ABZ Plus

Albendazole:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• How supplied/storage and handling
• Patient counseling information
• ABZ Plus (Albendazole) reviews

1 INDICATIONS AND USAGE

ABZ Plus is an anthelmintic drug indicated for:

• Treatment of parenchymal neurocysticercosis due to active lesions caused by larval forms of the pork tapeworm, Taenia solium. (1.1)
• Treatment of cystic hydatid disease of the liver, lung, and peritoneum, caused by the larval form of the dog tapeworm, Echinococcus granulosus. (1.2)

1.1 Neurocysticercosis

ABZ Plus (Albendazole) is indicated for the treatment of parenchymal neurocysticercosis due to active lesions caused by larval forms of the pork tapeworm, Taenia solium.

1.2 Hydatid Disease

ABZ Plus (Albendazole) is indicated for the treatment of cystic hydatid disease of the liver, lung, and peritoneum, caused by the larval form of the dog tapeworm, Echinococcus granulosus.

2 DOSAGE AND ADMINISTRATION

Patients weighing 60 kg or greater, 400 mg twice daily; less than 60 kg, 15 mg/kg/day in divided doses twice daily. ABZ Plus (Albendazole) tablets and ABZ Plus (Albendazole) chewable tablets should be taken with food. (2)

• Hydatid disease: 28-day cycle followed by 14-day albendazole-free interval for a total of 3 cycles. (2)
• Neurocysticercosis: 8 to 30 days. (2)

See additional important information in the Full Prescribing Information. (2)

2.1 Dosage

Dosing of ABZ Plus (Albendazole) will vary depending upon the indication. ABZ Plus (Albendazole) tablets may be crushed or chewed and swallowed with a drink of water. ABZ Plus (Albendazole) chewable tablets are also available for children and patients who may experience swallowing difficulties. ABZ Plus (Albendazole) tablets and ABZ Plus (Albendazole) chewable tablets should be taken with food [see Clinical Pharmacology (12.3)].

2.2 Concomitant Medication to Avoid Adverse Reactions

Patients being treated for neurocysticercosis should receive appropriate steroid and anticonvulsant therapy as required. Oral or intravenous corticosteroids should be considered to prevent cerebral hypertensive episodes during the first week of treatment [see Warnings and Precautions ].

2.3 Monitoring for Safety Before and During Treatment

• Monitor blood counts at the beginning of each 28-day cycle of therapy, and every 2 weeks while on therapy with ABZ Plus (Albendazole) in all patients [see Warnings and Precautions (5.1)].
• Monitor liver enzymes (transaminases) at the beginning of each 28-day cycle of therapy, and at least every 2 weeks during treatment with ABZ Plus (Albendazole) in all patients [see Warnings and Precautions (5.5)].
• Obtain a pregnancy test in women of reproductive potential prior to therapy [see Warnings and Precautions (5.2)].

3 DOSAGE FORMS AND STRENGTHS

• Tablet: 200 mg
• Chewable Tablet: 200 mg

• Tablet: 200 mg (3)
• Chewable Tablet: 200 mg (3)

4 CONTRAINDICATIONS

ABZ Plus (Albendazole) is contraindicated in patients with known hypersensitivity to the benzimidazole class of compounds or any components of ABZ Plus (Albendazole).

Patients with known hypersensitivity to the benzimidazole class of compounds or any components of ABZ Plus (Albendazole).

5 WARNINGS AND PRECAUTIONS

• Bone Marrow Suppression: Fatalities have been reported due to bone marrow suppression; monitor blood counts in all patients at the beginning of each 28-day cycle of therapy, and every 2 weeks while on therapy. Discontinue ABZ Plus if clinically significant changes in blood counts occur. (5.1, 5.4)
• Teratogenic Effects: Obtain pregnancy test in women of reproductive potential prior to therapy and avoid usage in pregnant women except in clinical circumstances where no alternative management is appropriate. Discontinue therapy if pregnancy occurs and apprise patient of potential hazard to the fetus. (5.2)
• Risk of Neurologic Symptoms: Neurocysticercosis patients may experience cerebral hypertensive episodes, seizures or focal neurologic deficits after initiation of therapy; begin appropriate steroid and anticonvulsant therapy. (5.3)
• Risk of Retinal Damage in Retinal Cysticercosis: Cases of retinal involvement have been reported; examine the patient for the presence of retinal lesions before initiating therapy for neurocysticercosis. (5.4)
• Hepatic Effects. Elevations of liver enzymes may occur. Monitor liver enzymes before the start of each treatment cycle and at least every 2 weeks while on ABZ Plus (Albendazole) therapy and discontinue if clinically significant elevations occur. (5.5)

