Clonidine Patch

Programmed delivery in vivo of 0.1 mg, 0.2 mg, or 0.3 mg clonidine per day, for one week.

Prescribing Information

Clonidine Patch Description

Clonidine Transdermal System is a transdermal system providing continuous systemic delivery of clonidine for 7 days at an approximately constant rate. Clonidine is a centrally acting alpha-agonist hypotensive agent. It is an imidazoline derivative with the chemical name 2, 6-dichloro-N-2-imidazolidinylidenebenzenamine and has the following chemical structure:

Meets USP Drug Release Test 3.

System Structure and Components

Clonidine Transdermal System is a multi-layered film, 0.25 mm thick, containing clonidine as the active agent. The system areas are 3.33 cm2 (0.1 mg/day), 6.67 cm2 (0.2 mg/day), and 10.0 cm2 (0.3 mg/day) and the amount of drug released is directly proportional to the area (see DESCRIPTION: Release Rate Concept). The composition per unit area is the same for all three doses.

Proceeding from the visible surface towards the surface attached to the skin, there are three consecutive layers: (1) a backing layer of pigmented polyethylene and polyester film, (2) a solid matrix reservoir of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide, (3) an adhesive formulation of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide. Prior to use, a protective slit release liner of polyester that covers the adhesive formulation layer is removed.

Clonidine Transdermal Systems are packaged with additional pieces of protective film above and below the system within each pouch. These pieces of protective film are removed and discarded at the time of use.

Cross Section of the System:

Release Rate Concept

Clonidine Transdermal System is programmed to release clonidine at an approximately constant rate for 7 days. The energy for drug release is derived from the concentration gradient existing between the patch and the much lower concentration prevailing in the skin. Clonidine flows in the direction of the lower concentration at a constant rate.

Following system application to intact skin, clonidine in the adhesive formulation layer saturates the skin site below the system. Clonidine from the patch then begins to flow into the systemic circulation via the capillaries beneath the skin. Therapeutic plasma clonidine levels are achieved 2 to 3 days after initial application of Clonidine Transdermal System.

The 3.33 cm2, 6.67 cm2, and 10.0 cm2 systems deliver 0.1 mg, 0.2 mg, and 0.3 mg of clonidine per day, respectively. To ensure constant release of drug for 7 days, the total drug content of the system is higher than the total amount of drug delivered. Application of a new system to a fresh skin site at weekly intervals continuously maintains therapeutic plasma concentrations of clonidine. If the Clonidine Transdermal System is removed and not replaced with a new system, therapeutic plasma clonidine levels will persist for about 8 hours and then decline slowly over several days. Over this time period, blood pressure returns gradually to pretreatment levels.

Clonidine Patch - Clinical Pharmacology

Clonidine stimulates alpha-adrenoreceptors in the brain stem. This action results in reduced sympathetic outflow from the central nervous system and in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact; therefore, orthostatic symptoms are mild and infrequent.

Acute studies with clonidine hydrochloride in humans have demonstrated a moderate reduction (15% to 20%) of cardiac output in the supine position with no change in the peripheral resistance; at a 45° tilt there is a smaller reduction in cardiac output and a decrease of peripheral resistance.

During long-term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic responses to exercise.

Tolerance to the antihypertensive effect may develop in some patients, necessitating a reevaluation of therapy.

Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines. The exact relationship of these pharmacologic actions to the antihypertensive effect of clonidine has not been fully elucidated.

Clonidine acutely stimulates the release of growth hormone in children as well as adults but does not produce a chronic elevation of growth hormone with long-term use.

Pharmacokinetics

The plasma half-life of clonidine is 12.7 ± 7 hours. Following oral administration, about 40% to 60% of the absorbed dose is recovered in the urine as unchanged drug within 24 hours. The remainder of the absorbed dose is metabolized in the liver.

Indications and Usage for Clonidine Patch

Clonidine Transdermal System, USP is indicated in the treatment of hypertension. It may be employed alone or concomitantly with other antihypertensive agents.

Contraindications

Clonidine Transdermal System should not be used in patients with known hypersensitivity to clonidine or to any other component of the therapeutic system.

Warnings

Withdrawal

Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine treatment has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and confusion accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with Clonidine Transdermal System, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptomatology.

An excessive rise in blood pressure following discontinuation of Clonidine Transdermal System therapy can be reversed by administration of oral clonidine hydrochloride or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of Clonidine Transdermal System.

Precautions

General

In patients who have developed localized contact sensitization to Clonidine Transdermal System continuation of Clonidine Transdermal System or substitution of oral clonidine hydrochloride therapy may be associated with development of a generalized skin rash.

In patients who develop an allergic reaction to Clonidine Transdermal System, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema).

Clonidine Transdermal System should be used with caution in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease, or chronic renal failure.

In rare instances, loss of blood pressure control has been reported in patients using Clonidine Transdermal System according to the instructions for use.

Perioperative Use

Clonidine Transdermal System therapy should not be interrupted during the surgical period. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required. Physicians considering starting Clonidine Transdermal System therapy during the perioperative period must be aware that therapeutic plasma clonidine levels are not achieved until 2 to 3 days after initial application of Clonidine Transdermal System (see DOSAGE AND ADMINISTRATION).

Defibrillation or Cardioversion

The transdermal clonidine systems should be removed before attempting defibrillation or cardioversion because of the potential for altered electrical conductivity which may increase the risk of arcing, a phenomenon associated with the use of defibrillators.

Information for Patients

Patients should be cautioned against interruption of Clonidine Transdermal System therapy without their physician’s advice.

Patients who engage in potentially hazardous activities, such as operating machinery or driving, should be advised of a possible sedative effect of clonidine. They should also be informed that this sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs.

Patients who wear contact lenses should be cautioned that treatment with Clonidine Transdermal System may cause dryness of eyes.

Patients should be instructed to consult their physicians promptly about the possible need to remove the patch if they observe moderate to severe localized erythema and/or vesicle formation at the site of application or generalized skin rash.

If a patient experiences isolated, mild localized skin irritation before completing 7 days of use, the system may be removed and replaced with a new system applied to a fresh skin site.

If the system should begin to loosen from the skin after application, the patient should be instructed to place the adhesive cover directly over the system to ensure adhesion during its 7-day use.

Used Clonidine Transdermal System patches contain a substantial amount of their initial drug content which may be harmful to infants and children if accidentally applied or ingested. THEREFORE, PATIENTS SHOULD BE CAUTIONED TO KEEP BOTH USED AND UNUSED CLONIDINE TRANSDERMAL SYSTEM PATCHES OUT OF THE REACH OF CHILDREN. After use, Clonidine Transdermal System should be folded in half with the adhesive sides together and discarded away from children’s reach.

Instructions for use, storage and disposal of the system are provided at the end of this monograph. These instructions are also included in each box of Clonidine Transdermal System.

Drug Interactions

Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. If a patient receiving clonidine is also taking tricyclic antidepressants, the hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose.

Monitor heart rate in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction, e.g., digitalis, calcium channel blockers and beta-blockers. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concomitantly with diltiazem or verapamil.

Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats (see PRECAUTIONS: Toxicology).

Toxicology

In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence and severity of spontaneous retinal degeneration was seen in albino rats treated for 6 months or longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in the choroid.

In view of the retinal degeneration seen in rats, eye examinations were performed during clinical trials in 908 patients before, and periodically after, the start of clonidine therapy. In 353 of these 908 patients, the eye examinations were carried out over periods of 24 months or longer. Except for some dryness of the eyes, no drug-related abnormal ophthalmological findings were recorded and, according to specialized tests such as electroretinography and macular dazzle, retinal function was unchanged.

In combination with amitriptyline, clonidine hydrochloride administration led to the development of corneal lesions in rats within 5 days.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Chronic dietary administration of clonidine was not carcinogenic to rats (132 weeks) or mice (78 weeks) dosed, respectively, at up to 46 to 70 times the maximum recommended daily human dose as mg/kg (9 or 6 times the MRDHD on a mg/m2 basis). There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity.

Fertility of male and female rats was unaffected by clonidine doses as high as 150 mcg/kg (approximately 3 times the MRDHD). In a separate experiment, fertility of female rats appeared to be affected at dose levels of 500 to 2000 mcg/kg (10 to 40 times the oral MRDHD on a mg/kg basis; 2 to 8 times the MRDHD on a mg/m2 basis).

Pregnancy

Teratogenic Effects

Pregnancy Category C

Reproduction studies performed in rabbits at doses up to approximately 3 times the oral maximum recommended daily human dose (MRDHD) of clonidine hydrochloride produced no evidence of a teratogenic or embryotoxic potential in rabbits. In rats, however, doses as low as 1/3 the oral MRDHD (1/15 the MRDHD on a mg/m2 basis) of clonidine were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the oral MRDHD) when the dams were treated on gestation days 6 to 15. Increases in resorption were observed at much higher dose levels (40 times the oral MRDHD on a mg/kg basis; 4 to 8 times the MRDHD on a mg/m2 basis) in mice and rats treated on gestation days 1 to 14 (lowest dose employed in the study was 500 mcg/kg).

No adequate well controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

As clonidine is excreted in human milk, caution should be exercised when Clonidine Transdermal System is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established in adequate and well controlled trials (see WARNINGS: Withdrawal).

Adverse Reactions

Clinical trial experience with Clonidine Transdermal System

Most systemic adverse effects during Clonidine Transdermal System therapy have been mild and have tended to diminish with continued therapy. In a 3-month multiclinic trial of Clonidine Transdermal System in 101 hypertensive patients, the systemic adverse reactions were, dry mouth (25 patients) and drowsiness (12), fatigue (6), headache (5), lethargy and sedation (3 each), insomnia, dizziness, impotence/sexual dysfunction, dry throat (2 each) and constipation, nausea, change in taste and nervousness (1 each).

In the above mentioned 3-month controlled clinical trial, as well as other uncontrolled clinical trials, the most frequent adverse reactions were dermatological and are described below.

