq/L of potassium and whole blood may contain up to 65 mEq/L if stored for >10 days^b
Chlorpropamide	Possible increased risk of severe hyponatremia^b ^c
Diuretics	Possible potentiation of diuretic effects^b
Diuretics, potassium-sparing (e.g. amiloride, spironolactone, other fixed-dose combination formulations containing triamterene)	Increased risk of hyperkalemia; fatalities reported^b	Concomitant use contraindicated^b
Laxatives	Possible decreased potassium-retaining effects of triamterene^c Chronic use or overuse of laxatives may reduce serum potassium concentrations by promoting excessive potassium loss from Gl tract^c
Lithium	Reduced renal clearance of lithium and increased risk of lithium toxicity^b ^c	Concomitant use generally contraindicated; if concomitant therapy is necessary, monitor serum lithium concentrations closely and adjust dosage^b ^c
Nondepolarizing neuromuscular blocking agents	Potential increase in neuromuscular blockade^b
NSAIAs (e.g., indomethacin)	Concomitant use with indomethacin may adversely affect renal function (e.g., decreased Cl_cr, acute anuric renal failure)¹⁰⁵ ¹⁰⁶	Concomitant use with indomethacin not recommended^a Use caution with other concomitant NSAIAs^a ^c
Preanesthetic agents	Possible potentiation of effects of preanesthetic agent^b
Potassium supplements, potassium-containing medications (e.g., parenteral penicillin G potassium) and/or foods containing potassium (e.g., salt substitutes, low-salt milk)	Increased risk of hyperkalemia, especially in patients with renal insufficiency^b	Concomitant use generally contraindicated^b
Tests, fluorometric (e.g., lactic dehydrogenase activity)	Possible interference due to pale blue fluorescence in urine^a
Tests, fluorometric assay for quinidine	Interferes with the fluorometric assay of quinidine; the two drugs have similar fluorescence spectra^b ^c

Triamterene Pharmacokinetics

Absorption

Bioavailability

Triamterene and fixed combinations with hydrochlorothiazide are rapidly absorbed following oral administration;^c ^d peak plasma concentrations achieved within 1–4 hours.^a ^b ^d Interindividual variation in degree of absorption reported.^a

Oral bioavailabilities of triamterene and hydrochlorothiazide from Dyazide capsules are comparable to those of aqueous suspensions of the individual drugs, averaging 85 and 82%, respectively, for the fixed-dose formulation and 100 and 100%, respectively, for the suspensions.¹¹¹ Dyazide capsules also are bioequivalent to single-entity 25-mg hydrochlorothiazide tablets and 37.5-mg triamterene capsules.¹¹⁰

Oral bioavailabilities of triamterene and hydrochlorothiazide from Maxzide tablets are comparable to those of aqueous suspensions of the individual drugs.^d The hydrochlorothiazide component of Maxzide tablets is bioequivalent to single-entity hydrochlorothiazide tablet formulations.^d

Onset

Onset of diuresis following oral administration of triamterene usually occurs within 2–4 hours; maximum therapeutic effect may not occur until after several days of therapy.^b

Onset of diuresis after oral administration of Dyazide usually occurs within 1 hour and peaks at 2–3 hours.^c

Duration

After oral administration of triamterene, diuresis diminishes in approximately 7–9 hours,^a ^b although the total duration of action may be ≥24 hours.^a

After oral administration of Dyazide, diuresis diminishes in approximately 7–9 hours.^c

Food

Administration of Dyazide with a high-fat meal in healthy adults increased the average bioavailabilities of triamterene, 6-p-hydroxytriamterene, and hydrochlorothiazide by about 67, 50, and 17%, respectively; increased the peak concentrations of triamterene and its p-hydroxy metabolite; and delayed absorption of the active drugs by up to 2 hours.¹¹⁰

Administration with food does not affect absorption of triamterene or hydrochlorothiazide from Maxzide tablets.^d

Distribution

Extent

Distributed into bile.^a

Crosses the placenta and distributes into milk in animals.^b

Plasma Protein Binding

Approximately 67%.^b

Elimination

Metabolism

Primarily metabolized to 6-p-hydroxytriamterene and its sulfate conjugate.^b ¹⁰⁷

Elimination Route

Excreted in urine, primarily as 6-p-hydroxytriamterene.^b

Half-life

100–150 minutes.^a

Special Populations

Renal clearances of triamterene, hydroxytriamterene sulfate, and hydrochlorothiazide may be reduced in geriatric patients receiving combined triamterene and hydrochlorothiazide therapy, principally as a result of age-related reductions in renal function.¹⁰⁷ ^a

Stability

Storage

Oral

Capsules

Tight, light resistant containers at 15–30°C.^a ^b

Fixed-dose Combination Formulations

Dyazide capsules: Tight, light resistant containers at 20–25°C.^c

Maxzide tablets: Tight, light resistant containers at 15–30°C.^d

ActionsActions

A pteridine derivative, potassium-sparing diuretic that is structurally related to folic acid.^a ^b

Does not competitively inhibit aldosterone; activity is independent of aldosterone concentrations.^b