5.1 Bone Marrow Suppression

Fatalities associated with the use of ABZ Plus (Albendazole) have been reported due to granulocytopenia or pancytopenia ABZ Plus (Albendazole) may cause bone marrow suppression, aplastic anemia, and agranulocytosis. Monitor blood counts at the beginning of each 28-day cycle of therapy, and every 2 weeks while on therapy with ABZ Plus (Albendazole) in all patients. Patients with liver disease and patients with hepatic echinococcosis are at increased risk for bone marrow suppression and warrant more frequent monitoring of blood counts. Discontinue ABZ Plus (Albendazole) if clinically significant decreases in blood cell counts occur.

5.2 Teratogenic Effects

ABZ Plus may cause fetal harm and should not be used in pregnant women except in clinical circumstances where no alternative management is appropriate. Obtain pregnancy test prior to prescribing ABZ Plus (Albendazole) to women of reproductive potential. Advise women of reproductive potential to use effective birth control for the duration of ABZ Plus (Albendazole) therapy and for one month after end of therapy. Immediately discontinue ABZ Plus (Albendazole) if a patient becomes pregnant and apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5.3 Risk of Neurologic Symptoms in Neurocysticercosis

Patients being treated for neurocysticercosis should receive steroid and anticonvulsant therapy to prevent neurological symptoms (e.g. seizures, increased intracranial pressure and focal signs) as a result of an inflammatory reaction caused by death of the parasite within the brain.

5.4 Risk of Retinal Damage in Patients with Retinal Neurocysticercosis

Cysticercosis may involve the retina. Before initiating therapy for neurocysticercosis, examine the patient for the presence of retinal lesions. If such lesions are visualized, weigh the need for anticysticeral therapy against the possibility of retinal damage resulting from inflammatory damage caused by ALBENZA-induced death of the parasite.

5.5 Hepatic Effects

In clinical trials, treatment with ABZ Plus has been associated with mild to moderate elevations of hepatic enzymes in approximately 16% of patients. These elevations have generally returned to normal upon discontinuation of therapy. There have also been case reports of acute liver failure of uncertain causality and hepatitis [see Adverse Reactions (6)].

Monitor liver enzymes (transaminases) before the start of each treatment cycle and at least every 2 weeks during treatment. If hepatic enzymes exceed twice the upper limit of normal, consideration should be given to discontinuing ABZ Plus (Albendazole) therapy based on individual patient circumstances. Restarting ABZ Plus (Albendazole) treatment in patients whose hepatic enzymes have normalized off treatment is an individual decision that should take into account the risk/benefit of further ABZ Plus (Albendazole) usage. Perform laboratory tests frequently if ABZ Plus (Albendazole) treatment is restarted.

Patients with elevated liver enzyme test results are at increased risk for hepatotoxicity and bone marrow suppression [see Warnings and Precautions (5.1)]. Discontinue therapy if liver enzymes are significantly increased or if clinically significant decreases in blood cell counts occur.

5.6 Unmasking of Neurocysticercosis in Hydatid Patients

Undiagnosed neurocysticercosis may be uncovered in patients treated with ABZ Plus (Albendazole) for other conditions. Patients with epidemiologic factors who are at risk for neurocysticercosis should be evaluated prior to initiation of therapy.

6 ADVERSE REACTIONS

• Adverse reactions 1% or greater in hydatid disease: abnormal liver function tests, abdominal pain, nausea/vomiting, reversible alopecia, headache, dizziness/vertigo, fever.
• Adverse reactions 1% or greater in neurocysticercosis: headache, nausea/vomiting, raised intracranial pressure, meningeal signs. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Amedra Pharmaceuticals LLC at 1-888-894-6528 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 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.

The adverse reaction profile of ABZ Plus (Albendazole) differs between hydatid disease and neurocysticercosis. Adverse reactions occurring with a frequency of 1% or greater in either disease are described in Table 2 below.

