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Wednesday 28 September 2016

Timoptic-XE Ocumeter Plus

Generic Name: timolol (Ophthalmic route)

TIM-oh-lol

Commonly used brand name(s)

In the U.S.

Betimol

Istalol

Timoptic Ocudose

Timoptic Ocumeter

Timoptic Ocumeter Plus

Timoptic-XE Ocumeter

Timoptic-XE Ocumeter Plus

Available Dosage Forms:

Solution

Gel Forming Solution

Therapeutic Class: Antiglaucoma

Pharmacologic Class: Beta-Adrenergic Blocker, Nonselective

Uses For Timoptic-XE Ocumeter Plus

Timolol is used alone or together with other medicines to treat increased pressure in the eye that is caused by open-angle glaucoma or a condition called ocular (eye) hypertension. This medicine is a beta-blocker .

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

Before Using Timoptic-XE Ocumeter Plus

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:

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 have not been performed on the relationship of age to the effects of timolol in the pediatric population. Safety and efficacy have not been established .

Geriatric

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of timolol in the elderly .

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during 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 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.

Albuterol

Amiodarone

Arformoterol

Bambuterol

Bitolterol

Broxaterol

Clenbuterol

Clonidine

Colterol

Diltiazem

Dronedarone

Epinephrine

Fenoldopam

Fenoterol

Formoterol

Hexoprenaline

Indacaterol

Isoetharine

Levalbuterol

Metaproterenol

Pirbuterol

Procaterol

Reproterol

Rimiterol

Ritodrine

Salmeterol

Terbutaline

Timolol

Tretoquinol

Tulobuterol

Verapamil

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.

Acarbose

Aceclofenac

Acemetacin

Acetohexamide

Alclofenac

Alfuzosin

Amlodipine

Apazone

Arbutamine

Benfluorex

Benoxaprofen

Bromfenac

Bufexamac

Bunazosin

Carprofen

Chlorpropamide

Cimetidine

Clometacin

Clonixin

Dexketoprofen

Diclofenac

Diflunisal

Digoxin

Dipyrone

Doxazosin

Droxicam

Etodolac

Etofenamate

Felbinac

Felodipine

Fenbufen

Fenoprofen

Fentiazac

Floctafenine

Flufenamic Acid

Flurbiprofen

Gliclazide

Glimepiride

Glipizide

Gliquidone

Glyburide

Guar Gum

Ibuprofen

Indomethacin

Indoprofen

Insulin

Insulin Aspart, Recombinant

Insulin Glulisine

Insulin Lispro, Recombinant

Isoxicam

Ketoprofen

Ketorolac

Lacidipine

Lercanidipine

Lornoxicam

Manidipine

Meclofenamate

Mefenamic Acid

Meloxicam

Metformin

Methyldopa

Mibefradil

Miglitol

Moxisylyte

Nabumetone

Naproxen

Nicardipine

Nifedipine

Niflumic Acid

Nilvadipine

Nimesulide

Nimodipine

Nisoldipine

Nitrendipine

Oxaprozin

Oxyphenbutazone

Phenoxybenzamine

Phentolamine

Phenylbutazone

Pirazolac

Piroxicam

Pirprofen

Pranidipine

Prazosin

Propyphenazone

Proquazone

Quinidine

Repaglinide

St John's Wort

Sulindac

Suprofen

Tamsulosin

Tenidap

Tenoxicam

Terazosin

Tiaprofenic Acid

Tolazamide

Tolbutamide

Tolmetin

Trimazosin

Troglitazone

Urapidil

Zomepirac

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. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Proper Use of timolol

This section provides information on the proper use of a number of products that contain timolol. It may not be specific to Timoptic-XE Ocumeter Plus. Please read with care.

Shake the regular eye drops well just before each use. If you are using the gel-forming eye drops, turn the bottle upside down and shake it once. You do not need to shake the gel-forming eye drops more than once .

To use the eye drops (solution and gel):

First, wash your hands. Tilt the head back and, pressing your finger gently on the skin just beneath the lower eyelid, pull the lower eyelid away from the eye to make a space. Drop the medicine into this space. Let go of the eyelid and gently close the eyes. Do not blink. Keep the eyes closed and apply pressure to the inner corner of the eye with your finger for 1 or 2 minutes to allow the medicine to be absorbed by the eye.

Immediately after using the medicine, wash your hands to remove any medicine that may be on them.

To keep the medicine as germ-free as possible, do not touch the applicator tip to any surface (including the eye). Also, keep the container tightly closed. Serious damage to the eye and possible loss of vision may result from using contaminated eye medicines .

If your doctor ordered two different eye medicines to be used together, wait at least 10 minutes after the regular eye drops before using the second medicine. This will help prevent the second medicine from “washing out” the first one. The gel-forming eye drops should always be the last medicine used if two medicines are ordered. Wait 10 minutes before using the gel-forming eye drops .

You should not use the regular eye drops if you have contact lenses in your eyes. Remove your contact lenses before you use this medicine. Wait at least 15 minutes after you use the medicine before putting the contact lenses back in .

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 glaucoma or ocular hypertension:
- For ophthalmic gel-forming solution dosage form (eye drops):
  - Adults—One drop in the affected eye(s) once a day.
  - Children—Use and dose must be determined by your doctor .
- For ophthalmic solution dosage form (eye drops):
  - Adults—One drop in the affected eye(s) two times a day.
  - Children—Use and dose must be determined by your doctor .

Missed Dose

If you miss a dose of this medicine, apply 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.

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 Timoptic-XE Ocumeter Plus

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and to check for unwanted effects .

If itching, redness, swelling, or other signs of eye or eyelid irritation occur, stop using this medicine and check with your doctor. These signs may mean that you are allergic to this medicine .

Timolol may cause heart failure in some patients. Check with your doctor right away if you are having chest pain or discomfort; dilated neck veins; extreme fatigue; irregular breathing; an irregular heartbeat; shortness of breath; swelling of the face, fingers, feet, or lower legs; weight gain; or wheezing .

This medicine may cause changes in your blood sugar levels. Also, this medicine may cover up signs of low blood sugar, such as a rapid pulse rate. Check with your doctor if you have these problems or if you notice a change in the results of your blood or urine sugar tests .

Make sure any doctor or dentist who treats you knows that you are using this medicine. You may need to stop using this medicine several days before having surgery .

The gel-forming eye drops may cause blurred vision or other vision problems that last about 30 seconds to 5 minutes after you put them in your eye. If any of these occur, do not drive, use machines, or do anything else that could be dangerous if you are not able to see well. If these eye changes are bothersome, check with your doctor .