Does not inhibit carbonic anhydrase.^a

Acts directly on the distal renal tubule of the nephron to depress aldosterone-stimulated reabsorption of sodium and excretion of potassium and hydrogen at that site.^b

Increases excretion of sodium, calcium, magnesium, and bicarbonate.^a

Potassium excretion usually reduced; serum concentrations of potassium and chloride are usually increased.^a ^b

Serum bicarbonate concentrations consistently decreased; urinary pH increased slightly.^a

Reductions in glomerular filtration observed during daily, but not intermittent, administration; suggests a reversible effect on renal blood flow.^a

Although effective alone, often used in combination with other diuretics that act at different sites in the nephron.^a

Little if any hypotensive effect when used alone.^a

Advice to Patients

Importance of taking drug after meals to help avoid stomach upset.^b

Importance of informing patients that if a single daily dose is prescribed, it may be preferable to take it in the morning to minimize the effect of increased frequency of urination on nighttime sleep.^b

Importance of informing patients that if a dose is missed, the patient should take only the prescribed dose at the next dosing interval.^b

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^b ^c ^d

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^b ^c ^d

Importance of informing patients of other important precautionary information. (See Cautions.)^b ^c ^d

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Triamterene
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	50 mg	Dyrenium (with benzyl alcohol and povidone)	WellSpring
		100 mg	Dyrenium (with benzyl alcohol and povidone)	WellSpring

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Triamterene and Hydrochlorothiazide (Co-triamterzide)
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	37.5 mg Triamterene and Hydrochlorothiazide 25 mg*	Dyazide (with benzyl alcohol and povidone)	GlaxoSmithKline
			Triamterene and Hydrochlorothiazide Capsules	Barr, Mylan, Sandoz, UDL
		50 mg Triamterene and Hydrochlorothiazide 25 mg*	Triamterene and Hydrochlorothiazide Capsules	TEVA, Sandoz
	Tablets	37.5 mg Triamterene and Hydrochlorothiazide 25 mg*	Maxzide-25 mg (scored)	Mylan
			Triamterene and Hydrochlorothiazide Tablets	Barr, Mylan, Pliva, Sandoz, Watson
		75 mg Triamterene and Hydrochlorothiazide 50 mg*	Maxzide (scored)	Mylan
			Triamterene and Hydrochlorothiazide Tablets	Barr, Mylan, Pliva, Sandoz, Teva, UDL, Watson

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Dyazide 37.5-25MG Capsules (GLAXO SMITH KLINE): 30/$45.99 or 90/$109.92

Dyrenium 100MG Capsules (WELLSPRING PHARMACEUTICAL CORP): 30/$75.99 or 90/$205.53

Dyrenium 50MG Capsules (WELLSPRING PHARMACEUTICAL CORP): 30/$49.83 or 90/$124.54

Maxzide 75-50MG Tablets (MYLAN): 30/$79.99 or 90/$219.96

Maxzide-25 37.5-25MG Tablets (MYLAN BERTEK): 30/$37.5 or 90/$85.87

Triamterene-HCTZ 37.5-25MG Capsules (SANDOZ): 100/$19.99 or 200/$25.98

Triamterene-HCTZ 37.5-25MG Tablets (SANDOZ): 100/$29.99 or 200/$45.96

Triamterene-HCTZ 50-25MG Capsules (SANDOZ): 100/$155.99 or 300/$439.98

Triamterene-HCTZ 75-50MG Tablets (SANDOZ): 100/$17.99 or 300/$39.96

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Upton RA, Williams RL, Lin ET et al. Absence of a significant pharmacokinetic interaction between hydrochlorothiazide and triamterene when coadministered. J Pharmacokinet Biopharm. 1984; 12:575-86. [IDIS 197834] [PubMed 6533293]

101. Blume CD, Williams RL, Upton RA et al. Bioequivalence study of a new tablet formulation of triamterene and hydrochlorothiazide. Am J Med. 1984; 77(Suppl 5A):59-61. [IDIS 192689] [PubMed 6496560]

102. Blume CD, Williams RL. A new antihypertensive agent: Maxzide (75 mg triamterene/50 mg hydrochlorothiazide). Am J Med. 1984; 77(Suppl 5A):52-8. [IDIS 192688] [PubMed 6388327]

104. Houston MC. Thiazides and thiazide-like diuretics in hypertension. Ann Intern Med. 1985; 103:303. [IDIS 202760] [PubMed 4014913]

105. Favre L, Glasson P, Vallotton MB. Reversible acute renal failure from combined triamterene and indomethacin. Ann Intern Med. 1982; 96:317-20. [IDIS 146179] [PubMed 6949485]

106. Weinberg MS, Quigg RJ, Salant DJ et al. Anuric renal failure precipitated by indomethacin and triamterene. Nephron. 1985; 40:216-8. [PubMed 4000350]

107. Williams RL, Thornhill MD, Upton RA et al. Absorption and disposition of two combination formulations of hydr

Friday, 13 April 2012

Cimetidine Sodium Chloride

Generic Name: cimetidine in 0.9% sodium chloride

Dosage Form: Injection, USP

300 mg (6 mg/mL) Cimetidine

Flexible Plastic Container

For Intravenous Infusion Only

Rx only

Cimetidine Sodium Chloride Description

Cimetidine in 0.9% Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution of cimetidine hydrochloride in 0.9% sodium chloride injection. It is administered by the intravenous route. Each mL contains cimetidine HCl equivalent to 6 mg cimetidine and sodium chloride 9 mg in water for injection. The osmolar concentration is 356 mOsmol/L (calc.); pH is 6.0 (5.0 to 7.0). May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. The solution contains no bacteriostat, antimicrobial agent or added buffer and is intended only for use as a single-dose administration. When smaller doses are required, the unused portion should be discarded.