These symptoms were usually mild and resolved without treatment. Treatment discontinuations were predominantly due to leukopenia (0.7%) or hepatic abnormalities (3.8% in hydatid disease). The following incidence reflects adverse reactions that were reported to be at least possibly or probably related to ABZ Plus (Albendazole).

The following adverse events were observed at an incidence of less than 1%:

Blood and Lymphatic System Disorders: There have been reports of leukopenia, granulocytopenia, pancytopenia, agranulocytosis, or thrombocytopenia [see Warnings and Precautions (5.1)].

Immune System Disorders: Hypersensitivity reactions, including rash and urticaria.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ABZ Plus (Albendazole). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Aplastic anemia, bone marrow suppression, neutropenia.

Eye Disorders: Vision blurred.

Gastrointestinal Disorders: Diarrhea.

General System Disorders: Asthenia.

Hepatobiliary Disorders: Elevations of hepatic enzymes, hepatitis, acute liver failure.

Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis.

Nervous System Disorders: Somnolence, convulsion.

Renal and Urinary Disorders: Acute renal failure.

Skin and Subcutaneous Tissue Disorders: Erythema multiforme, Stevens-Johnson syndrome.

7 DRUG INTERACTIONS

• Dexamethasone: Steady-state trough concentrations of ABZ Plus sulfoxide were about 56% higher when dexamethasone was coadministered with each dose of ABZ Plus (Albendazole). (7.1)
• Praziquantel: In the fed state increased mean maximum plasma concentration and area under the curve of ABZ Plus (Albendazole) sulfoxide by about 50% in healthy subjects. (7.2)
• Cimetidine: Increased ABZ Plus (Albendazole) sulfoxide concentrations in bile and cystic fluid by about 2-fold in hydatid cyst patients. (7.3)
• Theophylline: ABZ Plus (Albendazole) induces cytochrome P450 1A in human hepatoma cells; therefore, it is recommended that plasma concentrations of theophylline be monitored during and after treatment. (5.5, 7.4)

7.1 Dexamethasone

Steady-state trough concentrations of ABZ Plus (Albendazole) sulfoxide were about 56% higher when 8 mg dexamethasone was co-administered with each dose of ABZ Plus (Albendazole) (15 mg/kg/day) in 8 neurocysticercosis patients.

7.2 Praziquantel

In the fed state, praziquantel increased mean maximum plasma concentration and area under the curve of ABZ Plus (Albendazole) sulfoxide by about 50% in healthy subjects (n = 10) compared with a separate group of subjects (n = 6) given ABZ Plus (Albendazole) alone. Mean T_max and mean plasma elimination half-life of ABZ Plus (Albendazole) sulfoxide were unchanged. The pharmacokinetics of praziquantel were unchanged following co-administration with ABZ Plus (Albendazole) (400 mg).

7.3 Cimetidine

ABZ Plus (Albendazole) sulfoxide concentrations in bile and cystic fluid were increased (about 2-fold) in hydatid cyst patients treated with cimetidine (10 mg/kg/day) (n = 7) compared with ABZ Plus (Albendazole) (20 mg/kg/day) alone (n = 12). ABZ Plus (Albendazole) sulfoxide plasma concentrations were unchanged 4 hours after dosing.

7.4 Theophylline

Following a single dose of ABZ Plus (Albendazole) (400 mg), the pharmacokinetics of theophylline (aminophylline 5.8 mg/kg infused over 20 minutes) were unchanged. ABZ Plus (Albendazole) induces cytochrome P450 1A in human hepatoma cells; therefore, it is recommended that plasma concentrations of theophylline be monitored during and after treatment.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C.

There are no adequate and well-controlled studies of ABZ Plus administration in pregnant women. ABZ Plus (Albendazole) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

ABZ Plus (Albendazole) should not be used in pregnant women except in clinical circumstances where no alternative management is appropriate. Obtain pregnancy test prior to prescribing ABZ Plus (Albendazole) to women of reproductive potential. Advise women of reproductive potential to use effective birth control for the duration of ABZ Plus (Albendazole) therapy and for one month after end of therapy. If a patient becomes pregnant while taking this drug, ABZ Plus (Albendazole) should be discontinued immediately. If pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.