Timoptic-XE Ocumeter Plus 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

Blurred vision

burning or stinging in eye

Less common

Arm, back, or jaw pain

blisters, hives, welts, or itching

blue lips, fingernails, or skin

burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings

change in vision

chest pain or discomfort

chest tightness or heaviness

confusion about identity, place, and time

continuing ringing or buzzing or other unexplained noise in ears

coughing that sometimes produces a pink frothy sputum

depression

difficult, fast, noisy breathing, sometimes with wheezing

difficulty in chewing, swallowing, or talking

dilated neck veins

discharge, excessive tearing

disturbed color perception

dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly

double vision

drooping eyelids

dry or itching eyes

extreme fatigue

false sense of well-being

fast, slow, irregular, pounding, or racing heartbeat or pulse

fear, nervousness

feeling of having something in the eye

fever and chills

flashes of light, floaters in vision

general feeling of discomfort or illness

hair loss

halos around lights

headaches

inability to speak

increased sweating

irregular, fast or slow, or shallow breathing

large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs

lightheadedness, dizziness, or fainting

loss of vision

memory loss

mood swings

muscle or joint pain

muscle weakness

nausea

night blindness

no blood pressure or pulse

overbright appearance of lights

pain, tension, and weakness upon walking that subsides during periods of rest

pale skin

paleness or cold feeling in fingertips, toes, hands, and feet

personality changes

pounding in the ears

puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue

redness of skin

redness, pain, swelling or irritation of eye, eyelid, or inner lining of eyelid

seeing double

seeing, hearing, or feeling things that are not there

seizures

severe numbness, especially on one side of the face or body

severe or sudden headache

severe tiredness

shortness of breath or troubled breathing

skin irritation or rash, including rash that looks like psoriasis

slurred speech

sore throat

stopping of heart

sweating

swelling of face, fingers, feet, lower legs, and ankles

swollen glands

temporary blindness

tingling or pain in fingers or toes when exposed to cold

tunnel vision

unconsciousness

unusual tiredness or weakness

weakness in arm and/or leg on one side of the body, sudden and severe

weight gain

wheezing

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

Acid or sour stomach

belching

body aches or pain

diarrhea

dry mouth

ear congestion

hearing loss

heartburn

indigestion

lack or loss of strength

loss of appetite

loss of voice

nightmares

runny nose

sleepiness or unusual drowsiness

sleeplessness

sneezing

stomach discomfort, upset, or pain

stuffy nose

trouble sleeping

unable to sleep

weight loss

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: Timoptic-XE Ocumeter Plus side effects (in more detail)

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More Timoptic-XE Ocumeter Plus resources

Timoptic-XE Ocumeter Plus Side Effects (in more detail)
Timoptic-XE Ocumeter Plus Use in Pregnancy & Breastfeeding
Timoptic-XE Ocumeter Plus Drug Interactions
Timoptic-XE Ocumeter Plus Support Group
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Glaucoma, Open Angle
Intraocular Hypertension

Tygacil

tigecycline

Dosage Form: injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Tygacil

Tygacil is a tetracycline-class antibacterial indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the conditions listed below for patients 18 years of age and older:

Complicated Skin and Skin Structure Infections

Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis.

Complicated Intra-abdominal Infections

Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and ‑resistant isolates), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.

Community-Acquired Bacterial Pneumonia

Community-acquired bacterial pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates), and Legionella pneumophila.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tygacil and other antibacterial drugs, Tygacil should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to tigecycline. Tygacil may be initiated as empiric monotherapy before results of these tests are known.

Tygacil Dosage and Administration

General Dosage and Administration

The recommended dosage regimen for Tygacil is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous infusions of Tygacil should be administered over approximately 30 to 60 minutes every 12 hours.

The recommended duration of treatment with Tygacil for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5 to 14 days. The recommended duration of treatment with Tygacil for community-acquired bacterial pneumonia is 7 to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patient's clinical and bacteriological progress.

Patients With Hepatic Impairment

No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of Tygacil should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)].

Preparation and Handling

Each vial of Tygacil should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, or Lactated Ringer's Injection, USP to achieve a concentration of 10 mg/mL of tigecycline. (Note: Each vial contains a 6% overage. Thus, 5 mL of reconstituted solution is equivalent to 50 mg of the drug.) The vial should be gently swirled until the drug dissolves. Withdraw 5 mL of the reconstituted solution from the vial and add to a 100 mL intravenous bag for infusion (for a 100 mg dose, reconstitute two vials; for a 50 mg dose, reconstitute one vial). The maximum concentration in the intravenous bag should be 1 mg/mL. The reconstituted solution should be yellow to orange in color; if not, the solution should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration (e.g., green or black) prior to administration. Once reconstituted, Tygacil may be stored at room temperature for up to 24 hours (up to 6 hours in the vial and the remaining time in the intravenous bag). Alternatively, Tygacil mixed with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 48 hours following immediate transfer of the reconstituted solution into the intravenous bag.

Tygacil may be administered intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of Tygacil with 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP or Lactated Ringer's Injection, USP. Injection should be made with an infusion solution compatible with tigecycline and with any other drug(s) administered via this common line.

Compatibilities

Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer's Injection, USP. When administered through a Y-site, Tygacil is compatible with the following drugs or diluents when used with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP: amikacin, dobutamine, dopamine HCl, gentamicin, haloperidol, Lactated Ringer's, lidocaine HCl, metoclopramide, morphine, norepinephrine, piperacillin/tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine HCl, theophylline, and tobramycin.

Incompatibilities

The following drugs should not be administered simultaneously through the same Y-site as Tygacil: amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole and omeprazole.

Dosage Forms and Strengths

Each single-dose 5 mL glass vial and 10 mL glass vial contain 50 mg of tigecycline as an orange lyophilized powder for reconstitution.

Contraindications

Tygacil is contraindicated for use in patients who have known hypersensitivity to tigecycline.

Warnings and Precautions

All-Cause Mortality

An increase in all-cause mortality has been observed across Phase 3 and 4 clinical trials in Tygacil-treated patients versus comparator-treated patients. In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving Tygacil and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between Tygacil and comparator-treated patients. The cause of this increase has not been established. This increase in all-cause mortality should be considered when selecting among treatment options [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 )].

Anaphylaxis/Anaphylactoid Reactions

Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including Tygacil, and may be life-threatening. Tygacil is structurally similar to tetracycline-class antibiotics and should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics.

Hepatic Effects

Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Adverse events may occur after the drug has been discontinued.

Mortality Imbalance and Lower Cure Rates in Ventilator-Associated Pneumonia

A trial of patients with hospital acquired pneumonia failed to demonstrate the efficacy of Tygacil. In this trial, patients were randomized to receive Tygacil (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received Tygacil had lower cure rates (47.9% versus 70.1% for the clinically evaluable population).

In this trial, greater mortality was seen in patients with ventilator-associated pneumonia who received Tygacil (25/131 [19.1%] versus 15/122 [12.3%] in comparator-treated patients) [see Adverse Reactions (6.1)]. Particularly high mortality was seen among Tygacil-treated patients with ventilator-associated pneumonia and bacteremia at baseline (9/18 [50.0%] versus 1/13 [7.7%] in comparator-treated patients).

Pancreatitis

Acute pancreatitis, including fatal cases, has occurred in association with tigecycline treatment. The diagnosis of acute pancreatitis should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Cases have been reported in patients without known risk factors for pancreatitis. Patients usually improve after tigecycline discontinuation. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis [see Adverse Reactions ( 6.2 )].

Use During Pregnancy

Tygacil may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking tigecycline, the patient should be apprised of the potential hazard to the fetus. Results of animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline [see Use in Specific Populations (8.1)].

Tooth Development

The use of Tygacil during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). Results of studies in rats with Tygacil have shown bone discoloration. Tygacil should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated.

Clostridium difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Tygacil, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Patients With Intestinal Perforation

Caution should be exercised when considering Tygacil monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1642), 6 patients treated with Tygacil and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with Tygacil had higher APACHE II scores (median = 13) versus the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established.