In the 3-month trial, 51 of the 101 patients had localized skin reactions such as erythema (26 patients) and/or pruritus, particularly after using an adhesive cover throughout the 7-day dosage interval. Allergic contact sensitization to Clonidine Transdermal System was observed in 5 patients. Other skin reactions were localized vesiculation (7 patients), hyperpigmentation (5), edema (3), excoriation (3), burning (3), papules (1), throbbing (1), blanching (1), and a generalized macular rash (1).

In additional clinical experience, contact dermatitis resulting in treatment discontinuation was observed in 128 of 673 patients (about 19 in 100) after a mean duration of treatment of 37 weeks. The incidence of contact dermatitis was about 34 in 100 among white women, about 18 in 100 in white men, about 14 in 100 in black women, and approximately 8 in 100 in black men. Analysis of skin reaction data showed that the risk of having to discontinue Clonidine Transdermal System treatment because of contact dermatitis was greatest between treatment weeks 6 and 26, although sensitivity may develop either earlier or later in treatment.

In a large-scale clinical acceptability and safety study by 451 physicians in a total of 3,539 patients, other allergic reactions were recorded for which a causal relationship to Clonidine Transdermal System was not established: maculopapular rash (10 cases); urticaria (2 cases); and angioedema of the face (2 cases), which also affected the tongue in one of the patients.

Marketing Experience with Clonidine Transdermal System

The following adverse reactions have been identified during post-approval use of Clonidine Transdermal System. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Clonidine Transdermal System.

Body as a Whole: Fever; malaise; weakness; pallor; and withdrawal syndrome.

Cardiovascular: Congestive heart failure; cerebrovascular accident; electrocardiographic abnormalities (i.e., bradycardia, sick sinus syndrome disturbances and arrhythmias); chest pain; orthostatic symptoms; syncope; increases in blood pressure; sinus bradycardia and atrioventricular (AV) block with and without the use of concomitant digitalis; Raynaud’s phenomenon; tachycardia; bradycardia; and palpitations.

Central and Peripheral Nervous System/Psychiatric: Delirium; mental depression; hallucinations (including visual and auditory); localized numbness; vivid dreams or nightmares; restlessness; anxiety; agitation; irritability; other behavioral changes; and drowsiness.

Dermatological: Angioneurotic edema; localized or generalized rash; hives; urticaria; contact dermatitis; pruritus; alopecia; and localized hypo or hyper pigmentation.

Gastrointestinal: Anorexia and vomiting.

Genitourinary: Difficult micturition; loss of libido; and decreased sexual activity.

Metabolic: Gynecomastia or breast enlargement and weight gain.

Musculoskeletal: Muscle or joint pain; and leg cramps.

Ophthalmological: Blurred vision; burning of the eyes and dryness of the eyes.

Adverse Events Associated with Oral Clonidine Therapy

Most adverse effects are mild and tend to diminish with continued therapy. The most frequent (which appear to be dose-related) are dry mouth, occurring in about 40 of 100 patients; drowsiness, about 33 in 100; dizziness, about 16 in 100; constipation and sedation, each about 10 in 100. The following less frequent adverse experiences have also been reported in patients receiving clonidine hydrochloride, USP tablets, but in many cases patients were receiving concomitant medication and a causal relationship has not been established.

Body as a Whole: Fatigue, fever, headache, pallor, weakness, and withdrawal syndrome. Also reported were a weakly positive Coombs’ test and increased sensitivity to alcohol.

Cardiovascular: Bradycardia, congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block and arrhythmias), orthostatic symptoms, palpitations, Raynaud’s phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and AV block have been reported, both with and without the use of concomitant digitalis.

Central Nervous System: Agitation, anxiety, delirium, delusional perception, hallucinations (including visual and auditory), insomnia, mental depression, nervousness, other behavioral changes, paresthesia, restlessness, sleep disorder, and vivid dreams or nightmares.

Dermatological: Alopecia, angioneurotic edema, hives, pruritus, rash, and urticaria.

Gastrointestinal: Abdominal pain, anorexia, constipation, hepatitis, malaise, mild transient abnormalities in liver function tests, nausea, parotitis, pseudo-obstruction (including colonic pseudo-obstruction), salivary gland pain, and vomiting.

Genitourinary: Decreased sexual activity, difficulty in micturition, erectile dysfunction, loss of libido, nocturia, and urinary retention.

Hematologic: Thrombocytopenia.

Metabolic: Gynecomastia, transient elevation of blood glucose or serum creatine phosphokinase, and weight gain.

Musculoskeletal: Leg cramps and muscle or joint pain.

Oro-otolaryngeal: Dryness of the nasal mucosa.

Ophthalmological: Accommodation disorder, blurred vision, burning of the eyes, decreased lacrimation, and dryness of the eyes.

Overdosage

Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to 2 hours after exposure. As little as 0.1 mg of clonidine has produced signs of toxicity in children.

If symptoms of poisoning occur following dermal exposure, remove all Clonidine Transdermal Systems. After their removal, the plasma clonidine levels will persist for about 8 hours, then decline slowly over a period of several days. Rare cases of Clonidine Transdermal System poisoning due to accidental or deliberate mouthing or ingestion of the patch have been reported, many of them involving children.

There is no specific antidote for clonidine overdosage. Ipecac syrup-induced vomiting and gastric lavage would not be expected to remove significant amounts of clonidine following dermal exposure. If the patch is ingested, whole bowel irrigation may be considered and the administration of activated charcoal and/or cathartic may be beneficial. Supportive care may include atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for hypotension and vasodilators for hypertension. Naloxone may be a useful adjunct for the management of clonidine-induced respiratory depression, hypotension and/or coma; blood pressure should be monitored since the administration of naloxone has occasionally resulted in paradoxical hypertension. Tolazoline administration has yielded inconsistent results and is not recommended as first-line therapy. Dialysis is not likely to significantly enhance the elimination of clonidine.

The largest overdose reported to date, involved a 28-year old male who ingested 100 mg of clonidine hydrochloride powder. This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment. Plasma clonidine levels were 60 ng/mL after 1 hour, 190 ng/mL after 1.5 hours, 370 ng/mL after 2 hours, and 120 ng/mL after 5.5 and 6.5 hours. In mice and rats, the oral LD50 of clonidine is 206 and 465 mg/kg, respectively.

Clonidine Patch Dosage and Administration

Apply Clonidine Transdermal System once every 7 days to a hairless area of intact skin on the upper outer arm or chest. Each new application of Clonidine Transdermal System should be on a different skin site from the previous location. If the system loosens during 7-day wearing, the adhesive cover should be applied directly over the system to ensure good adhesion. There have been rare reports of the need for patch changes prior to 7 days to maintain blood pressure control.

To initiate therapy, Clonidine Transdermal System dosage should be titrated according to individual therapeutic requirements, starting with Clonidine Transdermal System 0.1 mg/day. If after one or two weeks the desired reduction in blood pressure is not achieved, increase the dosage by adding another Clonidine Transdermal System, 0.1 mg/day or changing to a larger system. An increase in dosage above two Clonidine Transdermal System 0.3 mg/day is usually not associated with additional efficacy.

When substituting Clonidine Transdermal System for oral clonidine or for other antihypertensive drugs, physicians should be aware that the antihypertensive effect of Clonidine Transdermal System may not commence until 2 to 3 days after initial application. Therefore, gradual reduction of prior drug dosage is advised. Some or all previous antihypertensive treatment may have to be continued, particularly in patients with more severe forms of hypertension.

Renal Impairment

Dosage must be adjusted according to the degree of impairment, and patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.

How is Clonidine Patch Supplied

Clonidine Transdermal System, USP, 0.1 mg/day, Clonidine Transdermal System, USP, 0.2 mg/day and Clonidine Transdermal System, USP, 0.3 mg/day are supplied as 4 pouched systems and 4 adhesive covers per carton. See chart below.

	Programmed Delivery Clonidine in vivo Per Day Over 1 Week	Clonidine Content	Size
Clonidine Transdermal System, USP NDC 0378-0871-99	0.1 mg	2.52 mg	3.33 cm2
Clonidine Transdermal System, USP NDC 0378-0872-99	0.2 mg	5.04 mg	6.67 cm2
Clonidine Transdermal System, USP NDC 0378-0873-99	0.3 mg	7.56 mg	10.0 cm2

STORAGE AND HANDLING

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Address medical inquiries to: 1-877-446-3679 (1-877-4-INFO-RX)

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

REVISED JULY 2011

CTS:R11

PATIENT INSTRUCTIONS

Clonidine Transdermal System, USP

(Read the following instructions carefully before using this medication. If you have any questions, please consult with your doctor.)

General Information

Clonidine Transdermal System is a peach colored, rectangular patch with rounded corners, containing an active blood-pressure-lowering medication. It is designed to deliver the drug into the body through the skin smoothly and consistently for one full week. Normal exposure to water, as in showering, bathing, and swimming, should not affect the patch.

The optional ivory adhesive cover should be applied directly over the patch, should the patch begin to separate from the skin. The adhesive cover ensures that the patch sticks to the skin. The Clonidine Transdermal System patch must be replaced with a new one on a fresh skin site if the one in use significantly loosens or falls off.

Figure 1

How to Apply the Clonidine Transdermal System patch

1) Apply the peach colored, rectangular patch with rounded corners, once a week, preferably at a convenient time on the same day of the week (i.e., prior to bedtime on Tuesday of week one; prior to bedtime on Tuesday of week two, etc.).

Each box of Clonidine Transdermal System contains two types of pouches:

Figure 2

2) Select a hairless area such as on the upper, outer arm or upper chest. The area chosen should be free of cuts, abrasions, irritation, scars or calluses and should not be shaved before applying the Clonidine Transdermal System patch. Do not place the Clonidine Transdermal System patch on skin folds or under tight undergarments, since premature loosening may occur.

3) Wash hands with soap and water and thoroughly dry them.

4) Clean the area chosen with soap and water. Rinse and wipe dry with a clean, dry tissue.