ABZ Plus (Albendazole) has been shown to be teratogenic (to cause embryotoxicity and skeletal malformations) in pregnant rats and rabbits. The teratogenic response in the rat was shown at oral doses of 10 and 30 mg/kg/day (0.10 times and 0.32 times the recommended human dose based on body surface area in mg/m², respectively) during gestation days 6 to 15 and in pregnant rabbits at oral doses of 30 mg/kg/day (0.60 times the recommended human dose based on body surface area in mg/m²) administered during gestation days 7 to 19. In the rabbit study, maternal toxicity (33% mortality) was noted at 30 mg/kg/day. In mice, no teratogenic effects were observed at oral doses up to 30 mg/kg/day (0.16 times the recommended human dose based on body surface area in mg/m²), administered during gestation days 6 to 15.

8.3 Nursing Mothers

ABZ Plus (Albendazole) is excreted in animal milk. It is not known whether it is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ABZ Plus (Albendazole) is administered to a nursing woman.

8.4 Pediatric Use

Hydatid disease is uncommon in infants and young children. In neurocysticercosis, the efficacy of ABZ Plus in children appears to be similar to that in adults.

8.5 Geriatric Use

In patients aged 65 and older with either hydatid disease or neurocysticercosis, there was insufficient data to determine whether the safety and effectiveness of ABZ Plus (Albendazole) is different from that of younger patients.

8.6 Patients with Impaired Renal Function

The pharmacokinetics of ABZ Plus in patients with impaired renal function has not been studied.

8.7 Patients with Extra-Hepatic Obstruction

In patients with evidence of extrahepatic obstruction (n = 5), the systemic availability of ABZ Plus (Albendazole) sulfoxide was increased, as indicated by a 2-fold increase in maximum serum concentration and a 7-fold increase in area under the curve. The rate of absorption/conversion and elimination of ABZ Plus (Albendazole) sulfoxide appeared to be prolonged with mean T_max and serum elimination half-life values of 10 hours and 31.7 hours, respectively. Plasma concentrations of parent ABZ Plus (Albendazole) were measurable in only 1 of 5 patients.

10 OVERDOSAGE

In case of overdosage, symptomatic therapy and general supportive measures are recommended.

11 DESCRIPTION

ABZ Plus (Albendazole) (albendazole) is an orally administered anthelmintic drug. Chemically, it is methyl 5-(propylthio)-2-benzimidazolecarbamate. Its molecular formula is C₁₂H₁₅N₃O₂S. Its molecular weight is 265.34. It has the following chemical structure:

ABZ Plus (Albendazole) is a white to yellowish powder. It is freely soluble in anhydrous formic acid and very slightly soluble in ether and in methylene chloride. ABZ Plus (Albendazole) is practically insoluble in alcohol and in water.

Tablets

Each white to off-white, circular, biconvex, bevel-edged film coated, TILTAB tablet is debossed with “ap” and “550” and contains 200 mg of ABZ Plus (Albendazole).

Inactive ingredients consist of: carnauba wax, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, sodium saccharin, sodium starch glycolate, and starch.

Chewable Tablets

Each round, mottled pink, concave chewable tablet is debossed with “ap” above “551” and contains 200 mg of ABZ Plus (Albendazole).

Inactive ingredients consist of: lactose monohydrate, microcrystalline cellulose, D-mannitol, sodium starch glycolate, povidone, N-C Wild Berry Type Flavor, magnesium stearate, crospovidone, polyvinyl acetate, sucralose, colloidal silicone dioxide, sodium lauryl sulfate, D&C Red #30/Helendon Pink Aluminum Lake.

methyl 5-(propylthio)-2-benzimidazolecarbamate

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

ABZ Plus (albendazole) is a synthetic, antihelminthic drug of the class benzimidazole [see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics

Absorption

ABZ Plus (Albendazole) is poorly absorbed from the gastrointestinal tract due to its low aqueous solubility. ABZ Plus (Albendazole) concentrations are negligible or undetectable in plasma as it is rapidly converted to the sulfoxide metabolite prior to reaching the systemic circulation. The systemic anthelmintic activity has been attributed to the primary metabolite, ABZ Plus (Albendazole) sulfoxide. Oral bioavailability appears to be enhanced when ABZ Plus (Albendazole) is coadministered with a fatty meal (estimated fat content 40 grams) as evidenced by higher (up to 5-fold on average) plasma concentrations of ABZ Plus (Albendazole) sulfoxide as compared to the fasted state.