Tetracycline-Class Effects

Tygacil is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of Tygacil [see Warnings and Precautions (5.5)].

Superinfection

As with other antibacterial drugs, use of Tygacil may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.

Development of Drug-Resistant Bacteria

Prescribing Tygacil in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials, 2514 patients were treated with Tygacil. Tygacil was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of treatment-emergent adverse reactions through test of cure reported in ≥2% of patients in these trials.

Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of Patients Treated in Clinical Studies
Body System Adverse Reactions	Tygacil (N=2514)	Comparatorsa (N=2307)
a Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid. b LFT abnormalities in Tygacil-treated patients were reported more frequently in the post therapy period than those in comparator-treated patients, which occurred more often on therapy.
Body as a Whole
Abdominal pain	6	4
Abscess	2	2
Asthenia	3	2
Headache	6	7
Infection	7	5
Cardiovascular System
Phlebitis	3	4
Digestive System
Diarrhea	12	11
Dyspepsia	2	2
Nausea	26	13
Vomiting	18	9
Hemic and Lymphatic System
Anemia	5	6
Metabolic and Nutritional
Alkaline Phosphatase Increased	3	3
Amylase Increased	3	2
Bilirubinemia	2	1
BUN Increased	3	1
Healing Abnormal	3	2
Hyponatremia	2	1
Hypoproteinemia	5	3
SGOT Increasedb	4	5
SGPT Increasedb	5	5
Respiratory System
Pneumonia	2	2
Nervous System
Dizziness	3	3
Skin and Appendages
Rash	3	4

In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving Tygacil and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between Tygacil and comparator-treated patients (see Table 2). The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities.

Table 2. Patients with Outcome of Death by Infection Type
	Tygacil		Comparator		Risk Difference*
Infection Type	n/N	%	n/N	%	% (95% CI)
CAP = Community-acquired pneumonia; cIAI = Complicated intra-abdominal infections; cSSSI = Complicated skin and skin structure infections; HAP = Hospital-acquired pneumonia; VAP = Ventilator-associated pneumonia; RP = Resistant pathogens; DFI = Diabetic foot infections. * The difference between the percentage of patients who died in Tygacil and comparator treatment groups. The 95% CI for each infection type was calculated using the normal approximation method without continuity correction. ** Overall adjusted (random effects model by trial weight) risk difference estimate and 95% CI. a These are subgroups of the HAP population. Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRSA or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DFI with and without osteomyelitis).

cSSSI	12/834	1.4	6/813	0.7	0.7 (-0.3, 1.7)
cIAI	42/1382	3.0	31/1393	2.2	0.8 (-0.4, 2.0)
CAP	12/424	2.8	11/422	2.6	0.2 (-2.0, 2.4)


HAP	66/467	14.1	57/467	12.2	1.9 (-2.4, 6.3)
Non-VAPa	41/336	12.2	42/345	12.2	0.0 (-4.9, 4.9)
VAPa	25/131	19.1	15/122	12.3	6.8 (-2.1, 15.7)
RP	11/128	8.6	2/43	4.7	3.9 (-4.0, 11.9)
DFI	7/553	1.3	3/508	0.6	0.7 (-0.5, 1.8)

Overall Adjusted	150/3788	4.0	110/3646	3.0	0.6 (0.1, 1.2)**

In comparative clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with Tygacil (7%) versus comparators (6%). Serious adverse events of sepsis/septic shock were more frequently reported for subjects treated with Tygacil (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established [see Warnings and Precautions (5.9)].

The most common treatment-emergent adverse reactions were nausea and vomiting which generally occurred during the first 1 – 2 days of therapy. The majority of cases of nausea and vomiting associated with Tygacil and comparators were either mild or moderate in severity. In patients treated with Tygacil, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe).

In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for Tygacil and 9% for vancomycin/aztreonam; vomiting incidence was 20% for Tygacil and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for Tygacil and 21% for imipenem/cilastatin; vomiting incidence was 20% for Tygacil and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for Tygacil and 8% for levofloxacin; vomiting incidence was 16% for Tygacil and 6% for levofloxacin.

Discontinuation from tigecycline was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea (<1%).

The following adverse reactions were reported infrequently (<2%) in patients receiving Tygacil in clinical studies:

Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis

Cardiovascular System: thrombophlebitis

Digestive System: anorexia, jaundice, abnormal stools

Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia

Special Senses: taste perversion

Hemic and Lymphatic System: partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia

Skin and Appendages: pruritus

Urogenital System: vaginal moniliasis, vaginitis, leukorrhea

Post-Marketing Experience

The following adverse reactions have been identified during postapproval use of Tygacil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.

anaphylaxis/anaphylactoid reactions

acute pancreatitis

hepatic cholestasis, and jaundice

severe skin reactions, including Stevens-Johnson Syndrome

Drug Interactions

Warfarin

Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin [see Clinical Pharmacology (12.3)].

Oral Contraceptives

Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective.

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic Effects—Pregnancy Category D [see Warnings and Precautions (5.6)]

Tigecycline was not teratogenic in the rat or rabbit. In preclinical safety studies, 14C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with slight reductions in fetal weights and an increased incidence of minor skeletal anomalies (delays in bone ossification) at exposures of 5 times and 1 times the human daily dose based on AUC in rats and rabbits, respectively (28 mcg·hr/mL and 6 mcg·hr/mL at 12 and 4 mg/kg/day). An increased incidence of fetal loss was observed at maternotoxic doses in the rabbits with exposure equivalent to human dose.

There are no adequate and well-controlled studies of tigecycline in pregnant women. Tygacil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Results from animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tygacil is administered to a nursing woman [see Warnings and Precautions (5.7)].

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of effects on tooth development, use in patients under 8 years of age is not recommended [see Warnings and Precautions (5.7)].

Geriatric Use

Of the total number of subjects who received Tygacil in Phase 3 clinical studies (n=2514), 664 were 65 and over, while 288 were 75 and over. No unexpected overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events of some older individuals cannot be ruled out.

No significant difference in tigecycline exposure was observed between healthy elderly subjects and younger subjects following a single 100 mg dose of tigecycline [see Clinical Pharmacology (12.3)].

Hepatic Impairment

No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of tigecycline should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response [see Clinical Pharmacology (12.3) and Dosage and Administration (2.2)].

Overdosage

No specific information is available on the treatment of overdosage with tigecycline. Intravenous administration of Tygacil at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. In single-dose intravenous toxicity studies conducted with tigecycline in mice, the estimated median lethal dose (LD50) was 124 mg/kg in males and 98 mg/kg in females. In rats, the estimated LD50 was 106 mg/kg for both sexes. Tigecycline is not removed in significant quantities by hemodialysis.

Tygacil Description

Tygacil (tigecycline) is a tetracycline derivative (a glycylcycline) for intravenous infusion. The chemical name of tigecycline is (4S,4aS,5aR,12aS) - 9 - [2 - (tert - butylamino)acetamido] - 4,7 - bis(dimethylamino) - 1,4,4a,5,5a,6,11,12a - octahydro - 3,10,12,12a - tetrahydroxy - 1,11 - dioxo - 2 - naphthacenecarboxamide. The empirical formula is C29H39N5O8 and the molecular weight is 585.65.

The following represents the chemical structure of tigecycline:

Tygacil is an orange lyophilized powder or cake. Each Tygacil vial contains 50 mg tigecycline lyophilized powder for reconstitution for intravenous infusion and 100 mg of lactose monohydrate. The pH is adjusted with hydrochloric acid, and if necessary sodium hydroxide. The product does not contain preservatives.

