Anusol Plus HC

Benzyl Benzoate:

• Active ingredients
• Uses
• Warnings
• Directions
• Other information
• Inactive ingredients
• Anusol Plus HC (Benzyl Benzoate) reviews

Active Ingredients

Anusol Plus HC Alcohol 10%

Camphor 0.6%

Menthol 0.4%

Purpose

External Analgesic

Uses

for the temporary relief of itching associated with insect bites and minor skin irritations.

Warnings

For external use only.

Do not use

• face or genital areas
• on a reas of blistered or broken skin
• with a compress after application

When using this product

do not get into eyes if contact occurs, flush eyes with water

Stop use and ask a doctor if

• condition worsens
• symptoms last more than 7 days or clear up and occur again within a few days.

If pregnant or breastfeeding

ask a health professional before use.

Keep out of reach of children.

If swallowed, get medical help or contact Poison Control Center right away.

Directions

• Apply to affected area not more than 3 times daily.
• Children under 2 years of age: do not use, ask a doctor.
• Severe reactions to Urushiol (the chemical released by the plant, which causes the irritation) can look like chemical burns and have a thick leathery appearance. Additional applications may be necessary.
  

• Test product on small patch of skin before applying to the entire body.

Other information

• Store at room temperature.
• You may report a serious adverse reaction to Report Reaction, LLC. PO Box 22, Plainsboro, NJ 08536-0222.
  

Inactive Ingredients

Water, Structure XL, Cutina GMS, Phenoxol T, Cremaphor CO 40, Butylene Glycol, Zinc Acetate, Steareth-2,

Steareth-20, Steareth 100, Proaqua ISL, Pelemol IPM, Estol 1543, Glydant Plus, Dimethicone, VE Acetate, Allantoin.

Made in the U.S.A. for:

IVY-DRY, INC.

299-B Fairfield Ave.

Fairfield, NJ 07070

©2012 Ivy-Dry, Inc.

Questions or Comments

www.ivydry.com

If you get Poison Ivy,

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Look no further than

Anusol Plus HC (Benzyl Benzoate) Products

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TEMPORARY

RELIEF

OF PAIN

AND ITCHING

Associated with Minor Skin

Irritations and Insect Bites

External Analgesic

Anusol Plus HC (Benzyl Benzoate) Cream Anusol Plus HC (Benzyl Benzoate) Cream

Bismuth Oxide:

• 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
• Clinical studies
• References
• How supplied/storage and handling
• Patient counseling information
• Anusol Plus HC (Bismuth Oxide) reviews

1 INDICATIONS AND USAGE

Anusol Plus HC is a combination metronidazole, a nitroimidazole antimicrobial, tetracycline,- a tetracycline class antimicrobial and Anusol Plus HC (Bismuth Oxide) subcitrate potassium, indicated for use, in combination with omeprazole,for the treatment of patients with Helicobacter pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori. (1.1)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Anusol Plus HC (Bismuth Oxide) and other antibacterial drugs, Anusol Plus HC (Bismuth Oxide) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.2)

1.1 Eradication of Helicobacter pylori in Patients with Active Duodenal Ulcer or History of Duodenal Ulcer Disease

Anusol Plus HC (Bismuth Oxide) in combination with omeprazole are indicated for the treatment of patients with Helicobacter pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori. The eradication of Helicobacter pylori has been shown to reduce the risk of duodenal ulcer recurrence.

1.2 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Anusol Plus HC (Bismuth Oxide) and other antibacterial drugs, Anusol Plus HC (Bismuth Oxide) should be used to treat only indicated 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.

2 DOSAGE AND ADMINISTRATION

Administer three Anusol Plus HC (Bismuth Oxide) capsules 4 times a day (after meals and at bedtime) for 10 days. One omeprazole 20 mg capsule should be taken twice a day with Anusol Plus HC (Bismuth Oxide) after the morning and evening meal for 10 days ( Table 1 ).