5) Select the pouch labeled Clonidine Transdermal System, USP and open it as illustrated in Figure 3. Remove the contents of the pouch and discard the additional pieces of clear protective film above and below the patch.

Figure 3

6) Remove the clear plastic protective backing from the peach colored, rectangular patch by gently peeling off one half of the backing at a time as shown in Figure 4. Avoid touching the sticky side of the Clonidine Transdermal System patch.

Figure 4

7) Place the Clonidine Transdermal System patch on the prepared skin site (sticky side down) by applying firm pressure over the patch to ensure good contact with the skin, especially around the edges (Figure 5). Discard the clear plastic protective backing and wash your hands with soap and water to remove any drug from your hands.

Figure 5

8) After one week, remove the old patch and discard it (refer to Instructions for Disposal). After choosing a different skin site, repeat instructions 2 through 7 for the application of your next Clonidine Transdermal System patch.

What to do if your Clonidine Transdermal System patch becomes loose while wearing:

How to Apply the adhesive cover

NOTE: The ivory adhesive cover does not contain any drug and should not be used alone. The cover should be applied directly over the Clonidine Transdermal System patch only if the patch begins to separate from the skin, thereby ensuring that it sticks to the skin for 7 full days.

1) Wash hands with soap and water and thoroughly dry them.

2) Using a clean, dry tissue, make sure that the area around the rectangular, peach Clonidine Transdermal System patch is clean and dry. Press gently on the Clonidine Transdermal System patch to ensure that the edges are in good contact with the skin.

3) Take the ivory adhesive cover (Figure 6) from the plain white pouch and remove the paper liner backing from the cover.

Figure 6

4) Carefully center the ivory adhesive cover over the rectangular, peach Clonidine Transdermal System patch and apply firm pressure, especially around the edges in contact with the skin.

Instructions for Disposal

KEEP OUT OF REACH OF CHILDREN

During or even after use, a patch contains active medication which may be harmful to infants and children if accidentally applied or ingested. After use, fold in half with the sticky sides together. Dispose of carefully out of reach of children.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

REVISED JULY 2011

PL:CTS:R9

PRINCIPAL DISPLAY PANEL - 0.1 mg/day

Contents:

4 Systems and

4 Adhesive Covers

NDC 0378-0871-99

Rx only

Clonidine

Transdermal System, USP

0.1 mg/day

 Programmed delivery in vivo of 0.1 mg

clonidine per day for one week.

Each system contains 2.52 mg of

clonidine. The inactive components

are mineral oil, polyisobutylene,

colloidal silicon dioxide, pigmented

polyethylene/polyester film, and

silicone/polyester film.

FOR TRANSDERMAL USE ONLY.

Keep this and all drugs

out of the reach of children.

See package insert for dosage information.

Store at 20° to 25°C (68° to 77°F). [See

USP Controlled Room Temperature.]

www.mylan.com

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

M0871-99-4C:R9

PRINCIPAL DISPLAY PANEL - 0.2 mg/day

Contents:

4 Systems and

4 Adhesive Covers

NDC 0378-0872-99

Rx only

Clonidine

Transdermal System, USP

0.2 mg/day

 Programmed delivery in vivo of 0.2 mg

clonidine per day for one week.

Each system contains 5.04 mg of

clonidine. The inactive components

are mineral oil, polyisobutylene,

colloidal silicon dioxide, pigmented

polyethylene/polyester film, and

silicone/polyester film.

FOR TRANSDERMAL USE ONLY.

Keep this and all drugs

out of the reach of children.

See package insert for dosage information.

Store at 20° to 25°C (68° to 77°F). [See

USP Controlled Room Temperature.]

www.mylan.com

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

M0872-99-4C:R9

PRINCIPAL DISPLAY PANEL - 0.3 mg/day

Contents:

4 Systems and

4 Adhesive Covers

NDC 0378-0873-99

Rx only

Clonidine

Transdermal System, USP

0.3 mg/day

 Programmed delivery in vivo of 0.3 mg

clonidine per day for one week.

Each system contains 7.56 mg of

clonidine. The inactive components

are mineral oil, polyisobutylene,

colloidal silicon dioxide, pigmented

polyethylene/polyester film, and

silicone/polyester film.

FOR TRANSDERMAL USE ONLY.

Keep this and all drugs

out of the reach of children.

See package insert for dosage information.

Store at 20° to 25°C (68° to 77°F). [See

USP Controlled Room Temperature.]

www.mylan.com

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

M0873-99-4C:R9

CLONIDINE  clonidine  patch

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0378-0871 Route of Administration TRANSDERMAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLONIDINE (CLONIDINE) CLONIDINE 0.1 mg  in 1 d

Inactive Ingredients Ingredient Name Strength MINERAL OIL   SILICON DIOXIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0378-0871-99 4  In 1 CARTON contains a POUCH (0378-0871-16) 1 0378-0871-16 1  In 1 POUCH This package is contained within the CARTON (0378-0871-99) and contains a PATCH 1 7 d In 1 PATCH This package is contained within a POUCH (0378-0871-16) and a CARTON (0378-0871-99)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA076166	01/09/2012

CLONIDINE  clonidine  patch

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0378-0872 Route of Administration TRANSDERMAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLONIDINE (CLONIDINE) CLONIDINE 0.2 mg  in 1 d

Inactive Ingredients Ingredient Name Strength MINERAL OIL   SILICON DIOXIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0378-0872-99 4  In 1 CARTON contains a POUCH (0378-0872-16) 1 0378-0872-16 1  In 1 POUCH This package is contained within the CARTON (0378-0872-99) and contains a PATCH 1 7 d In 1 PATCH This package is contained within a POUCH (0378-0872-16) and a CARTON (0378-0872-99)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA076166	01/09/2012

CLONIDINE  clonidine  patch

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0378-0873 Route of Administration TRANSDERMAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLONIDINE (CLONIDINE) CLONIDINE 0.3 mg  in 1 d

Inactive Ingredients Ingredient Name Strength MINERAL OIL   SILICON DIOXIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0378-0873-99 4  In 1 CARTON contains a POUCH (0378-0873-16) 1 0378-0873-16 1  In 1 POUCH This package is contained within the CARTON (0378-0873-99) and contains a PATCH 1

Chlorpheniramine Controlled-Release Capsules

Pronunciation: klor-fen-IHR-ah-meen
Generic Name: Chlorpheniramine
Brand Name: Generic only. No brands available.

Chlorpheniramine Controlled-Release Capsules are used for:

Relieving symptoms of sinus congestion, sinus pressure, runny nose, watery eyes, itching of the nose and throat, and sneezing due to upper respiratory infections (eg, colds), allergies, and hay fever. It may also be used for other conditions as determined by your doctor.

Chlorpheniramine Controlled-Release Capsules are an antihistamine. It works by blocking the action of histamine, which helps reduce symptoms such as watery eyes and sneezing.

Do NOT use Chlorpheniramine Controlled-Release Capsules if:

• you are allergic to any ingredient in Chlorpheniramine Controlled-Release Capsules


• you take sodium oxybate (GHB) or if you have taken furazolidone or a monoamine oxidase (MAO) inhibitor (eg, phenelzine) within the last 14 days

Contact your doctor or health care provider right away if any of these apply to you.

Before using Chlorpheniramine Controlled-Release Capsules:

Some medical conditions may interact with Chlorpheniramine Controlled-Release Capsules. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, plan to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a fast, slow, or irregular heartbeat


• if you have a history of asthma, lung problems (eg, emphysema), heart problems, high blood pressure, diabetes, heart blood vessel problems, stroke, glaucoma, a blockage of your stomach or intestines, ulcers, a blockage of your bladder, trouble urinating, an enlarged prostate, seizures, or an overactive thyroid

Some MEDICINES MAY INTERACT with Chlorpheniramine Controlled-Release Capsules. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Furazolidone, MAO inhibitors (eg, phenelzine), sodium oxybate (GHB), or tricyclic antidepressants (eg, amitriptyline) because side effects of Chlorpheniramine Controlled-Release Capsules may be increased


• Hydantoins (eg, phenytoin) because side effects may be increased by Chlorpheniramine Controlled-Release Capsules

This may not be a complete list of all interactions that may occur. Ask your health care provider if Chlorpheniramine Controlled-Release Capsules may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Chlorpheniramine Controlled-Release Capsules:

Use Chlorpheniramine Controlled-Release Capsules as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Chlorpheniramine Controlled-Release Capsules may be taken with or without food.


• Swallow Chlorpheniramine Controlled-Release Capsules whole. Do not break, crush, or chew before swallowing.


• If you miss a dose of Chlorpheniramine Controlled-Release Capsules, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Chlorpheniramine Controlled-Release Capsules.

Important safety information:

• Chlorpheniramine Controlled-Release Capsules may cause dizziness, drowsiness, or blurred vision. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to Chlorpheniramine Controlled-Release Capsules. Using Chlorpheniramine Controlled-Release Capsules alone, with certain other medicines, or with alcohol may lessen your ability to drive or perform other potentially dangerous tasks.


• Do NOT exceed the recommended dose or take Chlorpheniramine Controlled-Release Capsules for longer than prescribed without checking with your doctor.


• If your symptoms do not improve within 5 to 7 days or if they become worse, check with your doctor.


• Chlorpheniramine Controlled-Release Capsules may cause increased sensitivity to the sun. Avoid exposure to the sun, sunlamps, or tanning booths until you know how you react to Chlorpheniramine Controlled-Release Capsules. Use a sunscreen or protective clothing if you must be outside for a prolonged period.


• If you are scheduled for allergy skin testing, do not take Chlorpheniramine Controlled-Release Capsules for several days before the test because it may decrease your response to the skin tests.


• Before you have any medical or dental treatments, emergency care, or surgery, tell the doctor or dentist that you are using Chlorpheniramine Controlled-Release Capsules.


• Use Chlorpheniramine Controlled-Release Capsules with caution in the ELDERLY because they may be more sensitive to its effects.