Tygacil - Clinical Pharmacology

Mechanism of Action

Tigecycline is an antibacterial drug [see Clinical Pharmacology (12.4)].

Pharmacokinetics

The mean pharmacokinetic parameters of tigecycline after single and multiple intravenous doses based on pooled data from clinical pharmacology studies are summarized in Table 3. Intravenous infusions of tigecycline were administered over approximately 30 to 60 minutes.

Table 3. Mean (CV%) Pharmacokinetic Parameters of Tigecycline
	Single Dose	Multiple Dosea
	100 mg	50 mg every 12h
	(N=224)	(N=103)
a 100 mg initially, followed by 50 mg every 12 hours b 30-minute infusion c 60-minute infusion
Cmax (mcg/mL)b	1.45 (22%)	0.87 (27%)
Cmax (mcg/mL)c	0.90 (30%)	0.63 (15%)
AUC (mcg·h/mL)	5.19 (36%)	- -
AUC0-24h (mcg·h/mL)	- -	4.70 (36%)
Cmin (mcg/mL)	- -	0.13 (59%)
t½ (h)	27.1 (53%)	42.4 (83%)
CL (L/h)	21.8 (40%)	23.8 (33%)
CLr (mL/min)	38.0 (82%)	51.0 (58%)
Vss (L)	568 (43%)	639 (48%)

Distribution

The in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 mcg/mL). The steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the tissues.

Following the administration of tigecycline 100 mg followed by 50 mg every 12 hours to 33 healthy volunteers, the tigecycline AUC0-12h (134 mcg·h/mL) in alveolar cells was approximately 78-fold higher than the AUC0-12h in the serum, and the AUC0-12h (2.28 mcg·h/mL) in epithelial lining fluid was approximately 32% higher than the AUC0-12h in serum. The AUC0-12h (1.61 mcg·h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0-12h in the serum of 10 healthy subjects.

In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Concentrations at 4 hours after tigecycline administration were higher in gallbladder (38-fold, n=6), lung (3.7-fold, n=5), and colon (2.3-fold, n=6), and lower in synovial fluid (0.58-fold, n=5), and bone (0.35-fold, n=6) relative to serum. The concentration of tigecycline in these tissues after multiple doses has not been studied.

Metabolism

Tigecycline is not extensively metabolized. In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. In healthy male volunteers receiving 14C-tigecycline, tigecycline was the primary 14C-labeled material recovered in urine and feces, but a glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) were also present.

Elimination

The recovery of total radioactivity in feces and urine following administration of 14C‑tigecycline indicates that 59% of the dose is eliminated by biliary/fecal excretion, and 33% is excreted in urine. Approximately 22% of the total dose is excreted as unchanged tigecycline in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline and its metabolites. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.

Specific Populations

Patients with Hepatic Impairment

In a study comparing 10 patients with mild hepatic impairment (Child Pugh A), 10 patients with moderate hepatic impairment (Child Pugh B), and 5 patients with severe hepatic impairment (Child Pugh C) to 23 age and weight matched healthy control subjects, the single-dose pharmacokinetic disposition of tigecycline was not altered in patients with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25% and the half-life of tigecycline was prolonged by 23% in patients with moderate hepatic impairment (Child Pugh B). Systemic clearance of tigecycline was reduced by 55%, and the half-life of tigecycline was prolonged by 43% in patients with severe hepatic impairment (Child Pugh C). Dosage adjustment is necessary in patients with severe hepatic impairment (Child Pugh C) [see Use in Specific Populations (8.6) and Dosage and Administration (2.2)].

Patients with Renal Impairment

A single dose study compared 6 subjects with severe renal impairment (creatinine clearance <30 mL/min), 4 end stage renal disease (ESRD) patients receiving tigecycline 2 hours before hemodialysis, 4 ESRD patients receiving tigecycline 1 hour after hemodialysis, and 6 healthy control subjects. The pharmacokinetic profile of tigecycline was not significantly altered in any of the renally impaired patient groups, nor was tigecycline removed by hemodialysis. No dosage adjustment of Tygacil is necessary in patients with renal impairment or in patients undergoing hemodialysis.

Geriatric Patients

No significant differences in pharmacokinetics were observed between healthy elderly subjects (n=15, age 65-75; n=13, age >75) and younger subjects (n=18) receiving a single 100-mg dose of Tygacil. Therefore, no dosage adjustment is necessary based on age [see Use in Specific Populations (8.5)].

Gender

In a pooled analysis of 38 women and 298 men participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance between women (20.7±6.5 L/h) and men (22.8±8.7 L/h). Therefore, no dosage adjustment is necessary based on gender.

Race

In a pooled analysis of 73 Asian subjects, 53 Black subjects, 15 Hispanic subjects, 190 White subjects, and 3 subjects classified as “other” participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance among the Asian subjects (28.8±8.8 L/h), Black subjects (23.0±7.8 L/h), Hispanic subjects (24.3±6.5 L/h), White subjects (22.1±8.9 L/h), and “other” subjects (25.0±4.8 L/h). Therefore, no dosage adjustment is necessary based on race.

Drug Interactions

Tygacil (100 mg followed by 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg, orally, every 24 hours) were coadministered to healthy subjects in a drug interaction study. Tigecycline slightly decreased the Cmax of digoxin by 13%, but did not affect the AUC or clearance of digoxin. This small change in Cmax did not affect the steady-state pharmacodynamic effects of digoxin as measured by changes in ECG intervals. In addition, digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore, no dosage adjustment of either drug is necessary when Tygacil is administered with digoxin.

Concomitant administration of Tygacil (100 mg followed by 50 mg every 12 hours) and warfarin (25 mg single-dose) to healthy subjects resulted in a decrease in clearance of R‑warfarin and S‑warfarin by 40% and 23%, an increase in Cmax by 38% and 43% and an increase in AUC by 68% and 29%, respectively. Tigecycline did not significantly alter the effects of warfarin on INR. In addition, warfarin did not affect the pharmacokinetic profile of tigecycline. However, prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin.

In vitro studie

Tuesday 27 September 2016

Tylan Soluble

Dosage Form: FOR ANIMAL USE ONLY
Tylan® Soluble

Tylosin Tartrate

For Use In Chickens, Turkeys, Swine and Honey Bees Only

ELANCO* AF 1300-67X

Equivalent to 100 g tylosin base

An Antibiotic NADA #13-076, Approved by FDA

Indications

Chickens: As an aid in the treatment of chronic respiratory disease (CRD) associated with Mycoplasma gallisepticum sensitive to tylosin in broiler and replacement chickens. For the control of CRD associated with Mycoplasma gallisepticum sensitive to tylosin at the time of vaccination or other stress in chickens. For the control of CRD associated with Mycoplasma synoviae sensitive to tylosin in broiler chickens.

Turkeys: For maintaining weight gain and feed efficiency in the presence of infectious sinusitis associated with Mycoplasma gallisepticum sensitive to tylosin.

Swine: For the treatment and control of swine dysentery associated with Brachyspira hyodysenteriae. For the treatment and control of swine dysentery associated with Brachyspira hyodysenteriae when followed immediately by TYLAN Type A medicated article in feed. For the control of porcine proliferative enteropathies (PPE, ileitis) associated with Lawsonia intracellularis when followed immediately by TYLAN Type A medicated article in feed.