Instruct patients to swallow the Anusol Plus HC (Bismuth Oxide) capsules whole with a full glass of water (8 ounces). Ingestion of adequate amounts of fluid, particularly with the bedtime dose, is recommended to reduce the risk of esophageal irritation and ulceration by tetracycline hydrochloride.

If a dose is missed, patients should continue the normal dosing schedule until medication is gone. Patients should not take double doses. If more than 4 doses are missed, the prescriber should be contacted.

• Administer three Anusol Plus HC (Bismuth Oxide) capsules 4 times a day (after meals and at bedtime) for 10 days. (2)
• Administer Anusol Plus HC (Bismuth Oxide) with omeprazole 20 mg twice daily (after the morning and evening meals). (2)

3 DOSAGE FORMS AND STRENGTHS

Each Anusol Plus HC (Bismuth Oxide) capsule contains 140 mg of Anusol Plus HC (Bismuth Oxide) subcitrate potassium, 125 mg of metronidazole, and a smaller capsule inside containing 125 mg of tetracycline hydrochloride. The capsules are white and opaque, with the APTALIS_TM logo printed on the body and “BMT” printed on the cap.

Each capsule of Anusol Plus HC (Bismuth Oxide) contains: (3)

• 140 mg of Anusol Plus HC (Bismuth Oxide) subcitrate potassium
• 125 mg metronidazole
• 125 mg of tetracycline hydrochloride

4 CONTRAINDICATIONS

• Concurrent usage of Methoxyflurane.
• Disulfiram usage within the last two weeks.(4.2, 7.2)
• Alcoholic beverage consumption for at least three days during or after therapy. (4.3, 7.3)
• Severe renal impairment. (4.4)
• Women who are pregnant. (4.5, 8.1)
• Known hypersensitivity to product components. (4.6)

4.1 Methoxyflurane

Do not administer methoxyflurane to patients taking Anusol Plus HC (Bismuth Oxide). The concurrent use of tetracycline hydrochloride, a component of Anusol Plus HC (Bismuth Oxide), with methoxyflurane has been reported to result in fatal renal toxicity.

4.2 Disulfiram

Anusol Plus HC is contraindicated in patients who have taken disulfiram within the last two weeks. Psychotic reactions have been reported in alcoholic patients who are using metronidazole, a component of Anusol Plus HC (Bismuth Oxide), and disulfiram concurrently.

4.3 Alcohol

Alcoholic beverages or other products containing propylene glycol should not be consumed during and for at least 3 days after therapy with Anusol Plus HC (Bismuth Oxide). A disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) may occur due to the interaction between alcohol or propylene glycol and metronidazole, a component of Anusol Plus HC (Bismuth Oxide).

4.4 Severe Renal Impairment

Anusol Plus HC is contraindicated in patients with severe renal impairment. The antianabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN). In patients with significantly impaired renal function, higher serum concentrations of tetracyclines may lead to azotemia, hyperphosphatemia, and acidosis.

4.5 Pregnancy

Anusol Plus HC (Bismuth Oxide) is contraindicated during pregnancy.

4.6 Hypersensitivity Reactions

Anusol Plus HC (Bismuth Oxide) is contraindicated in patients with known hypersensitivity (e.g. urticaria, erythematous rash, flushing, and fever) to Anusol Plus HC (Bismuth Oxide) subcitrate potassium, metronidazole or other nitroimidazole derivatives, or tetracycline.