Cimetidine hydrochloride is a histamine H2-receptor antagonist. Chemically it is N"-cyano-N-methyl-N'-[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]-ethyl]-guanidine.

The molecular formula for cimetidine hydrochloride is C10H16N6S•HCl and the molecular weight is 288.80. The structural formula of cimetidine hydrochloride is:

Cimetidine Hydrochloride

Cimetidine contains an imidazole ring, and is chemically related to histamine.

Cimetidine hydrochloride has a bitter taste and characteristic odor.

Sodium Chloride, USP is chemically designated NaCI, a white crystalline compound freely soluble in water.

Water for Injection, USP is chemically designated H2O.

The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period.

Cimetidine Sodium Chloride - Clinical Pharmacology

Cimetidine competitively inhibits the action of histamine at the histamine H2 receptors of the parietal cells and thus is a histamine H2-receptor antagonist.

Cimetidine is not an anticholinergic agent. Studies have shown that cimetidine inhibits both daytime and nocturnal basal gastric acid secretion. Cimetidine also inhibits gastric acid secretion stimulated by food, histamine, pentagastrin, caffeine and insulin.

Antisecretory Activity

Acid Secretion:Nocturnal: Cimetidine 800 mg orally at bedtime reduces mean hourly H+ activity by greater than 85% over an eight-hour period in duodenal ulcer patients, with no effect on daytime acid secretion. Cimetidine 1600 mg orally h.s. produces 100% inhibition of mean hourly H+ activity over an eight-hour period in duodenal ulcer patients, but also reduces H+ activity by 35% for an additional five hours into the following morning. Cimetidine 400 mg b.i.d. and 300 mg q.i.d. decrease nocturnal acid secretion in a dose-related manner, i.e., 47% to 83% over a six- to eight-hour period and 54% over a nine-hour period, respectively.

Food Stimulated: During the first hour after a standard experimental meal, oral cimetidine 300 mg inhibited gastric acid secretion in duodenal ulcer patients by at least 50%. During the subsequent two hours cimetidine inhibited gastric acid secretion by at least 75%.

The effect of a 300 mg breakfast dose of cimetidine continued for at least four hours and there was partial suppression of the rise in gastric acid secretion following the luncheon meal in duodenal ulcer patients. This suppression of gastric acid output was enhanced and could be maintained by another 300 mg dose of cimetidine given with lunch.

In another study, cimetidine 300 mg given with the meal increased gastric pH as compared with placebo.

	Mean Gastric pH
	Cimetidine	Placebo
1 hour	3.5	2.6
2 hours	3.1	1.6
3 hours	3.8	1.9
4 hours	6.1	2.2

24-Hour Mean H+ Activity: Cimetidine 800 mg h.s., 400 mg b.i.d. and 300 mg q.i.d. all provide a similar, moderate (less than 60%) level of 24 hour acid suppression. However, the 800 mg h.s. regimen exerts its entire effect on nocturnal acid, and does not affect daytime gastric physiology.

Chemically Stimulated: Oral cimetidine significantly inhibited gastric acid secretion stimulated by betazole (an isomer of histamine), pentagastrin, caffeine and insulin as follows:

Stimulant	Stimulant Dose	Cimetidine	% Inhibition
Betazole	1.5 mg/kg (sc)	300 mg (po)	85% at 2½ hours
Pentagastrin	6 mcg/kg/hr (iv)	100 mg/hr (iv)	60% at 1 hour
Caffeine	5 mg/kg/hr (iv)	300 mg (po)	100% at 1 hour
Insulin	0.03 units/kg/hr (iv)	100 mg/hr (iv)	82% at 1 hour

When food and betazole were used to stimulate secretion, inhibition of hydrogen ion concentration usually ranged from 45 to 75% and the inhibition of volume ranged from 30 to 65%.

Parenteral administration also significantly inhibits gastric acid secretion. In a crossover study involving patients with active or healed duodenal or gastric ulcers, either continuous I.V. infusion of cimetidine 37.5 mg/hour (900 mg/day) or intermittent injection of cimetidine 300 mg q6h (1200 mg/day) maintained gastric pH above 4.0 for more than 50% of the time under steady-state conditions.

Pepsin: Oral cimetidine 300 mg reduced total pepsin output as a result of the decrease in volume of gastric juice.

Intrinsic Factor: Intrinsic factor secretion was studied with betazole as a stimulant. Oral cimetidine 300 mg inhibited the rise in intrinsic factor concentration produced by betazole, but some intrinsic factor was secreted at all times.