Maximal plasma concentrations of ABZ Plus (Albendazole) sulfoxide were achieved 2 hours to 5 hours after dosing and were on average 1310 ng/mL (range 460 ng/mL to 1580 ng/mL) following oral doses of ABZ Plus (Albendazole) (400 mg) in 6 hydatid disease patients, when administered with a fatty meal. Plasma concentrations of ABZ Plus (Albendazole) sulfoxide increased in a dose-proportional manner over the therapeutic dose range following ingestion of a high-fat meal (fat content 43.1 grams). The mean apparent terminal elimination half-life of ABZ Plus (Albendazole) sulfoxide ranged from 8 hours to 12 hours in 25 healthy subjects, as well as in 14 hydatid and 8 neurocysticercosis patients.

In a study conducted in 113 fed and 117 fasted healthy subjects, ABZ Plus (Albendazole) chewable tablets were bioequivalent to ABZ Plus (Albendazole) tablets following single 400 mg oral doses of ABZ Plus (Albendazole). In this study, the average time to reach the maximal plasma concentrations of ABZ Plus (Albendazole) sulfoxide was 4.5 hours (range 2 to 10 hours) with a fatty meal (fat content 60 grams) and at 3 hours (range 1 to 5 hours) in the fasted state. Following administration of ABZ Plus (Albendazole) chewable tablets, average maximal plasma concentrations of ABZ Plus (Albendazole) sulfoxide were 804 ng/mL (range 202 to 2244 ng/mL) and 218 ng/mL (range 54 to 592 ng/mL) in the fed and fasted states, respectively. The apparent elimination half-life of ABZ Plus (Albendazole) sulfoxide was comparable between ABZ Plus (Albendazole) chewable tablets and ABZ Plus (Albendazole) tablets when both were given either under fed or fasted conditions.

Following 4 weeks of treatment with ABZ Plus (Albendazole) (200 mg three times daily), 12 patients’ plasma concentrations of ABZ Plus (Albendazole) sulfoxide were approximately 20% lower than those observed during the first half of the treatment period, suggesting that ABZ Plus (Albendazole) may induce its own metabolism.

Distribution

ABZ Plus (Albendazole) sulfoxide is 70% bound to plasma protein and is widely distributed throughout the body; it has been detected in urine, bile, liver, cyst wall, cyst fluid, and cerebrospinal fluid (CSF). Concentrations in plasma were 3-fold to 10-fold and 2-fold to 4-fold higher than those simultaneously determined in cyst fluid and CSF, respectively.

Metabolism and Excretion

ABZ Plus (Albendazole) is rapidly converted in the liver to the primary metabolite, ABZ Plus (Albendazole) sulfoxide, which is further metabolized to ABZ Plus (Albendazole) sulfone and other primary oxidative metabolites that have been identified in human urine. Following oral administration, ABZ Plus (Albendazole) has not been detected in human urine. Urinary excretion of ABZ Plus (Albendazole) sulfoxide is a minor elimination pathway with less than 1% of the dose recovered in the urine. Biliary elimination presumably accounts for a portion of the elimination as evidenced by biliary concentrations of ABZ Plus (Albendazole) sulfoxide similar to those achieved in plasma.

Specific Populations

Pediatrics

Following single-dose administration of 200 mg to 300 mg (approximately 10 mg/kg) ABZ Plus (Albendazole) to 3 fasted and 2 fed pediatric patients with hydatid cyst disease (age range 6 to 13 years), ABZ Plus (Albendazole) sulfoxide pharmacokinetics were similar to those observed in fed adults.

Geriatrics

Although no studies have investigated the effect of age on ABZ Plus (Albendazole) sulfoxide pharmacokinetics, data in 26 hydatid cyst patients (up to 79 years) suggest pharmacokinetics similar to those in young healthy subjects.

12.4 Microbiology

Mechanism of Action

ABZ Plus (Albendazole) binds to the colchicine-sensitive site of β-tubulin inhibiting their polymerization into microtubules. The decrease in microtubules in the intestinal cells of the parasites decreases their absorptive function, especially the uptake of glucose by the adult and larval forms of the parasites, and also depletes glycogen storage. Insufficient glucose results in insufficient energy for the production of adenosine trisphosphate (ATP) and the parasite eventually dies.