Honey Bees: For the control of American Foulbrood (Paenibacillus larvae).

Ingredients

Tylosin (as tylosin tartrate) ……………………………………. 100 g

Mixing Directions

Chickens and Turkeys: To assure thorough dissolution, place the Tylan (contents of this jar) in a mixing container and add one gallon of water (3790 mL) to the material. Mix this concentrated solution with water to make 50 gallons (189 liters) of treated drinking water.

Swine: To assure thorough dissolution, place the Tylan (contents of this jar) in a mixing container and add one gallon of water (3790 mL) to the material. Mix this concentrated solution with water to make 400 gallons of treated drinking water resulting in 250 mg/gallon.

Honey Bees: Mix 200 mg tylosin in 20 g confectioners/powdered sugar. Use immediately.

When directed to mix the product with water, always add the water to the powder. Do not pour the powder into the water. Prepare a fresh Tylan solution every three days. When mixing and handling tylosin, use protective clothing and impervious gloves.

Directions for Use

Chickens should be treated for three days; however, treatment may be administered for one to five days depending upon severity of infection. Treated chickens must consume enough medicated water to provide 50 mg per pound of body weight per day. Only medicated water should be available to the birds.

Turkeys should be treated for three days; however, treatment may be administered for two to five days depending upon severity of infection. Treated turkeys must consume enough medicated water to provide 60 mg per pound of body weight per day. Only medicated water should be available to the birds.

Swine For the treatment and control of swine dysentery medicate with 250 mg tylosin per gallon in drinking water for 3 to 10 days, depending upon severity of infection. Alternatively, medicate with 250 mg tylosin per gallon in drinking water for 3 to 10 days, followed by 40 to 100 g tylosin per ton of complete feed (Type C medicated feed manufactured from TYLAN Type A medicated article) for 2 to 6 weeks. For control of porcine proliferative enteropathies (PPE, ileitis) medicate with 250 mg tylosin per gallon in drinking water for 3 to 10 days, followed by 40 to 100 g of tylosin per ton of complete feed (Type C medicated feed manufactured from TYLAN Type A medicated article) for 2 to 6 weeks. Swine must consume enough medicated water to provide a therapeutic dose. Only medicated water (250 mg tylosin per gallon) should be available while medicating with Tylan Soluble.

Honey Bee colonies should receive three treatments administered as a dust in confectioners/powdered sugar. The 200 mg dose is applied (dusted) over the top bars of the brood chamber once weekly for 3 weeks.

Notice: Organisms vary in their degree of susceptibility to any chemotherapeutic. If no improvement is observed after recommended treatment, diagnosis and susceptibility should be reconfirmed.

NOT FOR HUMAN USE

RESIDUE WARNING: Chickens must not be slaughtered for food within 24 hours after treatment. Turkeys must not be slaughtered for food within five days after treatment. Swine must not be slaughtered for food within 48 hours after treatment. Do not use in layers producing eggs for human consumption. Honey Bees: The drug should be fed early in the spring or fall and consumed by the bees before the main honey flow begins, to avoid contamination of production honey. Complete treatments at least 4 weeks prior to main honey flow.

Avoid contact with human skin. Exposure to tylosin may cause a rash.

Store at Room Temperature, 25°C (77°F).

(Excursions Permitted to 40°C).

Avoid Moisture.

Manufactured For:

Elanco Animal Health

A Division of Eli Lilly and Company

Indianapolis, IN 46285, USA

Restricted Drug (California) - Use Only as Directed.

To report adverse effects, access medical information, or obtain additional product information, call 1-800-428-4441.

*Elanco®, Tylan® and the diagonal color bar are trademarks of Eli Lilly and Company.

Lot/Exp. date YL0091DEAMX (V01-08-2008)

Principal Display Panel

Principal Display Panel – 100 g Bottle Label

ELANCO* AF 1300-67X

Tylan® Soluble

Tylosin Tartrate

For Use In Chickens, Turkeys, Swine and Honey Bees Only

Equivalent to 100 g tylosin base

An Antibiotic NADA #13-076, Approved by FDA

Tylan Soluble
tylosin tartrate powder

Product Information
Product Type	OTC ANIMAL DRUG	NDC Product Code (Source)	0986-1300
Route of Administration	ORAL	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
TYLOSIN TARTRATE (TYLOSIN)	TYLOSIN TARTRATE	100 g in 3790 mL

Inactive Ingredients
Ingredient Name	Strength
No Inactive Ingredients Found

Product Characteristics
Color		Score
Shape		Size
Flavor		Imprint Code
Contains

Packaging
#	NDC	Package Description	Multilevel Packaging
1	0986-1300-11	3790 mL In 1 BOTTLE, PLASTIC	None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA13076	05/10/2010

Labeler - Elanco Animal Health Co (807447169)

Establishment
Name	Address	ID/FEI	Operations
Catalent Pharma Solutions, LLC		043911403	MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
Eli Lilly and Company Limited (Speke Operations)		230761368	API MANUFACTURE

Revised: 05/2010Elanco Animal Health Co

Topiramat Desitin

Topiramat Desitin may be available in the countries listed below.

Ingredient matches for Topiramat Desitin

Topiramate

Topiramate is reported as an ingredient of Topiramat Desitin in the following countries:

Germany

Slovakia

Switzerland

International Drug Name Search

TechneLite

Dosage Form: injection

DESCRIPTION: Sodium Pertechnetate Tc 99m Injection, as eluted according to the elution instructions with Bristol-Myers Squibb Medical Imaging, Inc. TechneLite®, Technetium Tc 99m Generator, is in Sodium Chloride 0.9% as a sterile, non-pyrogenic, diagnostic radiopharmaceutical suitable for intravenous injection, oral administration, and direct instillation. The pH is 4.5-7.5. The eluate should be clear, colorless, and free from visible foreign material. Each eluate of the TechneLite®, Technetium Tc 99m Generator should not contain more than 0.0056MBq (0.15 microcuries) of Molybdenum Mo99 per 37MBq (1 millicurie) of Technetium Tc 99m per administered dose at the time of administration, and not more than 10 micrograms of aluminum per milliliter of the Technetium Tc 99m Generator eluate, both of which must be determined by the user before administration. Since the eluate does not contain an antimicrobial agent, it should not be used later than one (1) working day after the elution (12 hours).

Bristol-Myers Squibb Medical Imaging, Inc. TechneLite®, Technetium Tc 99m Generator consists of a column containing fission produced Molybdenum Mo99 adsorbed on alumina. The terminally sterilized and sealed column is enclosed in a lead shield; the shield and other components are sealed in a cylindrical plastic container with an attached handle. Built into the top surface are two recessed wells marked CHARGE and COLLECT. Needles protruding from these two wells accommodate supplied sterile eluant charge vials and sterile eluate collection vials. The eluting solvent consists of Sodium Chloride 0.9%, prepacked into septum-sealed vials.

The eluate collection vial is evacuated, sterile and non-pyrogenic. A sterile 0.22 micrometer bacteriological filter is incorporated between the column outlet and the collection vials. During and subsequent to elution, the eluate collection vial should be kept in a radiation shield. The Generator is shipped with a silicone needle seal over the charge needle and a vented needle cover over the collect needle. A sterile vial containing bacteriostat is supplied for the customer to aseptically reseal the collect needle after each elution.