Other

Lower Esophageal Sphincter Pressure and Gastric Emptying

Cimetidine has no effect on lower esophageal sphincter (LES) pressure or the rate of gastric emptying.

Pharmacokinetics

Cimetidine is rapidly absorbed after oral administration and peak levels occur in 45 to 90 minutes. The half-life of cimetidine is approximately 2 hours. Both oral and parenteral (I.V. or I.M.) administration provide comparable periods of therapeutically effective blood levels; blood concentrations remain above that required to provide 80% inhibition of basal gastric acid secretion for 4 to 5 hours following a dose of 300 mg.

Steady-state blood concentrations of cimetidine with continuous infusion of cimetidine hydrochloride are determined by the infusion rate and clearance of the drug in the individual patient. In a study of peptic ulcer patients with normal renal function, an infusion rate of 37.5 mg/hour produced average steady-state plasma cimetidine concentrations of about 0.9 mcg/mL. Blood levels with other infusion rates will vary in direct proportion to the infusion rate.

The principal route of excretion of cimetidine is the urine. Following parenteral administration, most of the drug is excreted as the parent compound; following oral administration, the drug is more extensively metabolized, the sulfoxide being the major metabolite. Following a single oral dose, 48% of the drug is recovered from the urine after 24 hours as the parent compound. Following I.V. or I.M. administration, approximately 75% of the drug is recovered from the urine after 24 hours as the parent compound.

Sodium chloride in water dissociates to provide sodium (Na+) and chloride (Cl¯) ions. Sodium (Na+) is the principal cation of the extracellular fluid and plays a large part in the therapy of fluid and electrolyte disturbances. Chloride (Cl¯) has an integral role in buffering action when oxygen and carbon dioxide exchange occurs in the red blood cells. The distribution and excretion of sodium (Na+) are largely under the control of the kidney which maintains a balance between intake and output.

Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight.

Average normal adult daily requirements range from two to three liters (1.0 to 1.5 liters each for insensible water loss by perspiration and urine production).

Waterbalance is maintained by various regulatory mechanisms. Water distribution depends primarily on the concentration of electrolytes in the body compartments and sodium (Na+) plays a major role in maintaining physiologic equilibrium.

Clinical Trials

Duodenal Ulcer

Cimetidine has been shown to be effective in the treatment of active duodenal ulcer and, at reduced dosage, in maintenance therapy following healing of active ulcers.

Active Duodenal Ulcer: Cimetidine accelerates the rate of duodenal ulcer healing. Healing rates reported in U.S. and foreign controlled trials with oral cimetidine are summarized below, beginning with the regimen providing the lowest nocturnal dose.

Duodenal Ulcer Healing Rates with Various Cimetidine Dosage Regimens*
Regimen	300 mg q.i.d.	400 mg b.i.d.	800 mg h.s.	1600 mg h.s.
week 4	68%	73%	80%	86%
week 6	80%	80%	89%	−
week 8	−	92%	94%	−

*Averages from controlled clinical trials.

A U.S., double-blind, placebo-controlled, dose-ranging study demonstrated that all once-daily at bedtime (h.s.) cimetidine regimens were superior to placebo in ulcer healing and that cimetidine 800 mg h.s. healed 75% of patients at four weeks. The healing rate with 800 mg h.s. was significantly superior to 400 mg h.s. (66%) and not significantly different from 1600 mg h.s. (81%).

In the U.S. dose-ranging trial, over 80% of patients receiving cimetidine 800 mg h.s. experienced nocturnal pain relief after one day. Relief from daytime pain was reported in approximately 70% of patients after two days. As with ulcer healing, the 800 mg h.s. dose was superior to 400 mg h.s. and not different from 1600 mg h.s.

In foreign, double-blind studies with cimetidine 800 mg h.s., 79% to 85% of patients were healed at four weeks.

While short-term treatment with cimetidine can result in complete healing of the duodenal ulcer, acute therapy will not prevent ulcer recurrence after cimetidine has been discontinued. Some follow-up studies have reported that the rate of recurrence once therapy was discontinued was slightly higher for patients healed on cimetidine than for patients healed on other forms of therapy; however, the cimetidine-treated patients generally had more severe disease.

Maintenance Therapy in Duodenal Ulcer: Treatment with a reduced dose of cimetidine has been proven effective as maintenance therapy following healing of active duodenal ulcers.

In numerous placebo-controlled studies conducted worldwide, the percent of patients with observed ulcers at the end of one year's therapy with cimetidine 400 mg h.s. was significantly lower (10 to 45%) than in patients receiving placebo (44% to 70%). Thus, from 55% to 90% of patients were maintained free of observed ulcers at the end of one year with cimetidine 400 mg h.s.

Factors such as smoking, duration and severity of disease, gender, and genetic traits may contribute to variations in actual percentages.

Trials of other anti-ulcer therapy, whether placebo-controlled, positive-controlled or open, have demonstrated a range of results similar to that seen with cimetidine.

Active Benign Gastric Ulcer

Cimetidine has been shown to be effective in the short-term treatment of active benign gastric ulcer.