Mechanism of Resistance

Parasitic resistance to ABZ Plus (Albendazole) is caused by changes in amino acids that result in changes in the β-tubulin protein. This causes reduced binding of the drug to β-tubulin.

In the specified treatment indications ABZ Plus (Albendazole) appears to be active against the larval forms of the following organisms:

Echinococcus granulosus

Taenia solium

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies were conducted in mice and rats.

No evidence of increased incidence of tumors was found in the mice or rats at up to 400 mg/kg/day or 20 mg/kg/day respectively (2 times and 0.2 times the recommended human dose on a body surface area basis).

In genotoxicity tests, ABZ Plus (Albendazole) was found negative in an Ames Salmonella/Microsome Plate mutation assay, Chinese Hamster Ovary chromosomal aberration test, and in vivo mouse micronucleus test. In the in vitro BALB/3T3 cells transformation assay, ABZ Plus (Albendazole) produced weak activity in the presence of metabolic activation while no activity was found in the absence of metabolic activation.

ABZ Plus (Albendazole) did not adversely affect male or female fertility in the rat at an oral dose of 30 mg/kg/day (0.32 times the recommended human dose based on body surface area in mg/m²).

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Tablets

Each white to off-white, circular, biconvex, bevel-edged film coated, TILTAB tablet is debossed with “ap” and “550” and contains 200 mg of ABZ Plus.

Bottles of 2 Tablets NDC 52054-550-22

Bottles of 28 Tablets NDC 52054-550-28

Chewable Tablets

Each round, mottled pink, concave chewable tablet is debossed with “ap” above “551” and contains 200 mg of ABZ Plus (Albendazole).

2 Tablets in 1 Blister Pack (configured as a Wallet Card) NDC 52054-551-22

6 Tablets in 1 Blister Pack; 2 Blister Packs in 1 Carton NDC 52054-551-12

16.2 Storage and Handling

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Patients should be advised that:

• Some people, particularly children, may experience difficulties swallowing the ABZ Plus (Albendazole) tablets whole. ABZ Plus (Albendazole) chewable tablet is available for children and patients who may be unable to swallow a tablet.
• Take ABZ Plus (Albendazole) with food.
• ABZ Plus (Albendazole) may cause fetal harm, therefore, obtain a pregnancy test in women of reproductive potential prior to initiating therapy.
• Advise women of reproductive potential to use effective birth control while on ABZ Plus (Albendazole) and for one month after completing treatment.
• During ABZ Plus (Albendazole) therapy, monitor blood counts and liver enzymes every 2 weeks because of the possibility of harm to the liver or bone marrow.

ABZ Plus (Albendazole) and TILTAB are registered trademarks of GlaxoSmithKline, used with permission.

Distributed by:

Amedra Pharmaceuticals LLC

Horsham, PA 19044

LB# 799-04

ABZ Plus (Albendazole) 2 count ABZ Plus (Albendazole) 28 count

Ivermectin:

• ABZ Plus (Ivermectin) reviews

ABZ Plus (Ivermectin)

(ivermectin)

POUR-ON for Cattle

Contains 5 MG ivermectin/mL

PARASITICIDE

Kills: Roundworms ( including Brown Stomach Worm), Lungworms, Grubs, Sucking Lice, Biting Lice, Mange Mites, Horn Files

NDC 13985-523-08

Restricted Drug (California) - Use Only as Directed

ANADA 200-318, Approved by FDA

WARNING! FLAMMABLE!

KEEP AWAY FROM HEAT,SPARKS,OPEN FLAME,

AND OTHER SOURCES OF IGNITION

WARNING! NOT FOR USE IN HUMANS

Net Contents: 169 fl oz (5 Liter)

Consult your veterinarian for assistance in the diagnosis, treatment and control of parasitism.

Introduction: ABZ Plus (Ivermectin) (ivermectin) Pour-On delivers internal and external parasite control in one

convenient low-volume application. Vetrimec Pour-On contains ABZ Plus (Ivermectin), a unique chemical

entity.

Indications: ABZ Plus (Ivermectin) (ivermectin) Pour-On applied at the recommended dose level of 500 mcg/kg is indicated for the effective treatment and control of these parasites.