• Caution is advised when using Chlorpheniramine Controlled-Release Capsules in CHILDREN because they may be more sensitive to its effects.


• PREGNANCY and BREAST-FEEDING: If you become pregnant while taking Chlorpheniramine Controlled-Release Capsules, discuss with your doctor the benefits and risks of using Chlorpheniramine Controlled-Release Capsules during pregnancy. It is unknown if Chlorpheniramine Controlled-Release Capsules are excreted in breast milk. Do not breast-feed while taking Chlorpheniramine Controlled-Release Capsules.

Possible side effects of Chlorpheniramine Controlled-Release Capsules:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; diarrhea; dizziness; drowsiness; dry mouth, nose, or throat; excitability; headache; loss of appetite; nausea; nervousness or anxiety; trouble sleeping; upset stomach; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); difficulty urinating or inability to urinate; fast or irregular heartbeat; hallucinations; seizures; severe dizziness, lightheadedness, or headache; tremor; trouble sleeping; vision changes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Chlorpheniramine side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include blurred vision; confusion; hallucinations; seizures; severe dizziness, lightheadedness, or headache; severe drowsiness; unusually fast, slow, or irregular heartbeat; vomiting.

Proper storage of Chlorpheniramine Controlled-Release Capsules:

Store Chlorpheniramine Controlled-Release Capsules at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Chlorpheniramine Controlled-Release Capsules out of the reach of children and away from pets.

General information:

• If you have any questions about Chlorpheniramine Controlled-Release Capsules, please talk with your doctor, pharmacist, or other health care provider.


• Chlorpheniramine Controlled-Release Capsules are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Chlorpheniramine Controlled-Release Capsules. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Chlorpheniramine resources

• Chlorpheniramine Side Effects (in more detail)
• Chlorpheniramine Use in Pregnancy & Breastfeeding
• Drug Images
• Chlorpheniramine Drug Interactions
• Chlorpheniramine Support Group
• 18 Reviews for Chlorpheniramine - Add your own review/rating

Compare Chlorpheniramine with other medications

• Allergic Reactions
• Cold Symptoms
• Hay Fever
• Urticaria

Vandazole

Generic Name: metronidazole (Vaginal route)

met-roe-NYE-da-zole

Commonly used brand name(s)

In the U.S.

• Metrogel-Vaginal


• Vandazole

In Canada

• Flagyl


• Neo-Metric


• Nidagel

Available Dosage Forms:

• Suppository


• Gel/Jelly


• Cream

Therapeutic Class: Antibacterial

Chemical Class: Nitroimidazole

Uses For Vandazole

Metronidazole vaginal is used to treat women with vaginal infections (e.g., bacterial vaginosis).

Metronidazole belongs to the class of medicines known as antibiotics. It works by killing the bacteria or preventing their growth. However, this medicine will not work for vaginal fungus or yeast infections.

This medicine is available only with your doctor's prescription.

Before Using Vandazole

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

In deciding whether to use a medicine, the risks of using the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For vaginal metronidazole, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies on the relationship of age to the effects of metronidazole vaginal gel have not been performed in the pediatric population. However, pediatric-specific problems that would limit the usefulness of this medication in teenagers are not expected. This medicine may be used for bacterial vaginosis in teenage females but should not be used before the start of menstruation.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of metronidazole vaginal gel in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amprenavir


• Disulfiram

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amiodarone


• Busulfan


• Fluorouracil


• Mycophenolate Mofetil


• Warfarin

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Carbamazepine


• Cholestyramine


• Cyclosporine


• Lithium


• Milk Thistle


• Tacrolimus

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is not recommended. Your doctor may decide not to treat you with this medication, change some of the other medicines you take, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Aseptic meningitis, history of or


• Encephalopathy (brain disorder), history of or


• Leukopenia (low white blood cells), history of or


• Optic neuropathy (eye disease with vision changes), history of or


• Peripheral neuropathy (nerve disease with pain, numbness, or tingling), history of or


• Seizures or epilepsy, history of—Use with caution. May make these conditions worse.

• Liver disease, severe—Patients with severe liver disease may have an increase in side effects.

Proper Use of metronidazole

This section provides information on the proper use of a number of products that contain metronidazole. It may not be specific to Vandazole. Please read with care.

Use this medicine exactly as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.

This medicine is to be used only in the vagina. Use it at bedtime, unless your doctor tells you otherwise.

Do not get it in your eyes, nose, mouth, or skin. If this medicine does get into your eyes, wash them out right away with large amounts of cool tap water. If your eyes still burn or are painful, check with your doctor.

This medicine usually come with patient directions. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Wash your hands with soap and water before and after using this medicine.

Metronidazole vaginal gel is in a tube. You will use an applicator to put the gel into your vagina. The applicator has a plastic tube called a barrel that is open at one end and has a plunger (another piece of plastic that can move inside the barrel) at the other end.

• To fill the applicator:
  
  • For cream or gel dosage forms:
    
    • Break the metal seal at the opening of the tube by using the point on the top of the cap.
    
    
    • Screw the applicator onto the tube.
    
    
    • Squeeze the medicine into the applicator slowly until it is full.
    
    
    • Remove the applicator from the tube. Replace the cap on the tube.
    
    
  
  
  • For vaginal tablet dosage form:
    
    • Place the vaginal tablet into the applicator. Wet the vaginal tablet with water for a few seconds.
    
    
  
  


• To insert vaginal metronidazole using the applicator
  
  • For all dosage forms:
    
    • Relax while lying on your back with your knees bent (or in any position that you feel comfortable).
    
    
    • Hold the full applicator in one hand. Insert it slowly into the vagina. Stop before it becomes uncomfortable.
    
    
    • Slowly press the plunger until it stops.
    
    
    • Withdraw the applicator. The medicine will be left behind in the vagina.
    
    
    • Remove the applicator from your vagina. Use each applicator only once, and then throw it away.
    
    
  
  

To help clear up your infection completely, it is very important that you keep using this medicine for the full time of treatment, even if your symptoms begin to clear up after a few days. If you stop using this medicine too soon, your symptoms may return. Do not miss any doses. Also, continue using this medicine even if your menstrual period starts during the time of treatment.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For bacterial vaginal infections:
  
  • For vaginal dosage form (cream):
    
    • Adults and teenagers—One applicatorful (500 milligrams [mg]), inserted into the vagina. Use the medicine one or two times a day for 10 or 20 days.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For vaginal dosage form (gel):
    
    • Adults and teenagers—One applicatorful (5000 milligrams [mg]) inserted into the vagina once a day (at bedtime) for 5 days. Each applicatorful contains 37.5 mg of metronidazole.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For vaginal dosage form (tablets):
    
    • Adults and teenagers—One 500 milligram (mg) tablet, inserted high into the vagina. Use the medicine once a day in the evening for 10 or 20 days.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Vandazole

It is important that your doctor check your progress after you finish using this medicine. This is to make sure that the infection is cleared up.

If your symptoms do not improve within a few days after you start this medicine or if they become worse, check with your doctor.

You should not use this medicine if you have taken disulfiram (Antabuse®) within the last 2 weeks. Disulfiram is used to help people who have a drinking problem. If these 2 medicines are taken close together, serious unwanted effects may occur.

Drinking alcoholic beverages while using this medicine may cause stomach pain, nausea, vomiting, headache, or flushing or redness of the face. Alcohol-containing medicines (e.g., elixirs, cough syrups, tonics) may also cause problems. The chance of these problems occurring may continue for at least a day after you stop using metronidazole. You should not drink alcoholic beverages or take other alcohol-containing medicines while you are using this medicine and for at least 3 days after stopping it.

Stop using this medicine and check with your doctor right away if you have dizziness, problems with muscle control or coordination, shakiness or an unsteady walk, slurred speech, or trouble with speaking. These may be symptoms of a serious brain condition called encephalopathy.

Stop using this medicine and call your doctor right away if you have confusion, drowsiness, fever, a general feeling of illness, a headache, loss of appetite, nausea, a stiff neck or back, or vomiting. These could be symptoms of a serious condition called aseptic meningitis.

Stop using this medicine and check with your doctor right away if you are having burning, numbness, tingling, or painful sensations in the arms, hands, legs, or feet. These could be symptoms of a condition called peripheral neuropathy.

This medicine may cause some people to become dizzy or lightheaded. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert. If these reactions are especially bothersome, check with your doctor.

Vaginal medicines usually leak out of the vagina during treatment. To keep the medicine from getting on your clothing, wear a mini-pad or sanitary napkin. Do not use tampons (like those used for menstrual periods) since they may soak up the medicine.

To help clear up your infection completely and to help make sure it does not return, good health habits are also required.

• Wear cotton panties (or panties or pantyhose with cotton crotches) instead of synthetic (e.g., nylon or rayon) panties.


• Wear only freshly washed panties daily.

Do not have sexual intercourse while you are using this medicine. Having sexual intercourse may reduce the strength of the medicine. This may keep the medicine from working properly. Also, oils in the cream and vaginal tablets (but not the vaginal gel) may damage latex (rubber) contraceptive devices (e.g., cervical caps, condoms, or diaphragms), causing them to leak, wear out sooner, or not work properly.

Avoid using douches or other vaginal products unless your doctor tells you to.

Many vaginal infections (e.g., trichomoniasis) are spread by having sexual intercourse. You can give the infection to your sexual partner, and the infection could be given back to you. Your partner may also need to be treated for some infections. Until you are sure that the infection is completely cleared up after your treatment with this medicine, your partner should wear a condom during sexual intercourse . If you have any questions about this, check with your doctor.

Before you have any medical tests, tell the medical doctor in charge that you are using this medicine. The results of some tests may be affected by this medicine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Vandazole Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Itching in the vagina


• pain during sexual intercourse


• thick, white vaginal discharge with no odor or with a mild odor

Less common

• Abdominal or stomach cramping or pain


• burning on urination or need to urinate more often


• burning or irritation of penis of sexual partner


• itching, stinging, or redness of the genital area

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Diarrhea


• dizziness or lightheadedness


• dryness of the mouth


• feeling of a furry tongue


• headache


• loss of appetite


• metallic taste or other change in taste sensation


• nausea


• vomiting

Metronidazole may cause your urine to become dark. This is harmless and will go away when you stop using this medicine.