In a multicenter, double-blind U.S. study, patients with endoscopically confirmed benign gastric ulcer were treated with cimetidine 300 mg four times a day or with placebo for six weeks. Patients were limited to those with ulcers ranging from 0.5 to 2.5 cm in size. Endoscopically confirmed healing at six weeks was seen in significantly* more cimetidine-treated patients than in patients receiving placebo, as shown below:

	Cimetidine	Placebo
week 2	14/63 (22%)	7/63 (11%)
total at week 6	43/65 (66%)*	30/67 (45%)
*p<0.05

In a similar multicenter U.S. study of the 800 mg h.s. oral regimen, the endoscopically confirmed healing rates were:

	Cimetidine	Placebo
total at week 6	63/83 (76%)*	44/80 (55%)
*p=0.005

Similarly, in worldwide double-blind clinical studies, endoscopically evaluated benign gastric ulcer healing rates were consistently higher with cimetidine than with placebo.

Preventionof Upper Gastrointestinal Bleeding in Critically Ill Patients

A double-blind, placebo-controlled randomized study of continuous infusion cimetidine was performed in 131 critically ill patients (mean APACHE II score = 15.99) to compare the incidence of upper gastrointestinal bleeding, manifested as hematemesis or bright red blood which did not clear after adjustment of the nasogastric tube and a 5 to 10 minute lavage, persistent Gastroccult (R) positive coffee grounds for 8 consecutive hours which did not clear with 100 cc lavage and/or which were accompanied by a drop in hematocrit of 5 percent points, or melena, with an endoscopically documented upper gastrointestinal source of bleed. 14% (9/65) of patients treated with cimetidine continuous infusion developed bleeding compared to 33% (22/66) of the placebo group. Coffee grounds was the manifestation of bleeding that accounted for the difference between groups. Another randomized, double-blind placebo-controlled study confirmed these results for an end point of upper gastrointestinal bleeding with a confirmed upper gastrointestinal source noted on endoscopy, and by post hoc analyses of bleeding episodes between groups.

Pathological Hypersecretory Conditions (such as Zollinger-Ellison Syndrome)

Cimetidine significantly inhibited gastric acid secretion and reduced occurrence of diarrhea, anorexia and pain in patients with pathological hypersecretion associated with Zollinger-Ellison Syndrome, systemic mastocytosis and multiple endocrine adenomas. Use of cimetidine was also followed by healing of intractable ulcers.

Indications and Usage for Cimetidine Sodium Chloride

Cimetidine hydrochloride injection is indicated in:

(1) Short-term treatment of active duodenal ulcer. Most patients heal within 4 weeks and there is rarely reason to use cimetidine at full dosage for longer than 6 to 8 weeks (see DOSAGE AND ADMINISTRATION− Duodenal Ulcer). Concomitant antacids should be given as needed for relief of pain. However, simultaneous administration of oral cimetidine and antacids is not recommended, since antacids have been reported to interfere with the absorption of oral cimetidine.

(2) Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of active ulcer. Patients have been maintained on continued treatment with cimetidine 400 mg h.s. for periods of up to five years.

(3) Short-term treatment of active benign gastric ulcer. There is no information concerning usefulness of treatment periods of longer than 8 weeks.

(4) Prevention of upper gastrointestinal bleeding in critically ill patients.

(5) The treatment of pathological hypersecretory conditions (i.e., Zollinger-Ellison Syndrome, systemic mastocytosis, multiple endocrine adenomas).

Contraindications

Cimetidine is contraindicated for patients known to have hypersensitivity to the product.

Precautions

General:

Rare instances of cardiac arrhythmias and hypotension have been reported following the rapid administration of cimetidine hydrochloride injection by intravenous bolus.

Symptomatic response to cimetidine therapy does not preclude the presence of a gastric malignancy. There have been rare reports of transient healing of gastric ulcers despite subsequently documented malignancy.

Reversible confusional states (see ADVERSE REACTIONS) have been observed on occasion, predominantly, but not exclusively, in severely ill patients. Advancing age (50 or more years) and preexisting liver and/or renal disease appear to be contributing factors. In some patients these confusional states have been mild and have not required discontinuation of cimetidine therapy. In cases where discontinuation was judged necessary, the condition usually cleared within 3 to 4 days of drug withdrawal.

Drug Interactions:

Cimetidine, apparently through an effect on certain microsomal enzyme systems, has been reported to reduce the hepatic metabolism of warfarin-type anticoagulants, phenytoin, propranolol, nifedipine, chlordiazepoxide, diazepam, certain tricyclic antidepressants, lidocaine, theophylline and metronidazole, thereby delaying elimination and increasing blood levels of these drugs.

Clinically significant effects have been reported with the warfarin anticoagulants; therefore, close monitoring of prothrombin time is recommended, and adjustment of the anticoagulant dose may be necessary when cimetidine is administered concomitantly. Interaction with phenytoin, lidocaine and theophylline has also been reported to produce adverse clinical effects.

However, a crossover study in healthy subjects receiving either cimetidine 300 mg q.i.d. or 800 mg h.s. concomitantly with a 300 mg b.i.d. dosage of theophylline extended-release tablets demonstrated less alteration in steady-state theophylline peak serum levels with the 800 mg h.s. regimen, particularly in subjects aged 54 years and older. Data beyond ten days are not available. (Note: All patients receiving theophylline should be monitored appropriately, regardless of concomitant drug therapy.)