Persistent Activity: ABZ Plus (Ivermectin)^TM (ivermectin) Pour-On has been proved to effectively control infections and to protect cattle from re-infection with: Oesophagostomum radiatum and Dictyocaulus viviparous for 28 days after treatment. Cooperia punctata and Trichostrongylus axei for 21 days after treatment; Ostertagia ostertagi, Haemonchus placei, Cooperia oncophora and Cooperia surnabada for 14 days after treatment; Damalinia bovis for 56 days after treatment.

Treatment of Cattle for Horn Flies: ABZ Plus (Ivermectin)^TM (ivermectin) Pour-On controls horn flies (Haematobia irritans) for up to 28 days after dosing. For best results ABZ Plus (Ivermectin)^TM (ivermectin) Pour-On should be part of a parasite control program for both internal and external parasites based on the epidemiology of these parasites. Consult your veterinarian or an entomologist for the most effective timing of applications.

Dosage: The dose rate is 1 mL for each 22 lb. of body weight. The formulation should be applied along the topline in a narrow strip extending from the withers to the tailhead.

Administration: Squeeze-Measure-Pour System (33.8 fl oz for 1 Liter Bottle with 25 mL Measuring Cap) Attach metering cap to the bottle.

Select the correct dose rate by rotating the adjuster cap in either direction to position the dose indicator to the appropriate dose.

Gently squeeze the bottle to fill to level (any excess will return to the bottle) and then tip and apply to animal along topline.

Back Pack (84.5 fl oz/2.5 Liter Pack and 169 fl oz/5 Liter Pack).

Connect the applicator gun to the backpack as follows: Attach the open end of the draw-off tubing to the dosing equipment. (Because of the solvents used in the formulation, only the Protector Drench Gun from Instrument Supplies Limited, or equivalent, is recommended. Other applicators may exhibit compatibility problems resulting in locking, incorrect dosage or leakage).

Replace the shipping cap with the draw-off cap and tighten down.

Attach draw-off tubing to the draw-off cap.

Gently prime the applicator gun, checking for leaks.

Follow the manufacturer's directions for adjusting the dose.

When the interval between use of the applicator gun is expected to exceed 12 hours, disconnect the gun and draw-off tubing from the product container and empty the product from the gun and tubing back into the product container. To prevent removal of special lubricants from the Protector Drench Gun, the gun and tubing must not be washed.

Free standing 338 fl oz/10 Liter Bottle

Connect the applicator gun to the 338 fl oz/10 L Bottle as follows: Attach the open end of the draw-off tubing to the dosing equipment. (Because of the solvents used in the formulation, only the Protector Drench Gun from Instrument Supply Limited, or equivalent is recommend. Other applicators may exhibit compatibility problems resulting in locking, incorrect dosage or leakage.)

Replace the shipping cap with the draw-off cap and tighten down.

Attach draw-off tubing to the draw-off cap.

Gently prime the applicator gun, checking for leaks.

Follow the manufacture's dirctions for adjusting the dose.

When the interval between uses of the applicator gun is expected to exceed 12 hours, disconnect the gun and draw-off tubing from the product container and empty the product from the gun and the tubing back into the product container. To prevent removal of special lubricants from the Protector Drench Gun, the gun and tubing must not be washed.

Mode of Action: ABZ Plus (Ivermectin) is a member of the macrocyclic lactone class of endectocides which have a uniques mode of action. Compounds of the class bind selectively and with high affinity to glutamate-gated chloride ion channels which occur in ivertebrate nerve and muscle cells. This leads to an increase in the permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell, resulting in paralysis and death of the parasite. Compounds of this class may also interact with other ligand-gated chloride channels, such as those gated by the neurotransmitter gamma-aminobutyric acid (GABA). The margin of safety for compounds of this class is attributable to the fact that mammals do not have the glutamate-gated chloride channel and they do not readily cross the blood-brain barrier.

Animal Safety: Studies conducted in the U.S.A. have demonstrated the safety margin for ABZ Plus (Ivermectin). Based on plasma levels, the topically applied formulation is expected to be at least as well tolerated by breeding animals as is the subcataneous formulation which had no effect on breeding performance.

RESIDUE WARNING: Cattle must not be treated within 48 days of slaughter for human consumption. Because of withdrawal time in milk has not been established, do not use in female dairy cattle of breeding age. A withdrawal period has not been established for this product in pre-ruminating calves. Do not use in calves to be processed for veal.