After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

• Any vaginal or genital irritation or itching


• pain during sexual intercourse


• thick, white vaginal discharge not present before treatment, with no odor or with a mild odor

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Vandazole side effects (in more detail)

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More Vandazole resources

• Vandazole Side Effects (in more detail)
• Vandazole Use in Pregnancy & Breastfeeding
• Vandazole Drug Interactions
• Vandazole Support Group
• 2 Reviews for Vandazole - Add your own review/rating

• Vandazole Prescribing Information (FDA)


• Vandazole Concise Consumer Information (Cerner Multum)


• MetroCream Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• MetroCream Concise Consumer Information (Cerner Multum)


• MetroCream Prescribing Information (FDA)


• MetroGel Prescribing Information (FDA)


• Metrocream


• Metrolotion


• Noritate Prescribing Information (FDA)


• Rozex Emulsion MedFacts Consumer Leaflet (Wolters Kluwer)


• Vitazol Prescribing Information (FDA)

Compare Vandazole with other medications

• Bacterial Vaginitis

Stadol

butorphanol tartrate

Dosage Form: Injection, USP and Nasal Spray

CIV

Stadol Description

Butorphanol tartrate is a synthetically derived opioid agonist-antagonist analgesic of the phenanthrene series. The chemical name is (-)-17-(cyclobutylmethyl) morphinan-3, 14-diol [S-(R*,R*)] - 2,3 - dihydroxybutanedioate (1:1) (salt). The molecular formula is C21H29NO2,C4H6O6, which corresponds to a molecular weight of 477.55 and the following structural formula:

Butorphanol tartrate is a white crystalline substance. The dose is expressed as the tartrate salt. One milligram of the salt is equivalent to 0.68 mg of the free base. The n-octanol/aqueous buffer partition coefficient of butorphanol is 180:1 at pH 7.5.

Stadol (butorphanol tartrate) Injection, USP, is a sterile, parenteral, aqueous solution of butorphanol tartrate for intravenous or intramuscular administration. In addition to 1 or 2 mg of butorphanol tartrate, each mL of solution contains 3.3 mg of citric acid, 6.4 mg sodium citrate, and 6.4 mg sodium chloride, and 0.1 mg benzethonium chloride (in multiple dose vial only) as a preservative.

Stadol NS (butorphanol tartrate) Nasal Spray is an aqueous solution of butorphanol tartrate for administration as a metered spray to the nasal mucosa. Each bottle of Stadol NS contains 2.5 mL of a 10 mg/mL solution of butorphanol tartrate with sodium chloride, citric acid, and benzethonium chloride in purified water with sodium hydroxide and/or hydrochloric acid added to adjust the pH to 5.0. The pump reservoir must be fully primed (see PATIENT INSTRUCTIONS) prior to initial use. After initial priming each metered spray delivers an average of 1.0 mg of butorphanol tartrate and the 2.5-mL bottle will deliver an average of 14–15 doses of Stadol NS. If not used for 48 hours or longer, the unit must be reprimed (see PATIENT INSTRUCTIONS). With intermittent use requiring repriming before each dose, the 2.5-mL bottle will deliver an average of 8–10 doses of Stadol NS depending on how much repriming is necessary.

Stadol - Clinical Pharmacology

General Pharmacology and Mechanism of Action

Butorphanol is a mixed agonist-antagonist with low intrinsic activity at receptors of the µ-opioid type (morphine-like). It is also an agonist at κ-opioid receptors.

Its interactions with these receptors in the central nervous system apparently mediate most of its pharmacologic effects, including analgesia.

In addition to analgesia, CNS effects include depression of spontaneous respiratory activity and cough, stimulation of the emetic center, miosis, and sedation. Effects possibly mediated by non-CNS mechanisms include alteration in cardiovascular resistance and capacitance, bronchomotor tone, gastrointestinal secretory and motor activity, and bladder sphincter activity.

In an animal model, the dose of butorphanol tartrate required to antagonize morphine analgesia by 50% was similar to that for nalorphine, less than that for pentazocine and more than that for naloxone.

The pharmacological activity of butorphanol metabolites has not been studied in humans; in animal studies, butorphanol metabolites have demonstrated some analgesic activity.

In human studies of butorphanol (see Clinical Trials), sedation is commonly noted at doses of 0.5 mg or more. Narcosis is produced by 10–12 mg doses of butorphanol administered over 10–15 minutes intravenously.

Butorphanol, like other mixed agonist-antagonists with a high affinity for the κ-receptor, may produce unpleasant psychotomimetic effects in some individuals.

Nausea and/or vomiting may be produced by doses of 1 mg or more administered by any route.

In human studies involving individuals without significant respiratory dysfunction, 2 mg of butorphanol IV and 10 mg of morphine sulfate IV depressed respiration to a comparable degree. At higher doses, the magnitude of respiratory depression with butorphanol is not appreciably increased; however, the duration of respiratory depression is longer. Respiratory depression noted after administration of butorphanol to humans by any route is reversed by treatment with naloxone, a specific opioid antagonist (see OVERDOSAGE: Treatment).

Butorphanol tartrate demonstrates antitussive effects in animals at doses less than those required for analgesia.

Hemodynamic changes noted during cardiac catheterization in patients receiving single 0.025 mg/kg intravenous doses of butorphanol have included increases in pulmonary artery pressure, wedge pressure and vascular resistance, increases in left ventricular end diastolic pressure, and in systemic arterial pressure.

Pharmacodynamics

The analgesic effect of butorphanol is influenced by the route of administration. Onset of analgesia is within a few minutes for intravenous administration, within 15 minutes for intramuscular injection, and within 15 minutes for the nasal spray doses.

Peak analgesic activity occurs within 30–60 minutes following intravenous and intramuscular administration and within 1–2 hours following the nasal spray administration.

The duration of analgesia varies depending on the pain model as well as the route of administration, but is generally 3–4 hours with IM and IV doses as defined by the time 50% of patients required remedication. In postoperative studies, the duration of analgesia with IV or IM butorphanol was similar to morphine, meperidine, and pentazocine when administered in the same fashion at equipotent doses (see Clinical Trials). Compared to the injectable form and other drugs in this class, Stadol NS has a longer duration of action (4–5 hours) (see Clinical Trials).

Pharmacokinetics

Stadol Injection is rapidly absorbed after IM injection and peak plasma levels are reached in 20–40 minutes.

After nasal administration, mean peak blood levels of 0.9–1.04 ng/mL occur at 30–60 minutes after a 1 mg dose (see Table 1). The absolute bioavailability of Stadol NS is 60–70% and is unchanged in patients with allergic rhinitis. In patients using a nasal vasoconstrictor (oxymetazoline) the fraction of the dose absorbed was unchanged, but the rate of absorption was slowed. The peak plasma concentrations were approximately half those achieved in the absence of the vasoconstrictor.

Following its initial absorption/distribution phase, the single dose pharmacokinetics of butorphanol by the intravenous, intramuscular, and nasal routes of administration are similar (see Figure 1).

Figure 1—Butorphanol Plasma Levels After IV, IM, and Nasal Spray Administration of 2-mg Dose

Serum protein binding is independent of concentration over the range achieved in clinical practice (up to 7 ng/mL) with a bound fraction of approximately 80%.

The volume of distribution of butorphanol varies from 305–901 liters and total body clearance from 52–154 liters/hour (see Table 1).

(a) Young subjects (n=24) are from 20 to 40 years old and elderly (n=24) are greater than 65 years of age.
(b) Time to peak plasma concentration.
(c) Peak plasma concentration normalized to 1-mg dose.
(d) Area under the plasma concentration-time curve after a 1-mg dose.
(e) Mean (1 S.D.)
(f) Derived from IV data.
(g) (range of observed values)
Table 1:	Mean Pharmacokinetic Parameters of Butorphanol in Young and Elderly Subjectsa
	Intravenous		Nasal
Parameters	Young	Elderly	Young	Elderly
Tmaxb (h)			0.62 (0.32)e (0.15-1.50)g	1.03 (0.74) (0.25-3.00)
Cmaxc (ng/mL)			1.04 (0.40) (0.35-1.97)	0.90 (0.57) (0.10-2.68)
AUC (inf)d (h•ng/mL)	7.24 (1.57) (4.40-9.77)	8.71 (2.02) (4.76-13.03)	4.93 (1.24) (2.16-7.27)	5.24 (2.27) (0.30-10.34)
Half-life (h)	4.56 (1.67) (2.06-8.70)	5.61 (1.36) (3.25-8.79)	4.74 (1.57) (2.89-8.79)	6.56 (1.51) (3.75-9.17)
Absolute Bioavailability (%)			69 (16) (44-13)	61 (25) (3-121)
Volume of Distributionf (L)	487 (155) (305-901)	552 (124) (305-737)
Total Body Clearance (L/h)	99 (23) (70-154)	82 (21) (52-143)

Dose proportionality for Stadol NS has been determined at steady state in doses up to 4 mg at 6 hour intervals. Steady state is achieved within 2 days. The mean peak plasma concentration at steady state was 1.8-fold (maximal 3-fold) following a single dose.

The drug is transported across the blood brain and placental barriers and into human milk (see PRECAUTIONS: Labor and Delivery and Nursing Mothers).

Butorphanol is extensively metabolized in the liver. Metabolism is qualitatively and quantitatively similar following intravenous, intramuscular, or nasal administration. Oral bioavailability is only 5–17% because of extensive first pass metabolism of butorphanol.

The major metabolite of butorphanol is hydroxybutorphanol, while norbutorphanol is produced in small amounts. Both have been detected in plasma following administration of butorphanol, with norbutorphanol present at trace levels at most time points. The elimination half-life of hydroxybutorphanol is about 18 hours and, as a consequence, considerable accumulation (~5-fold) occurs when butorphanol is dosed to steady state (1 mg transnasally q6h for 5 days).