Dosage of the drugs mentioned above and other similarly metabolized drugs, particularly those of low therapeutic ratio or in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered cimetidine to maintain optimum therapeutic blood levels.

Alteration of pH may affect absorption of certain drugs (e.g. ketoconazole). If these products are needed, they should be given at least 2 hours before cimetidine administration.

Additional clinical experience may reveal other drugs affected by the concomitant administration of cimetidine.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

In a 24-month toxicity study conducted in rats, at dose levels of 150, 378 and 950 mg/kg/day (approximately 8 to 48 times the recommended human dose), there was a small increase in the incidence of benign Leydig cell tumors in each dose group: when the combined drug-treated groups and control groups were compared, this increase reached statistical significance. In a subsequent 24 month study, there were no differences between the rats receiving 150 mg/kg/day and the untreated controls. However, a statistically significant increase in benign Leydig cell tumor incidence was seen in the rats that received 378 and 950 mg/kg/day. These tumors were common in control groups as well as treated groups and the difference became apparent only in aged rats.

Cimetidine has demonstrated a weak antiandrogenic effect. In animal studies this was manifested as reduced prostate and seminal vesicle weights. However, there was no impairment of mating performance or fertility, nor any harm to the fetus in these animals at doses 8 to 48 times the full therapeutic dose of cimetidine, as compared with controls. The cases of gynecomastia seen in patients treated for one month or longer may be related to this effect.

In human studies, cimetidine has been shown to have no effect on spermatogenesis, sperm count, motility, morphology or in vitro fertilizing capacity.

Studies with solutions from flexible plastic containers have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.

Pregnancy:

Teratogenic Effects: Pregnancy Category B: Reproduction studies have been performed in rats, rabbits and mice at doses up to 40 times the normal human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cimetidine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers:

Cimetidine is secreted in human milk and, as a general rule, nursing should not be undertaken while a patient is on a drug.

Caution should be exercised when solutions from flexible plastic containers are administered to a nursing mother.

Pediatric Use:

Clinical experience in pediatric patients is limited. Therefore, cimetidine therapy cannot be recommended for pediatric patients under 16, unless, in the judgment of the physician, anticipated benefits outweigh the potential risks. In very limited experience, doses of 20 to 40 mg/kg per day have been used.

Safety and effectiveness of solutions from flexible plastic containers in pediatric patients have not been well established.

Immunocompromised Patients: In immunocompromised patients, decreased gastric acidity, including that produced by acid-suppressing agents such as cimetidine, may increase the possibility of a hyperinfection of strongyloidiasis.

Adverse Reactions

Adverse effects reported in patients taking cimetidine are described below by body system. Incidence figures of 1 in 100 and greater are generally derived from controlled clinical studies.

The collection of this information has been derived largely from trials associated with oral cimetidine.

Gastrointestinal: Diarrhea (usually mild) has been reported in approximately 1 in 100 patients.

CNS: Headaches, ranging from mild to severe, have been reported in 3.5% of 924 patients taking 1600 mg/day, 2.1% of 2,225 patients taking 800 mg/day and 2.3% of 1,897 patients taking placebo. Dizziness and somnolence (usually mild) have been reported in approximately 1 in 100 patients on either 1600 mg/day or 800 mg/day.

Reversible confusional states, e.g., mental confusion, agitation, psychosis, depression, anxiety, hallucinations, disorientation, have been reported predominantly, but not exclusively, in severely ill patients. They have usually developed within 2 to 3 days of initiation of cimetidine therapy and have cleared within 3 to 4 days of discontinuation of the drug.

Endocrine: Gynecomastia has been reported in patients treated for one month or longer. In patients being treated for pathological hypersecretory states, this occurred in about 4% of cases while in all others the incidence was 0.3% to 1% in various studies. No evidence of induced endocrine dysfunction was found, and the condition remained unchanged or returned toward normal with continuing cimetidine treatment.

Reversible impotence has been reported in patients with pathological hypersecretory disorders, e.g., Zollinger−Ellison Syndrome, receiving cimetidine particularly in high doses, for at least 12 months (range 12 to 79 months, mean 38 months). However, in large-scale surveillance studies at regular dosage, the incidence has not exceeded that commonly reported in the general population.

Hematologic: Decreased white blood cell counts in cimetidine-treated patients (approximately 1 per 100,000 patients), including agranulocytosis (approximately 3 per million patients), have been reported, including a few reports of recurrence on rechallenge. Most of these reports were in patients who had serious concomitant illnesses and received drugs and/or treatment known to produce neutropenia. Thrombocytopenia (approximately 3 per million patients) and, very rarely, cases of pancytopenia or aplastic anemia have also been reported. As with some other H2 receptor antagonists, there have been extremely rare reports of immune hemolytic anemia.