WARNING! NOT FOR USE IN HUMANS.

This product should not be applied to self or others because it may be irritating to human skin and eyes and absorbed through the skin. To minimize accidental skin contact, the user should wear a long-sleeved shirt and rubber gloves. If accidental skin contact occurs, wash immediately with soap and water. If accidental eye exposure occurs, flush eyes immediately with water and seek medical attention.

Keep this and all drugs out of reach of children.

Restricted Drug (California) - Use Only as Directed

The Material Safety Data Sheets (MSDS) contains more detailed occupational safety information. To report adverse effects, obtain an MSDS or for assistance contact Bimeda Inc. at 1-888-524-6332.

WARNING! FLAMMABLE!

KEEP AWAY FROM HEAT, SPARKS, OPEN

FLAME, AND OTHER SOURCES OF IGNITION.

PRECAUTIONS

Store at 20°C - 25°C (68°F-77°F), excursions permitted between 15°C and 30°C (between 59°F - 86°F). Brief exposure to temperature up to 40°C (104°F) may be tolerated provided the mean kinetic temperature does not exceed 25"C (77°F); however such exposure should be minimized and protect from light.

Use only in well-ventilated areas or outdoors.

Close container tightly when not in use.

Cattle should not be treated when hair or hide is wet since reduced efficacy may be experienced.

Do not use when rain is expected to wet cattle within six hours after treatment.

This product is for application to skin surface only. Do not give orally or parenterally.

Cloudiness in the formulation may occur when ABZ Plus (Ivermectin) (ivermectin) Pour-On is stored at temperatures below 32°F. Allowing to warm at room temperature will restore the normal appearance without affecting efficacy.

Antiparasitic activity of ABZ Plus (Ivermectin) will be impaired if the formulation is applied to areas of the skin with mange scabs or lesions, or with dermatoses or adherent materials, e.g., caked mud or manure.

lvermectin has been associated with adverse reactions in sensitive dogs; therefore, ABZ Plus (Ivermectin) (ivermectin) Pour-On is not recommended for use in species other than cattle.

When to Treat Cattle with Grubs: Vetrimec (ivermectin) Pour-On effectively controls all stages of cattle grubs. However, proper timing of treatment is important. For the most effective results, cattle should be treated as soon as possible after the end of the heel fly (warble fly) season. While this is not peculiar to ABZ Plus (Ivermectin), destruction of Hypoderma larvae (cattle grubs) at the period when these grubs are in vital areas may cause undesirable host-parasite reactions. Killing Hypoderma lineatum when it is in the esophageal tissues may cause bloat; killing H. bovis when it is in the vertebral canal may cause staggering or paralysis. Cattle should be treated either before or after these stages of grub development.

Cattle treated with ABZ Plus (Ivermectin) (ivermectin) Pour-On at the end of the fly season may be re-treated with ABZ Plus (Ivermectin) (ivermectin) Pour-On during the winter without danger of grub-related reactions. For further information and advice on a planned parasite control program, consult your veterinarian.

Environmental Safety: Studies indicate that when ABZ Plus (Ivermectin) comes in contact with soil, it readily and tightly binds to the soil and becomes inactive over time. Free ABZ Plus (Ivermectin) may adversely affect fish or certain aquatic organisms. Do not permit cattle to enter lakes, streams, or ponds for at least 6 hours after treatment. Do not contaminate water by direct application or by the improper disposal of drug containers. Dispose of containers in an approved landfill or by incineration.

As with other avermectins, ABZ Plus (Ivermectin) is excreted in the dung of treated animals and can inhibit the reproduction and growth of pest and beneficial insects that use dung as a source of food and for reproduction. The magnitude and duration of such effects are species and life-cycle specific. When used according to label directions, the product is not expected to have an adverse impact on populations of dung-dependant insects.

Package lnformation: ABZ Plus (Ivermectin) (ivermectin) Pour-on is available in a 33.8 II oz/1 Liter Bottle with a measure-pour system, an 84.5 fl. oz/2.5 Liter Pack, a 169 fl. oz/5 Liter Pack, and a 338 fl oz/10 Liter Bottle intended for use with appropriate automatic dosing equipment.

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