Elimination occurs by urine and fecal excretion. When 3H labelled butorphanol is administered to normal subjects, most (70–80%) of the dose is recovered in the urine, while approximately 15% is recovered in the feces.

About 5% of the dose is recovered in the urine as butorphanol. Forty-nine percent is eliminated in the urine as hydroxybutorphanol. Less than 5% is excreted in the urine as norbutorphanol.

Butorphanol pharmacokinetics in the elderly differ from younger patients (see Table 1). The mean absolute bioavailability of Stadol NS in elderly women (48%) was less than that in elderly men (75%), young men (68%), or young women (70%). Elimination half-life is increased in the elderly (6.6 hours as opposed to 4.7 hours in younger subjects).

In renally impaired patients with creatinine clearances <30 mL/min, the elimination half-life was approximately doubled and the total body clearance was approximately one half (10.5 hours [clearance 150 L/h] compared to 5.8 hours [clearance 260 L/h] in healthy subjects). No effect on Cmax or Tmax was observed after a single dose.

After intravenous administration to patients with hepatic impairment, the elimination half-life of butorphanol was approximately tripled and total body clearance was approximately one half (half-life 16.8 hours, clearance 92 L/h) compared to healthy subjects (half-life 4.8 hours, clearance 175 L/h). The exposure of hepatically impaired patients to butorphanol was significantly greater (about 2-fold) than that in healthy subjects. Similar results were seen after nasal administration. No effect on Cmax or Tmax was observed after a single intranasal dose.

For further recommendations refer to PRECAUTIONS: Hepatic and Renal Disease, Drug Interactions, and Geriatric Use and CLINICAL PHARMACOLOGY: Individualization of Dosage.

Clinical Trials

The effectiveness of opioid analgesics varies in different pain syndromes. Studies with Stadol Injection have been performed in postoperative (primarily abdominal and orthopedic) pain and pain during labor and delivery, as preoperative and preanesthetic medication, and as a supplement to balanced anesthesia (see below).

Studies with Stadol NS have been performed in postoperative (general, orthopedic, oral, cesarean section) pain, in postepisiotomy pain, in pain of musculoskeletal origin, and in migraine headache pain (see below).

Use in the Management of Pain

Postoperative pain: The analgesic efficacy of Stadol Injection in postoperative pain was investigated in several double-blind active-controlled studies involving 958 butorphanol-treated patients. The following doses were found to have approximately equivalent analgesic effect: 2 mg butorphanol, 10 mg morphine, 40 mg pentazocine and 80 mg meperidine.

After intravenous administration of Stadol Injection, onset and peak analgesic effect occurred by the time of first observation (30 minutes). After intramuscular administration, pain relief onset occurred at 30 minutes or less, and peak effect occurred between 30 minutes and 1 hour. The duration of action of Stadol Injection was 3–4 hours when defined as the time necessary for pain intensity to return to pretreatment level or the time to retreatment.

The analgesic efficacy of Stadol NS was evaluated (approximately 35 patients per treatment group) in a general and orthopedic surgery trial. Single doses of Stadol NS (1 or 2 mg) and IM meperidine (37.5 or 75 mg) were compared. Analgesia provided by 1 and 2 mg doses of Stadol NS was similar to 37.5 and 75 mg meperidine, respectively, with onset of analgesia within 15 minutes and peak analgesic effect within 1 hour. The median duration of pain relief was 2.5 hours with 1 mg Stadol NS, 3.5 hours with 2 mg Stadol NS and 3.3 hours with either dose of meperidine.

In a postcesarean section trial, Stadol NS administered to 35 patients as two 1-mg doses 60 minutes apart was compared with a single 2-mg dose of Stadol NS or a single 2-mg IV dose of Stadol Injection (37 patients each). Onset of analgesia was within 15 minutes for all Stadol regimens. Peak analgesic effects of 2 mg intravenous Stadol Injection and Stadol NS were similar in magnitude. The duration of pain relief provided by both 2-mg Stadol NS regimens was approximately 4.5 hours and was greater than intravenous Stadol Injection (2.6 hours).

Migraine headache pain: The analgesic efficacy of two 1-mg doses 1 hour apart of Stadol NS in migraine headache pain was compared with a single dose of 10 mg IM methadone (31 and 32 patients, respectively). Significant onset of analgesia occurred within 15 minutes for both Stadol NS and IM methadone. Peak analgesic effect occurred at 2 hours for Stadol NS and 1.5 hours for methadone. The median duration of pain relief was 6 hours with Stadol NS and 4 hours with methadone as judged by the time when approximately half of the patients remedicated.

In two other trials in patients with migraine headache pain, a 2-mg initial dose of Stadol NS followed by an additional 1-mg dose 1 hour later (76 patients) was compared with either 75 mg IM meperidine (24 patients) or placebo (72 patients). Onset, peak activity, and duration were similar with both active treatments; however, the incidence of adverse experiences (nausea, vomiting, dizziness) was higher in these two trials with the 2-mg initial dose of Stadol NS than in the trial with the 1-mg initial dose.

Preanesthetic Medication

Stadol Injection (2 mg and 4 mg) and meperidine (80 mg) were studied for use as preanesthetic medication in hospitalized surgical patients. Patients received a single intramuscular dose of either Stadol Injection or meperidine approximately 90 minutes prior to anesthesia. The anesthesia regimen included barbiturate induction, followed by nitrous oxide and oxygen with halothane or enflurane, with or without a muscle relaxant.

Anesthetic preparation was rated as satisfactory in all 42 Stadol Injection patients regardless of the type of surgery.

Balanced Anesthesia

Stadol Injection administered intravenously (mean dose 2 mg) was compared to intravenous morphine sulfate (mean dose 10 mg) as premedication shortly before thiopental induction, followed by balanced anesthesia in 50 ASA Class 1 and 2 patients. Anesthesia was then maintained by repeated intravenous doses, averaging 4.6 mg Stadol Injection and 22.8 mg morphine per patient.

Anesthetic induction and maintenance were generally rated as satisfactory with both Stadol Injection (25 patients) and morphine (25 patients) regardless of the type of surgery performed. Emergence from anesthesia was comparable with both agents.

Labor

(see PRECAUTIONS)

The analgesic efficacy of intravenous Stadol Injection was studied in pain during labor. In a total of 145 patients, Stadol Injection (1 mg and 2 mg) was as effective as 40 mg and 80 mg of meperidine (144 patients) in the relief of pain in labor with no effect on the duration or progress of labor. Both drugs readily crossed the placenta and entered fetal circulation. The condition of the infants in these studies, determined by Apgar scores at 1 and 5 minutes (8 or above) and time to sustained respiration, showed that Stadol Injection had the same effects on the infants as meperidine.

In these studies, neurobehavioral testing in infants exposed to Stadol Injection at a mean of 18.6 hours after delivery showed no significant differences between treatment groups.

Individualization of Dosage

Use of butorphanol in geriatric patients, patients with renal impairment, patients with hepatic impairment, and during labor requires extra caution (see below and the appropriate sections in PRECAUTIONS).

Stadol Injection

For pain relief the recommended initial dosage regimen of Stadol Injection is 1 mg IV or 2 mg IM with repeated doses every 3 to 4 hours, as necessary. This dosage regimen is likely to be effective for the majority of patients. Dosage adjustments of Stadol Injection should be based on observations of its beneficial and adverse effects. The initial dose in the elderly and in patients with renal or hepatic impairment should generally be half the recommended adult dose (0.5 mg IV and 1.0 mg IM). Repeat doses in these patients should be determined by the patient’s response rather than at fixed intervals but will generally be no less than 6 hours (see PRECAUTIONS).

The usual preoperative dose is 2 mg IM given 60–90 minutes before surgery or 2 mg IV shortly before induction. This is approximately equivalent in sedative effect to 10 mg morphine or 80 mg of meperidine. This single preoperative dose should be individualized based on age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and the surgical procedure involved.

During maintenance in balanced anesthesia the usual incremental dose of Stadol Injection is 0.5 to 1.0 mg IV. The incremental dose may be higher, up to 0.06 mg/kg (4 mg/70 kg), depending on previous sedative, analgesic, and hypnotic drugs administered. The total dose of Stadol Injection will vary; however, patients seldom require less than 4 mg or more than 12.5 mg (approximately 0.06 to 0.18 mg/kg).

As with other opioids of this class, Stadol Injection may not provide adequate intraoperative analgesia in every patient or under all conditions. A failure to achieve successful analgesia during balanced anesthesia is commonly reflected by increases in general sympathetic tone. Consequently, if blood pressure or heart rate continues to rise, consideration should be given to adding a potent volatile liquid inhalation anesthetic or another intravenous medication.

In labor, the recommended initial dose of Stadol Injection is 1 or 2 mg IM or IV in mothers with fetuses of 37 weeks gestation or beyond and without signs of fetal distress. Dosage adjustments of Stadol Injection in labor should be based on initial response with consideration given to concomitant analgesic or sedative drugs and the expected time of delivery. A dose should not be repeated in less than 4 hours nor administered less than 4 hours prior to the anticipated delivery (see PRECAUTIONS).

Stadol NS

The usual recommended dose for initial nasal administration is 1 mg (1 spray in one nostril). If adequate pain relief is not achieved within 60–90 minutes, an additional 1-mg dose may be given.

The initial dose sequence outlined above may be repeated in 3–4 hours as required after the second dose of the sequence.

For the management of severe pain, an initial dose of 2 mg (1 spray in each nostril) may be used in patients who will be able to remain recumbent in the event drowsiness or dizziness occurs. In such patients additional doses should not be given for 3-4 hours. The incidence of adverse events is higher with an initial 2-mg dose (see Clinical Trials).

The initial dose sequence in elderly patients and patients with renal or hepatic impairment should be limited to 1 mg followed, if needed, by 1 mg in 90-120 minutes. The repeat dose sequence in these patients should be determined by the patient’s response rather than at fixed times but will generally be no less than at 6-hour intervals (see PRECAUTIONS).