PHYSICAL CHARACTERISTICS

Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours.1 Photons that are useful for imaging studies are listed in Table 1.

Table 1. Principal Radiation Emission Data - Technetium Tc 99m
1Kocher, David C., "Radioactive Decay Data Tables," DOE/TIC-11026, 108 (1981).
Radiation	Mean %/Disintegration	Mean Energy (keV)
Gamma-2	89.07	140.5

EXTERNAL RADIATION

The specific gamma ray constant for Technetium Tc 99m is 5.4 microcoulombs/Kg-MBq-hr (0.78 R/mCi-hr) at 1cm. The first half-value thickness is 0.017cm of lead (Pb). To facilitate control of radiation exposure from millicurie amounts of Technetium Tc 99m, for example, the use of a 0.25 cm thick standard radiation elution lead shield will attenuate the radiation emitted by a factor of about 1000. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of lead is shown in Table 2.

NOTE: Because the generator is well contained and essentially dry, there is little likelihood of contamination due to damage in transit. The most probable source of leakage resulting from damage in transit is the nonradioactive eluant charge vial.

Table 2. Radiation Attenuation of Technetium Tc 99m by Lead Shielding
Shield Thickness lead (Pb) cm	Coefficient of Attenuation
0.017	0.5
0.08	10-1
0.16	10-2
0.25	10-3
0.33	10-4

Molybdenum Mo99 decays to Technetium Tc 99m with a Molybdenum Mo99 half-life of 66 hours. The physical decay characteristics of Molybdenum Mo99 are such that only 88.6% of the decaying Molybdenum Mo99 atoms form Technetium Tc 99m. This means that only 78% of the activity remains after 24 hours; 60% remains after 48 hours, etc. All units have a minimum of 38 mm, 1.5 inches (~ 6 half-value layers) of lead surrounding the activity. Since the Molybdenum Mo99 is constantly decaying to fresh Technetium Tc 99m, it is possible to elute the generator at any time. (See Table 3.)

Table 3. Molybdenum Mo99 Decay Chart Half-Life 66.0 Hours
Days	Percent Remaining	Days	Percent Remaining
0	100	8	13
1	78	9	10
2	60	10	8
3	47	11	6
4	36	12	5
5	28	13	4
6	22	14	3
7	17

Generator elutions may be made at any time, but the amount of Technetium Tc 99m available will depend on the interval from the last elution. Approximately 47% of maximum Technetium Tc 99m is reached after 6 hours and 95% after 24 hours.

The elution vial shield has a wall thickness of 7.9 mm, 0.31 inches, and reduces transmitted Technetium Tc 99m radiation essentially to zero. To correct for physical decay of Tc 99m, the fractions that remain at selected intervals of time are shown in Table 4.

Table 4. Physical Decay Chart: Technetium Tc 99m Half-Life 6.02 Hours
*Calibration Time
Hours	Percent Remaining	Hours	Percent Remaining
0*	100.0	7	44.7
1	89.1	8	39.8
2	79.4	9	35.5
3	70.8	10	31.6
4	63.1	11	28.2
5	56.2	12	25.1
6	50.1

CLINICAL PHARMACOLOGY: The pertechnetate ion distributes in the body similarly to the iodide ion but is not organified when trapped in the thyroid gland. Pertechnetate tends to accumulate in intracranial lesions with excessive neovascularity or an altered blood-brain barrier. It also concentrates in the choroid plexus, thyroid gland, salivary glands, and stomach. However, in contrast to the iodide ion, the pertechnetate ion is released unchanged from the thyroid gland.

After intravascular administration it remains in the circulatory system for sufficient time to permit blood pool, organ perfusion, and major vessel studies. It gradually equilibrates with the extracellular space. A fraction is promptly excreted via the kidneys.

Following the administration of Sodium Pertechnetate Tc 99m Injection as an eye drop, the drug mixes with tears within the conjunctival space. Within seconds to minutes it leaves the conjunctival space and escapes into the inferior meatus of the nose through the nasolacrimal drainage system. During this process the pertechnetate ion passes through the canaliculi, the lacrimal sac and the nasolacrimal duct. In the event of any anatomical or functional blockage of the drainage system there will be a backflow resulting in tearing (epiphora). Thus the pertechnetate escapes the conjunctival space in the tears.

While the major part of the pertechnetate escapes within a few minutes of normal drainage and tearing, it has been documented that there is some degree of transconjunctival absorption with a fractional turnover rate of 0.015/min in normal individuals, 0.021/min in patients without any sac and 0.027/min in patients with inflamed conjunctiva due to chronic dacryocystitis. Individual values may vary but these rates are probably representative and indicate that the maximum possible pertechnetate absorbed will remain below one thousandth of that used in other routine diagnostic procedures.

INDICATIONS AND USAGE: Sodium Pertechnetate Tc 99m Injection is used IN ADULTS as an agent for:

: Brain Imaging (including cerebral radionuclide angiography)
: Thyroid Imaging
: Salivary Gland Imaging
: Placenta Localization
: Blood Pool Imaging (including radionuclide angiography)
: Urinary Bladder Imaging (direct isotopic cystography) for the detection of vesico-ureteral reflux.
: Nasolacrimal Drainage System Imaging

Sodium Pertechnetate Tc 99m Injection is used IN CHILDREN as an agent for:

: Brain Imaging (including cerebral radionuclide angiography)
: Thyroid Imaging
: Blood Pool Imaging
: Urinary Bladder Imaging (direct isotopic cystography) for the detection of vesico-ureteral reflux.

CONTRAINDICATIONS: None known.

WARNINGS: Radiation risks associated with the use of Sodium Pertechnetate Tc 99m Injection are greater in children than in adults and, in general, the younger the child, the greater the risk owing to greater absorbed radiation doses and longer life-expectancy. These greater risks should be taken firmly into account in all benefit-risk assessments involving children.

PRECAUTIONS:

General

As in the use of any radioactive material, care should be taken to minimize radiation exposure to the patient consistent with proper patient management and to ensure minimum radiation exposure to occupational workers.

Since the eluate does not contain an antimicrobial agent, it should not be used after 12 hours from the time of TechneLite®, Technetium Tc 99m Generator elution.

After the termination of the nasolacrimal imaging procedure, blowing the nose and washing the eyes with sterile distilled water or an isotonic sodium chloride solution will further minimize the radiation dose.

Radiopharmaceuticals should be used only by physicians who are qualified by training and experience in the safe handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been performed to evaluate carcinogenic potential or whether Sodium Pertechnetate Tc 99m affects fertility in males or females.

Pregnancy Category C

Animal reproductive studies have not been conducted with Sodium Pertechnetate Tc 99m. It is also not known whether Sodium Pertechnetate Tc 99m can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Pertechnetate Tc 99m Injection should be given to a pregnant woman only if clearly needed.

Ideally examinations using radiopharmaceuticals, especially those elective in nature, of a woman of childbearing capability should be performed during the first few (approximately 10) days following the onset of menses.

Nursing Mothers

Sodium Pertechnetate Tc 99m is excreted in human milk during lactation; therefore formula feedings should be substituted for breast feeding.

This radiopharmaceutical preparation should not be administered to pregnant or lactating women unless expected benefits to be gained outweigh the potential risks.