Hepatobiliary: Dose-related increases in serum transaminase have been reported. In most cases they did not progress with continued therapy and returned to normal at the end of therapy. There have been rare reports of cholestatic or mixed cholestatic hepatocellular effects. These were usually reversible. Because of the predominance of cholestatic features, severe parenchymal injury is considered highly unlikely. However, as in the occasional liver injury with other H2-receptor antagonists, in exceedingly rare circumstances fatal outcomes have been reported.

There has been reported a single case of biopsy-proven periportal hepatic fibrosis in a patient receiving cimetidine.

Rare cases of pancreatitis, which cleared on withdrawal of the drug, have been reported.

Hypersensitivity: Rare cases of fever and allergic reactions including anaphylaxis and hypersensitivity vasculitis, which cleared on withdrawal of the drug, have been reported.

Renal: Small, possibly dose-related increases in plasma creatinine, presumably due to competition for renal tubular secretion, are not uncommon and do not signify deteriorating renal function. Rare cases of interstitial nephritis and urinary retention, which cleared on withdrawal of the drug, have been reported.

Cardiovascular: Rare cases of bradycardia, tachycardia and A-V heart block have been reported with H2-receptor antagonists.

Musculoskeletal: There have been rare reports of reversible arthralgia and myalgia; exacerbation of joint symptoms in patients with preexisting arthritis has also been reported. Such symptoms have usually been alleviated by a reduction in cimetidine dosage. Rare cases of polymyositis have been reported, but no causal relationship has been established.

Integumental: Mild rash and, very rarely, cases of severe generalized skin reactions including Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis and generalized exfoliative erythroderma have been reported with H2-receptor antagonists. Reversible alopecia has been reported very rarely.

Immune Function: There have been extremely rare reports of strongyloidiasis hyperinfection in immunocompromised patients.

Overdosage

Studies in animals indicate that toxic doses are associated with respiratory failure and tachycardia that may be controlled by assisted respiration and the administration of a beta blocker.

Reported acute ingestions orally of up to 20 grams have been associated with transient adverse effects similar to those encountered in normal clinical experience. The usual measures to remove unabsorbed material from the gastrointestinal tract, clinical monitoring and supportive therapy, should be employed.

There have been reports of severe CNS symptoms, including unresponsiveness, following ingestion of between 20 and 40 grams of cimetidine, and extremely rare reports following concomitant use of multiple CNS-active medications and ingestion of cimetidine at doses less than 20 grams. An elderly, terminally ill dehydrated patient with organic brain syndrome receiving concomitant antipsychotic agents and cimetidine 4800 mg intravenously over a 24 hour period experienced mental deterioration with reversal on cimetidine discontinuation.

There have been two deaths in adults who have been reported to have ingested over 40 grams orally on a single occasion.

Cimetidine Sodium Chloride Dosage and Administration

Parenteral Administration

In hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or in patients who are unable to take oral medication, cimetidine may be administered parenterally.

Intermittent Intravenous Infusion: 300 mg every 6 to 8 hours, infused over 15 to 20 minutes. In some patients it may be necessary to increase dosage. When this is necessary, the increases should be made by more frequent administration of a 300 mg dose, but should not exceed 2400 mg per day.

Continuous Intravenous Infusion: 37.5 mg/hour (900 mg/day). For patients requiring a more rapid elevation of gastric pH, continuous infusion may be preceded by a 150 mg loading dose administered by I.V. infusion as described above. Note: A volumetric pump is recommended if the volume for 24-hour infusion is less than 250 mL. In one study in patients with pathological hypersecretory states, the mean infused dose of cimetidine was 160 mg/hour with a range of 40 to 600 mg/hour.

These doses maintained the intragastric acid secretory rate at 10 mEq/hour or less. The infusion rate should be adjusted to individual patient requirements.

NOTE: The products accompanying this insert are for I.V. infusion only. Much of the following relates to the use of oral cimetidine and is for informational purposes only. See Parenteral Administration (above) for specific dosing recommendations.

Duodenal Ulcer

Active Duodenal Ulcer: Clinical studies have indicated that suppression of nocturnal acid is the most important factor in duodenal ulcer healing (see CLINICAL PHARMACOLOGY − Acid Secretion). This is supported by recent clinical trials (see Clinical Trials−Active DuodenalUlcer). Therefore, there is no apparent rationale, except for familiarity with use, for treating with anything other than a once-daily at bedtime oral dosage regimen (h.s.).

In a U.S. oral dose-ranging study of 400 mg h.s., 800 mg h.s. and 1600 mg h.s., a continuous dose response relationship for ulcer healing was demonstrated.

However, 800 mg h.s. is the dose of choice for most patients, as it provides a high healing rate (the difference between 800 mg h.s. and 1600 mg h.s. being small), maximal pain relief, a decreased potential for drug interactions (see PRECAUTIONS − Drug Interactions) and maximal patient convenience. Patients unhealed at four weeks, or those with persistent symptoms, have been shown to benefit from two to four weeks of continued therapy.

It has been shown that patients who both have an endoscopically demonstrated ulcer larger than 1 cm and are also heavy smokers (i.e., smoke one pack of cigarettes or more per day) are more difficult to heal. There is some evidence which suggests that more rapid healing can be achieved in this subpopulation with cimetidine 1600 mg at bedtime. While early pain relief with either 800 mg h.s. or 1600 mg h.s. is equivalent in all patients, 1600 mg h.s. provides an appropriate alternative when it is important to ensure healing within four weeks for this subpopulation. Alternatively, approximately 94% of all patients will also heal in eight weeks with cimetidine 800 mg h.s.