Indications and Usage for Stadol

Stadol (butorphanol tartrate) Injection and Stadol NS (butorphanol tartrate) Nasal Spray are indicated for the management of pain when the use of an opioid analgesic is appropriate.

Stadol Injection is also indicated as a preoperative or preanesthetic medication, as a supplement to balanced anesthesia, and for the relief of pain during labor.

Contraindications

Stadol Injection and Stadol NS are contraindicated in patients hypersensitive to butorphanol tartrate or the preservative benzethonium chloride in Stadol NS or Stadol Injection in the multi-dose vial.

Warnings

Patients Dependent on Narcotics

Because of its opioid antagonist properties, butorphanol is not recommended for use in patients dependent on narcotics. Such patients should have an adequate period of withdrawal from opioid drugs prior to beginning butorphanol therapy. In patients taking opioid analgesics chronically, butorphanol has precipitated withdrawal symptoms such as anxiety, agitation, mood changes, hallucinations, dysphoria, weakness, and diarrhea.

Because of the difficulty in assessing opioid tolerance in patients who have recently received repeated doses of narcotic analgesic medication, caution should be used in the administration of butorphanol to such patients.

Drug Abuse and Dependence

Drug Abuse—Butorphanol tartrate, by all routes of administration, has been associated with episodes of abuse. Of the cases received, there were more reports of abuse with the nasal spray formulation than with the injectable formulation.

Physical Dependence, Tolerance, and Withdrawal—Prolonged, continuous use of butorphanol tartrate may result in physical dependence or tolerance (a decrease in response to a given dose). Abrupt cessation of use by patients with physical dependence may result in symptoms of withdrawal.

Note—Proper patient selection, dose and prescribing limitations, appropriate directions for use, and frequent monitoring are important to minimize the risk of abuse and physical dependence. (See DRUG ABUSE AND DEPENDENCE.)

Precautions

General

Hypotension associated with syncope during the first hour of dosing with Stadol NS has been reported rarely, particularly in patients with past history of similar reactions to opioid analgesics. Therefore, patients should be advised to avoid activities with potential risks.

Head Injury and Increased Intracranial Pressure

As with other opioids, the use of butorphanol in patients with head injury may be associated with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, drug-induced miosis, and alterations in mental state that would obscure the interpretation of the clinical course of patients with head injuries. In such patients, butorphanol should be used only if the benefits of use outweigh the potential risks.

Disorders of Respiratory Function or Control

Butorphanol may produce respiratory depression, especially in patients receiving other CNS active agents, or patients suffering from CNS diseases or respiratory impairment.

Hepatic and Renal Disease

In patients with hepatic or renal impairment, the initial dose of Stadol Injection should generally be half the recommended adult dose (0.5 mg IV and 1.0 mg IM). Repeat doses in these patients should be determined by the patient’s response rather than at fixed intervals but will generally be no less than 6 hours apart. The initial dose sequence of Stadol NS should be limited to 1 mg followed, if needed, by 1 mg in 90–120 minutes. The repeat dose sequence in these patients should be determined by the patient’s response rather than at fixed times but will generally be at intervals of no less than 6 hours (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Individualization of Dosage).

Cardiovascular Effects

Because butorphanol may increase the work of the heart, especially the pulmonary circuit, the use of butorphanol in patients with acute myocardial infarction, ventricular dysfunction, or coronary insufficiency should be limited to those situations where the benefits clearly outweigh the risk (see CLINICAL PHARMACOLOGY).

Severe hypertension has been reported rarely during butorphanol therapy. In such cases, butorphanol should be discontinued and the hypertension treated with antihypertensive drugs. In patients who are not opioid dependent, naloxone has also been reported to be effective.

Use in Ambulatory Patients

1. Opioid analgesics, including butorphanol, impair the mental and physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Effects such as drowsiness or dizziness can appear, usually within the first hour after dosing. These effects may persist for varying periods of time after dosing. Patients who have taken butorphanol should not drive or operate dangerous machinery for at least 1 hour and until the effects of the drug are no longer present.


2. Alcohol should not be consumed while using butorphanol. Concurrent use of butorphanol with drugs that affect the central nervous system (eg, alcohol, barbiturates, tranquilizers, and antihistamines) may result in increased central nervous system depressant effects such as drowsiness, dizziness, and impaired mental function.


3. Butorphanol is one of a class of drugs known to be abused and thus should be handled accordingly (see DRUG ABUSE AND DEPENDENCE).


4. Patients should be instructed on the proper use of Stadol NS (see PATIENT INSTRUCTIONS).

Drug Interactions

Concurrent use of butorphanol with central nervous system depressants (eg, alcohol, barbiturates, tranquilizers, and antihistamines) may result in increased central nervous system depressant effects. When used concurrently with such drugs, the dose of butorphanol should be the smallest effective dose and the frequency of dosing reduced as much as possible when administered concomitantly with drugs that potentiate the action of opioids.

In healthy volunteers, the pharmacokinetics of a 1-mg dose of butorphanol administered as Stadol NS were not affected by the coadministration of a single 6-mg subcutaneous dose of sumatriptan. However, in another study in healthy volunteers, the pharmacokinetics of butorphanol were significantly altered (29% decrease in AUC and 38% decrease in Cmax) when a 1-mg dose of Stadol NS was administered 1 minute after a 20-mg dose of sumatriptan nasal spray. (The two drugs were administered in opposite nostrils.) When the Stadol NS was administered 30 minutes after the sumatriptan nasal spray, the AUC of butorphanol increased 11% and Cmax decreased 18%. In neither case were the pharmacokinetics of sumatriptan affected by coadministration with Stadol NS. These results suggest that the analgesic effect of Stadol NS may be diminished when it is administered shortly after sumatriptan nasal spray, but by 30 minutes any such reduction in effect should be minimal.

The safety of using Stadol NS and IMITREX® (sumatriptan) Nasal Spray during the same episode of migraine has not been established. However, it should be noted that both products are capable of producing transient increases in blood pressure.

The pharmacokinetics of a 1-mg dose of butorphanol administered as Stadol NS were not affected by the coadministration of cimetidine (300 mg QID). Conversely, the administration of Stadol NS (1 mg butorphanol QID) did not alter the pharmacokinetics of a 300-mg dose of cimetidine.

It is not known if the effects of butorphanol are altered by other concomitant medications that affect hepatic metabolism of drugs (erythromycin, theophylline, etc.), but physicians should be alert to the possibility that a smaller initial dose and longer intervals between doses may be needed.

The fraction of Stadol NS absorbed is unaffected by the concomitant administration of a nasal vasoconstrictor (oxymetazoline), but the rate of absorption is decreased. Therefore, a slower onset can be anticipated if Stadol NS is administered concomitantly with, or immediately following, a nasal vasoconstrictor.

No information is available about the use of butorphanol concurrently with MAO inhibitors.

Information for Patients

(see PRECAUTIONS: Use in Ambulatory Patients)

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies were conducted in mice and rats given butorphanol tartrate in the diet up to 60 mg/kg/day (180 mg/m2 for mice and 354 mg/m2 for rats). There was no evidence of carcinogenicity in either species in these studies.

Butorphanol was not genotoxic in S. typhimurium or E. coli assays or in unscheduled DNA synthesis and repair assays conducted in cultured human fibroblast cells.

Rats treated orally with 160 mg/kg/day (944 mg/m2) had a reduced pregnancy rate. However, a similar effect was not observed with a 2.5 mg/kg/day (14.75 mg/m2) subcutaneous dose.

Pregnancy

Pregnancy Category C: Reproduction studies in mice, rats, and rabbits during organogenesis did not reveal any teratogenic potential to butorphanol. However, pregnant rats treated subcutaneously with butorphanol at 1 mg/kg (5.9 mg/m2) had a higher frequency of stillbirths than controls. Butorphanol at 30 mg/kg/oral (360 mg/m2) and 60 mg/kg/oral (720 mg/m2) also showed higher incidences of post-implantation loss in rabbits.

There are no adequate and well-controlled studies of Stadol in pregnant women before 37 weeks of gestation. Stadol should be used during pregnancy only if the potential benefit justifies the potential risk to the infant.

Labor and Delivery

There have been rare reports of infant respiratory distress/apnea following the administration of Stadol Injection during labor. The reports of respiratory distress/apnea have been associated with administration of a dose within 2 hours of delivery, use of multiple doses, use with additional analgesic or sedative drugs, or use in preterm pregnancies (see OVERDOSAGE: Treatment).

In a study of 119 patients, the administration of 1 mg of IV Stadol Injection during labor was associated with transient (10–90 minutes) sinusoidal fetal heart rate patterns, but was not associated with adverse neonatal outcomes. In the presence of an abnormal fetal heart rate pattern, Stadol Injection should be used with caution.

Stadol NS is not recommended during labor or delivery because there is no clinical experience with its use in this setting.

Nursing Mothers

Butorphanol has been detected in milk following administration of Stadol Injection to nursing mothers. The amount an infant would receive is probably clinically insignificant (estimated 4 µg/L of milk in a mother receiving 2 mg IM four times a day).

Although there is no clinical experience with the use of Stadol NS in nursing mothers, it should be assumed that butorphanol will appear in the milk in similar amounts following the nasal route of administration.

Pediatric Use

Butorphanol is not recommended for use in patients below 18 years of age because safety and efficacy have not been established in this population.

Geriatric Use

Of the approximately 1500 patients treated with Stadol Injection in clinical studies, 15% were 61 years of age or older and 1% were 76 years or older. Of the approximately 1700 patients treated with Stadol NS in clinical studies, 8% were 65 years of age or older and 2% were 75 years or older.