Pediatric Use

See INDICATIONS and DOSAGE AND ADMINISTRATION sections. Also see the description of additional risks under WARNINGS.

Geriatric Use

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

ADVERSE REACTIONS: Allergic reactions including anaphylaxis have been reported infrequently following the administration of Sodium Pertechnetate Tc 99m Injection.

DOSAGE AND ADMINISTRATION: Sodium Pertechnetate Tc 99m Injection is usually administered by intravascular injection but can be given orally. For imaging the urinary bladder and ureters (direct isotopic cystography), the Sodium Pertechnetate Tc 99m Injection is administered by direct instillation aseptically into the bladder via a urethral catheter, following which the catheter is flushed with approximately 200 mL of sterile saline directly into the bladder. The dosage employed varies with each diagnostic procedure. If the oral route is elected, the patient should fast for at least six (6) hours before and two (2) hours after administration. When imaging the nasolacrimal drainage system, instill the Sodium Pertechnetate Tc 99m Injection by the use of a device such as a micropipette or similar method which will ensure the accuracy of the dose.

The suggested dose range employed for various diagnostic indications in the average ADULT PATIENT (70kg) is:

Vesico-ureteral Imaging	18.5 to 37MBq (0.5 to 1mCi)
Brain Imaging	370 to 740MBq (10 to 20mCi)
Thyroid Gland Imaging	37 to 370MBq (1 to 10mCi)
Salivary Gland Imaging	37 to 185MBq (1 to 5mCi)
Placenta Localization	37 to 111 MBq (1 to 3mCi)
Blood Pool Imaging	370 to 1110MBq (10 to 30mCi)
Nasolacrimal Drainage System	Max. 3.7MBq (100μCi)

The recommended dosage range in PEDIATRIC PATIENTS is:

Vesico-ureteral Imaging	18.5 to 37MBq (0.5 to 1mCi)
Brain Imaging	5.18 to 10.36MBq (140 to 280μCi)/kg body weight
Thyroid Gland Imaging	2.22 to 2.96MBq (60 to 80μCi)/kg body weight
Blood Pool Imaging	5.18 to 10.36MBq (140 to 280μCi)/kg body weight

A minimum dose of 111 to 185MBq (3 to 5 mCi) should be employed if radionuclide angiography is performed as part of the blood pool or brain imaging procedure.

NOTE: Up to one (1) gram of pharmaceutical grade potassium perchlorate in a suitable base or capsule may be given prior to administration of Sodium Pertechnetate Tc 99m Injection. When Sodium Pertechnetate Tc 99m Injection is used in children for brain or blood pool imaging, the administration of potassium perchlorate is especially important in order to minimize the absorbed radiation dose to the thyroid gland.

The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration of the dose.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The solution to be administered as the patient dose should be clear and contain no particulate matter. Do not use an eluate of the TechneLite®, Technetium Tc 99m Generator later than one (1) working day after elution (12 hours).

RADIATION DOSIMETRY

The estimated absorbed radiation doses2 to an average ADULT patient (70 kg) from an intravenous injection of a maximum dose of 1110MBq (30 millicuries) of Sodium Pertechnetate Tc 99m Injection distributed uniformly in the total body of subjects not pretreated with blocking agents such as pharmaceutical grade potassium perchlorate are shown in Table 5. For placenta localization studies, when a maximum of 111MBq (3 millicuries) is used, it is assumed to be uniformly equilibrated between maternal and fetal tissues.

Table 5. Absorbed Radiation Doses (Adults)
mGy/1110MBq (rads/30 millicuries)
Tissue	Resting Population	Active Population	mGy/111MBq (rads/3mCi)
Bladder Wall	15.9 (1.59)	25.5 (2.55)	-
Gastrointestinal Tract:
Stomach Wall	75.0 (7.50)	15.3 (1.53)	-
Upper Large Intestine Wall	20.4 (2.04)	36.0 (3.60)	-
Lower Large Intestine Wall	18.3 (1.83)	33.0 (3.30)	-
Red Marrow	5.7 (0.57)	5.1 (0.51)	-
Testes	2.7 (0.27)	2.7 (0.27)	-
Ovaries	6.6 (0.66)	9.0 (0.90)	-
Thyroid	39.0 (3.90)	39.0 (3.90)	-
Brain	4.2 (0.42)	3.6 (0.36)	-
Whole-Body	4.2 (0.42)	3.3 (0.33)	-
Placenta	-	-	0.5(0.05)
Fetus	-	-	0.5(0.05)

In pediatric patients, the maximum radiation doses of 185MBq (5 millicuries) of Sodium Pertechnetate Tc 99m Injection administered to a neonate (3.5 kg) for brain or blood pool imaging with radionuclide angiography are shown in Table 6. In pediatric patients, an average 30 minute exposure to 37MBq (1 millicurie) of Sodium Pertechnetate Tc 99m Injection following instillation for direct cystography, results in an estimated absorbed radiation dose of approximately 0.30mGy (30 millirads) to the bladder wall and 0.04 to 0.05mGy (4 to 5 millirads) to the gonads.3

Table 6. Absorbed Radiation Doses (Pediatric)
	Absorbed Radiation Doses
Tissue	mGy/ 37MBq	(rads/ 1mCi)	mGy/ 185MBq	(rads/ 5mCi)
2 Modified from: Summary of Current Radiation Dose Estimates to Normal Humans from 99m-Tc as Sodium Pertechnetate. MIRD Dose Estimates Report No. 8. J. Nucl. Med. 17(1): 74-77, 1976.
3 Conway, JJ, et al: Direct and Indirect radionuclide cystography. J. Urol. 113: 689-693 May 1975.
Thyroid (without perchlorate)	46.0	(4.6)	230.0	(23.0)
Thyroid (with perchlorate)	9.7	(1.0)	48.5	(4.9)
Large Bowel (with perchlorate)	19.0	(1.9)	95.5	(9.6)
Testes	1.0	(0.1)	5.1	(0.5)
Ovaries	2.2	(0.2)	11.0	(1.1)
Whole-Body	1.5	(0.2)	7.6	(0.8)

Table 7. Absorbed Radiation Dose from Dacryoscintigraphy Using Sodium Pertechnetate Tc 99m
	Absorbed Dose
Target Organ	mGy/ 3.7MBq	(mrad/ 100μCi)
* Assuming no blockage of drainage system. MIRD Dose Estimate Report No. 8, J. Nucl Med. 17: 74-77, 1976.
Eye Lens: If lacrimal fluid turnover is 16%/min If lacrimal fluid turnover is 100%/min If drainage system is blocked Total Body* Ovaries* Testes* Thyroid*	0.140 0.022 4.020 0.011 0.030 0.009 0.130	14.0 2.2 402.0 1.1 3.0 0.9 13.0

HOW SUPPLIED: Bristol-Myers Squibb Medical Imaging TechneLite®, Technetium Tc 99m Generator is available in the following quantities of radioactivity: 37.0 (NDC #11994-090-36), 74.0 (NDC #11994-090-73), 92.5 (NDC #11994-090-92), 111.0 (NDC #11994-090-01), 148.0 (NDC #11994-090-03), 166.5 (NDC #11994-090-04), 185.0 (NDC #11994-090-05), 222.0 (NDC #11994-090-06), 277.5 (NDC #11994-090-07), 370.0 (NDC #11994-090-09), 462.5 (NDC #11994-090-10), 555.0 GBq(NDC #11994-090-11), 666.0 GBq (NDC #11994-090- 12) (1000, 2000, 2500, 3000, 4000, 4500, 5000, 6000, 7500, 10,000, 12,500, 15,000 18,000 mCi) of Mo99 on the calibration date (date of manufacture) as specified on the product lot identification label affixed to the generator. Each generator is supplied with the following standard components:

: 1 Collect Needle Seal Vial
: 6 Eluant Charge Vials (may be supplied separately)
: 6 Eluate Collection Vials (may be supplied separately)
: 1 Package Insert
: 6 Radiation Labels (Collection Vial)
: 6 Radiation Labels (Eluting Shield)
: 1 Molybdenum Mo99 Activity Record (optional)

First order generators are shipped with the following accessory components:

: 2 Eluting Shields

Extra quantities of these components may be obtained at the customer's request.