Other cimetidine oral regimens in the U.S. which have been shown to be effective are: 300 mg four times daily, with meals at bedtime, the original regimen with which U.S. physicians have the most experience, and 400 mg twice daily, in the morning and at bedtime (see Clinical Trials−Active Duodenal Ulcer).

Concomitant antacids should be given as needed for relief of pain. However, simultaneous administration of oral cimetidine and antacids is not recommended, since antacids have been reported to interfere with the absorption of oral cimetidine.

While healing with cimetidine often occurs during the first week or two, treatment should be continued for 4 to 6 weeks unless healing has been demonstrated by endoscopic examination.

Maintenance Therapy for Duodenal Ulcer: In those patients requiring maintenance therapy, the recommended adult oral dose is 400 mg at bedtime.

Active Benign Gastric Ulcer

The recommended adult oral dosage for short-term treatment of active benign gastric ulcer is 800 mg h.s., or 300 mg four times a day with meals and at bedtime. Controlled clinical studies were limited to six weeks of treatment (see Clinical Trials). 800 mg h.s. is the preferred regimen for most patients based upon convenience and reduced potential for drug interactions. Symptomatic response to cimetidine does not preclude the presence of a gastric malignancy. It is important to follow gastric ulcer patients to assure rapid progress to complete healing.

Prevention of Upper Gastrointestinal Bleeding

The recommended adult dosing regimen is continuous I.V. infusion of 50 mg/hour. Patients with creatinine clearance less than 30 cc/min. should receive half the recommended dose. Treatment beyond 7 days has not been studied.

Pathological Hypersecretory Conditions (such as Zollinger−Ellison Syndrome)

Recommended adult oral dosage: 300 mg four times a day with meals and at bedtime. In some patients it may be necessary to administer higher doses more frequently. Doses should be adjusted to individual patient needs, but should not usually exceed 2400 mg per day and should continue as long as clinically indicated.

Dosage Adjustment for Patients with Impaired Renal Function

Patients with severely impaired renal function have been treated with cimetidine. However, such usage has been very limited. On the basis of this experience the recommended dosage is 300 mg every 12 hours orally or by intravenous injection. Should the patient's condition require, the frequency of dosing may be increased to every 8 hours or even further with caution. In severe renal failure, accumulation may occur and the lowest frequency of dosing compatible with an adequate patient response should be used. When liver impairment is also present, further reductions in dosage may be necessary. Hemodialysis reduces the level of circulating cimetidine. Ideally, the dosage schedule should be adjusted so that the timing of a scheduled dose coincides with the end of hemodialysis.

Patients with creatinine clearance less than 30 cc/min. who are being treated for prevention of upper gastrointestinal bleeding should receive half the recommended dose.

Do not add other drugs to premixed Cimetidine in 0.9% Sodium Chloride Injection, USP in plastic containers.

All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

INSTRUCTIONS FOR USE

To Open

Tear outer wrap at notch and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

Preparation for Administration

(Use aseptic technique)

Close flow control clamp of administration set.

Remove cover from outlet port at bottom of container.

Insert piercing pin of administration set into port with a twisting motion until the set is firmly seated. NOTE: See full directions on administration set carton.

Suspend container from hanger.

Squeeze and release drip chamber to establish proper fluid level in chamber.

Open flow control clamp and clear air from set. Close clamp.

Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.

Regulate rate of administration with flow control clamp.

WARNING: Do not use flexible container in series connections.

How is Cimetidine Sodium Chloride Supplied

Cimetidine in 0.9% Sodium Chloride Injection, USP is supplied in a single-dose flexible container as follows:

List No.	Volume	Total Cimetidine Content
7447	50 mL	300 mg

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the product be stored at room temperature (25°C/77°F).


©Hospira 2004	EN-0499	Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

CIMETIDINE IN SODIUM CHLORIDE
cimetidine and sodium chloride injection, solution

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	NDC Product Code (Source)	0409-7447
Route of Administration	INTRAVENOUS	DEA Schedule

INGREDIENTS
Name (Active Moiety)	Type	Strength
Cimetidine (Cimetidine)	Active	6 MILLIGRAM In 1 MILLILITER
Sodium Chloride	Inactive	9 MILLIGRAM In 1 MILLILITER
Water	Inactive
Hydrochloric Acid	Inactive
Sodium Hydroxide	Inactive

Product Characteristics
Color		Score
Shape		Size
Flavor		Imprint Code
Contains

Packaging
#	NDC	Package Description	Multilevel Packaging
1	0409-7447-16	4 BOX In 1 CASE	contains a BOX
1		12 BAG In 1 BOX	This package is contained within the CASE (0409-7447-16) and contains a BAG
1		50 mL (MILLILITER) In 1 BAG	This package is contained within a BOX and a CASE (0409-7447-16)

Revised: 04/2006HOSPIRA, INC.

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