Due to changes in clearance, the mean half-life of butorphanol is increased by 25% (to over 6 hours) in patients over the age of 65 years (see CLINICAL PHARMACOLOGY: Pharmacokinetics). Elderly patients may be more sensitive to the side effects of butorphanol. In clinical studies of Stadol NS, elderly patients had an increased frequency of headache, dizziness, drowsiness, vertigo, constipation, nausea and/or vomiting, and nasal congestion compared with younger patients. There are insufficient efficacy data for patients ≥65 years to determine whether they respond differently from younger patients.

The initial dose of Stadol Injection recommended for elderly patients should generally be half the recommended adult dose (0.5 mg IV and 1.0 mg IM). Repeat doses should be determined by the patient’s response rather than at fixed intervals, but will generally be no less than 6 hours apart (see CLINICAL PHARMACOLOGY: Individualization of Dosage).

Initially a 1-mg dose of Stadol NS should generally be used in geriatric patients and 90–120 minutes should elapse before administering a second 1-mg dose, if needed (see CLINICAL PHARMACOLOGY: Individualization of Dosage).

Butorphanol and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection.

Adverse Reactions

Clinical Trial Experience

A total of 2446 patients were studied in premarketing clinical trials of butorphanol. Approximately half received Stadol Injection with the remainder receiving Stadol NS. In nearly all cases the type and incidence of side effects with butorphanol by any route were those commonly observed with opioid analgesics.

The adverse experiences described below are based on data from short-term and long-term clinical trials in patients receiving butorphanol by any route. There has been no attempt to correct for placebo effect or to subtract the frequencies reported by placebo-treated patients in controlled trials.

The most frequently reported adverse experiences across all clinical trials with Stadol Injection and Stadol NS were somnolence (43%), dizziness (19%), nausea and/or vomiting (13%). In long-term trials with Stadol NS only, nasal congestion (13%) and insomnia (11%) were frequently reported.

The following adverse experiences were reported at a frequency of 1% or greater in clinical trials and were considered to be probably related to the use of butorphanol.

Body as a Whole: asthenia/lethargy, headache, sensation of heat.

Cardiovascular: vasodilation, palpitations.

Digestive: anorexia, constipation, dry mouth, nausea and/or vomiting, stomach pain.

Nervous: anxiety, confusion, dizziness, euphoria, floating feeling, insomnia, nervousness, paresthesia, somnolence, tremor.

Respiratory: bronchitis, cough, dyspnea, epistaxis, nasal congestion, nasal irritation, pharyngitis, rhinitis, sinus congestion, sinusitis, upper respiratory infection.

Skin and Appendages: sweating/clammy, pruritus.

Special Senses: blurred vision, ear pain, tinnitus, unpleasant taste.

The following adverse experiences were reported with a frequency of less than 1% in clinical trials and were considered to be probably related to the use of butorphanol.

Cardiovascular: hypotension, syncope.

Nervous: abnormal dreams, agitation, dysphoria, hallucinations, hostility, withdrawal symptoms.

Skin and Appendages: rash/hives.

Urogenital: impaired urination.

The following infrequent additional adverse experiences were reported in a frequency of less than 1% of the patients studied in short-term Stadol NS trials and under circumstances where the association between these events and butorphanol administration is unknown. They are being listed as alerting information for the physician.

Body as a Whole: edema.

Cardiovascular: chest pain, hypertension, tachycardia.

Nervous: depression.

Respiratory: shallow breathing.

Postmarketing Experience

Postmarketing experience with Stadol NS and Stadol Injection has shown an adverse event profile similar to that seen during the premarketing evaluation of butorphanol by all routes of administration. Adverse experiences that were associated with the use of Stadol NS or Stadol Injection and that are not listed above have been chosen for inclusion below because of their seriousness, frequency of reporting, or probable relationship to butorphanol. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These adverse experiences include apnea, convulsion, delusion, drug dependence, excessive drug effect associated with transient difficulty speaking and/or executing purposeful movements, overdose, and vertigo. Reports of butorphanol overdose with a fatal outcome have usually but not always been associated with ingestion of multiple drugs.

Drug Abuse and Dependence

Stadol (butorphanol tartrate) Injection and Stadol NS (butorphanol tartrate) Nasal Spray are listed in Schedule IV of the Controlled Substances Act (CSA).

Proper patient selection, dose and prescribing limitations, appropriate directions for use, and frequent monitoring are important to minimize the risk of abuse and physical dependence with butorphanol tartrate. Special care should be exercised in administering butorphanol to patients with a history of drug abuse or to patients receiving the drug on a continuous basis for an extended period.

Clinical Trial Experience

In all clinical trials, less than 1% of patients using Stadol NS had experiences that suggested the development of physical dependence or tolerance. Much of this information is based on experience with patients who did not have prolonged continuous exposure to Stadol NS. However, in one controlled clinical trial where patients with chronic pain from nonmalignant disease were treated with Stadol NS (n=303) or placebo (n=99) for up to 6 months, overuse (which may suggest the development of tolerance) was reported in nine (2.9%) patients receiving Stadol NS and no patients receiving placebo. Probable withdrawal symptoms were reported in eight (2.6%) patients using Stadol NS and no patients receiving placebo in the chronic nonmalignant pain study. Most of these patients abruptly discontinued Stadol NS after extended use or high doses. Symptoms suggestive of withdrawal included anxiety, agitation, tremulousness, diarrhea, chills, sweats, insomnia, confusion, incoordination, and hallucinations.

Postmarketing Experience

Butorphanol tartrate has been associated with episodes of abuse and dependence. Of the cases received, there were more reports of abuse with the nasal spray formulation than with the injectable formulation.

Overdosage

Clinical Manifestations

The clinical manifestations of butorphanol overdose are those of opioid drugs in general. Consequences of overdose vary with the amount of butorphanol ingested and individual response to the effects of opiates. The most serious symptoms are hypoventilation, cardiovascular insufficiency, coma, and death. Butorphanol overdose may be associated with ingestion of multiple drugs (see ADVERSE REACTIONS: Postmarketing Experience).

Overdose can occur due to accidental or intentional misuse of butorphanol, especially in young children who may gain access to the drug in the home.

Treatment

The management of suspected butorphanol overdosage includes maintenance of adequate ventilation, peripheral perfusion, normal body temperature, and protection of the airway. Patients should be under continuous observation with adequate serial measures of mental state, responsiveness, and vital signs. Oxygen and ventilatory assistance should be available with continual monitoring by pulse oximetry if indicated. In the presence of coma, placement of an artificial airway may be required. An adequate intravenous portal should be maintained to facilitate treatment of hypotension associated with vasodilation.

The use of a specific opioid antagonist such as naloxone should be considered. As the duration of butorphanol action usually exceeds the duration of action of naloxone, repeated dosing with naloxone may be required.

In managing cases of suspected butorphanol overdosage, the possibility of multiple drug ingestion should always be considered.

Stadol Dosage and Administration

Factors to be considered in determining the dose are age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and surgical procedure involved. Use in the elderly, in patients with hepatic or renal disease, or in labor requires extra caution (see PRECAUTIONS and CLINICAL PHARMACOLOGY: Individualization of Dosage). The following doses are for patients who do not have impaired hepatic or renal function and who are not on CNS active agents.

Use for Pain

Stadol Injection

Intravenous: The usual recommended single dose for IV administration is 1 mg repeated every 3 to 4 hours as necessary. The effective dosage range, depending on the severity of pain, is 0.5 to 2 mg repeated every 3 to 4 hours.

Intramuscular: The usual recommended single dose for IM administration is 2 mg in patients who will be able to remain recumbent, in the event drowsiness or dizziness occurs. This may be repeated every 3 to 4 hours, as necessary. The effective dosage range depending on the severity of pain is 1 to 4 mg repeated every 3 to 4 hours. There are insufficient clinical data to recommend single doses above 4 mg.

Stadol NS

The usual recommended dose for initial nasal administration is 1 mg (1 spray in one nostril). Adherence to this dose reduces the incidence of drowsiness and dizziness. If adequate pain relief is not achieved within 60–90 minutes, an additional 1-mg dose may be given.

The initial dose sequence outlined above may be repeated in 3–4 hours as required after the second dose of the sequence.

Depending on the severity of the pain, an initial dose of 2 mg (1 spray in each nostril) may be used in patients who will be able to remain recumbent in the event drowsiness or dizziness occurs. In such patients single additional 2-mg doses should not be given for 3–4 hours.

Use as Preoperative/Preanesthetic Medication

The preoperative medication dosage of Stadol Injection should be individualized (see CLINICAL PHARMACOLOGY: Individualization of Dosage). The usual adult dose is 2 mg IM, administered 60–90 minutes before surgery. This is approximately equivalent in sedative effect to 10 mg morphine or 80 mg meperidine.

Use in Balanced Anesthesia

The usual dose of Stadol Injection is 2 mg IV shortly before induction and/or 0.5 to 1.0 mg IV in increments during anesthesia. The increment may be higher, up to 0.06 mg/kg (4 mg/70 kg), depending on previous sedative, analgesic, and hypnotic drugs administered. The total dose of Stadol Injection will vary; however, patients seldom require less than 4 mg or more than 12.5 mg (approximately 0.06 to 0.18 mg/kg).

The use of Stadol NS is not recommended because it has not been studied in induction or maintenance of anesthesia.

Labor

In patients at full term in early labor a 1–2 mg dose of Stadol Injection IV or IM may be administered and repeated after 4 hours. Alternative analgesia should be used for pain associated with delivery or if delivery is expected to occur within 4 hours.

If concomitant use of Stadol with drugs that may potentiate its effects is deemed necessary (see PRECAUTIONS: Drug Interactions), the lowest effective dose should be employed.

The use of Stadol NS is not recommended as it has not been studied in labor.

Safety and Handling

Stadol Injection is supplied in sealed delivery systems that have a low risk of accidental exposure to health care workers.

Iopamidolo Bioindustria Lim

Iopamidolo Bioindustria Lim may be available in the countries listed below.

Ingredient matches for Iopamidolo Bioindustria Lim

Iopamidol

Iopamidol is reported as an ingredient of Iopamidolo Bioindustria Lim in the following countries:

• Italy

International Drug Name Search