STORAGE: Controlled room temperature 20° to 25°C (68° to 77°F) [See USP].

EXPIRATION: The expiration time of the Sodium Pertechnetate Tc 99m Injection is not later than 12 hours after elution. (If the eluate is to be used to reconstitute a kit for the preparation of a Technetium Tc 99m radiopharmaceutical, the kit should not be used after 12 hours from time of Generator elution or after six hours from the time of reconstitution of the kit.)

The expiration date of the TechneLite®, Technetium Tc 99m Generator is fourteen days post-manufacture.

ELUTION INSTRUCTIONS - TOTAL ELUTION METHOD

Waterproof gloves should be worn during elution.

Remove dust (clear plastic) cover of generator.

Perform all subsequent operations aseptically.

Remove silicone needle seal from eluant charge well. Discard as radioactive waste.

Remove flip-off seal and swab septum of eluant charge vial with a bactericide (such as 70% isopropyl alcohol), allow to dry, and insert the vial into charge well. Vial should be firmly inserted to assure puncture of septum.

Open elution shield base and insert an eluate collection vial from which the flip-off seal has been removed. Screw base back on securely. Swab the exposed vial septum with a bactericide.

Remove vented needle cover from collect well. Discard as radioactive waste.

Insert shielded eluate collection vial in collect well. Elution should commence within 30 seconds and can be visually checked by the appearance of bubbles in the eluant charge vial.**

**NOTE: If bubbles do not appear in the eluant charge vial within 30 seconds, either one of the vials has not been properly placed on its needle or the eluate vial has no vacuum. Remove the eluate collection vial to prevent vacuum loss; then remove and reinsert the charge vial. Reinsert the eluate collection vial and if elution does not commence, use a second shielded collection vial.

Caution: Tampering with the internal components could compromise sterility and present a radiation hazard. This generator should not be dismantled.

To assure proper yield and functioning, elution must proceed to completion as evidenced by emptying of the charge vial. Allow generator to elute for at least 3 minutes after the charge has been drained, or for a total of 6 minutes.

After elution has been completed, remove shield containing the collection vial. Obtain the collect needle seal vial, and using a bactericide, swab the septum of the collect needle seal vial and insert over the collect needle. The eluant vial is sterile and should stay in place until the next elution, functioning as a seal for the needles within the charge well. Upon initiating the next elution, discard the empty eluant vial as radioactive waste.

Fill out and attach the appropriate supplied pressure sensitive radioactivity labels to the elution shield containing the filled eluate collection vial. Do not use an eluate of the Technetium Tc 99m Generator later than 1 working day after the time of elution (12 hours).

Use a shielded syringe when introducing the Sodium Pertechnetate Tc 99m solution into mixing vials.

Maintain adequate shielding during the life of the radioactive preparation by using a lead vial shield and cover, and use a shielded syringe for withdrawing and injecting the preparation.

ASSAY INSTRUCTIONS FOR THE TechneLite®, TECHNETIUM Tc 99m GENERATOR ELUATE

The TechneLite®, Technetium Tc 99m Generator Eluate may be assayed using an ionization chamber dose calibrator. The manufacturer's instructions for operation of the dose calibrator should be followed for measurement of Technetium Tc 99m and Molybdenum Mo99 activity in the generator eluate. The Molybdenum 99/Technetium 99m ratio should be determined at the time of elution prior to administration, and from that ratio, the expiration time (up to 12 hours) of the eluate mathematically determined. Each eluate should meet or exceed the purity requirements of the current United States Pharmacopeia; that is, not more than 0.0056MBq (0.15 microcurie) of Molybdenum 99 per 37MBq (1 millicurie) of Technetium 99m per administered dose at the time of administration.

RADIOMETRIC MOLYBDENUM TEST PROCEDURE

This method is based on the fact that most Technetium Tc 99m radiation can be readily shielded and only the more energetic gamma rays from Molybdenum Mo99 (739KeV and 778KeV) are counted in the 550-850KeV energy range. The entire eluate may be assayed for Molybdenum Mo99 activity as follows:

A Cesium Cs 137 reference source which has the same geometry as the generator eluate must be used to standardize the well counter.

Determine the background after setting the window to the 550-850KeV energy range.

Count the Technetium Tc 99m eluate in its lead shield (thereby shielding out Technetium Tc 99m) by placing over the well or probe.

Count the Cs 137 reference source in the same shield geometry for the same time period.

Compute Molybdenum Mo99 activity in the eluate as follows:

μCi Molybdenum = μCi simulated Mo99 x net cpm Eluate

Mo99 (total) net cpm simulated Mo99 reference source

Divide this number by the mCi of Technetium Tc 99m. This result (μCi Mo99/mCi Tc 99m) can be converted to MBq Mo99/MBq Tc 99m by multiplying by 10-3. The U.S. Pharmacopeia and the U.S. Nuclear Regulatory Commission or equivalent Agreement State regulations specify a limit of 0.00015MBq Molybdenum Mo99 per MBq of Technetium Tc 99m (0.15μCi Mo99/mCi Tc 99m) at the time of administration to each patient.

COLORIMETRIC ALUMINUM ION TEST PROCEDURE

Bristol-Myers Squibb Medical Imaging, Inc. offers an Aluminum Ion Indicator Kit as an accessory to permit monitoring the aluminum ion in each eluate. It is based on a colorimetric reaction performed on a paper strip impregnated with indicator. A bottle of aluminum ion standard is included. Complete information is available on request.

DISPOSAL: All components shipped with the TechneLite®, Technetium Tc 99m Generator should be monitored for contamination prior to disposing into routine trash systems. The Technetium Tc 99m should not be disposed of into routine trash systems. The generator should be disposed through a USNRC or Agreement State licensed disposal agency or by a method approved by the appropriate regulatory authority. Spent generators may be returned; complete return instructions are provided regularly with generator shipments and are also available on request.

This radioactive drug is approved for distribution to persons licensed pursuant to the Code of Massachusetts Regulations 105 CMR 120.500 for the uses listed in 105 CMR 120.533 or under equivalent licenses of the U.S. Nuclear Regulatory Commision, an Agreement State or a Licensing State.

Bristol-Myers Squibb

Medical Imaging

331 Treble Cove Road

N. Billerica, MA 01862 USA

For Ordering Call Toll-Free: 800-225-1572 All other business: 800-362-2668

(In Massachusetts and International, call 978-667-9531)

U.S. Patent 5,109,160

Bristol-Myers Squibb

Medical Imaging

Printed in U.S.A.

513160-0205

February 2005