5 WARNINGS AND PRECAUTIONS

• Fetal Toxicity: Advise pregnant women of the risk throughout pregnancy for retardation of skeletal development seen in animal studies and permanent discoloration of teeth with tetracycline if used during the second or third trimester.
• Maternal Toxicity: Risk of hepatotoxicity in pregnant women with high doses of intravenous tetracycline also resulting in stillborn or premature birth. (5.3, 8.1)
• Tooth Enamel discoloration and hypoplasia: permanent discoloration may develop with use during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years). (5.4)
• Central and Peripheral Nervous System Effects: encephalopathy, convulsive seizures, aseptic meningitis and peripheral neuropathy with metronidazole, intracranial hypertension with tetracycline and neurotoxicity with bismuth-containing products. Monitor patients with CNS conditions closely and discontinue promptly if abnormal neurologic signs develop. (5.5)
• Photosensitivity: avoid exposure to sun and sun lamps. (5.7)
• Blood Dyscrasias: Use with caution in patients with a history of blood dyscrasias (5.9)
• Hepatic Impairment: Not recommended in patients with severe hepatic impairment. (5.10)
• Cutaneous Reactions: Stevens-Johnson, toxic epidermal necrolysis, DRESS syndrome. Discontinue treatment at the first evidence of a cutaneous reaction. (5.13)

5.1 Potential for Carcinogenicity

Metronidazole, a component of Anusol Plus HC (Bismuth Oxide), has been shown to be carcinogenic in mice and rats. Tumors affecting the liver, lungs, mammary and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters [see Nonclinical Toxicology (13)]. It is unknown whether metronidazole is associated with carcinogenicity in humans.

5.2 Fetal Toxicity

Tetracycline can cause fetal harm when administered to a pregnant woman. Based on animal data, use of drugs of the tetracycline class during the second and third trimester of pregnancy can cause permanent discoloration of the teeth and possibly inhibit bone development. Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in the newborn animals. If Anusol Plus HC (Bismuth Oxide) is used during pregnancy, or if the patient becomes pregnant while taking Anusol Plus HC (Bismuth Oxide), advise the patient of the potential risk to the fetus [see Contraindications (4.5) and Use in Specific Populations (8.1)].

5.3 Maternal Toxicity

Tetracycline, a component of Anusol Plus HC (Bismuth Oxide), administered during pregnancy at high doses (> 2 g IV) was associated with rare but serious cases of maternal hepatotoxicity. This syndrome may result in stillborn or premature birth due to maternal pathology.

5.4 Tooth Enamel Discoloration and Hypoplasia

The use of drugs of the tetracycline class during tooth development may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug, but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Anusol Plus HC (Bismuth Oxide), therefore, should not be used in this age group unless other drugs are not likely to be effective or are contraindicated.

5.5 Central and Peripheral Nervous System Effects

Metronidazole: Convulsive seizures, encephalopathy, aseptic meningitis and peripheral neuropathy (including optic neuropathy) have been reported. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity. Aseptic meningitis symptoms may occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued.

Tetracycline: Intracranial hypertension (IH), including pseudotumor cerebri, has been associated with the use of tetracyclines. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin should be avoided because isotretinoin is also known to cause IH.

Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation, patients should be monitored until they stabilize.

Bismuth-containing products: Cases of neurotoxicity associated with excessive doses of various bismuth-containing products have been reported. Effects have been reversible with discontinuation of Anusol Plus HC (Bismuth Oxide) therapy.

The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of Anusol Plus HC (Bismuth Oxide) therapy.

5.6 Development of Potential for Microbial Overgrowth

Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with an antifungal agent. As with other antibacterial drugs, use of tetracycline hydrochloride may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, discontinue Anusol Plus HC and institute appropriate therapy.

5.7 Photosensitivity

Photosensitivity, manifested by an exaggerated sunburn reaction, has been observed in patients taking tetracycline. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs. Instruct patients taking Anusol Plus HC (Bismuth Oxide) to avoid exposure to the sun or sun lamps. Discontinue treatment at the first evidence of skin erythema.

5.8 Darkening of the Tongue and/or Black Stool

Anusol Plus HC subcitrate potassium may cause temporary and harmless darkening of the tongue and/or black stools, generally reversible within several days after treatment is stopped. Stool darkening should not be confused with melena.

5.9 Use in Patients with Blood Dyscrasias

Metronidazole is a nitroimidazole, and should be used with care in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy.

5.10 Increased Plasma Concentrations in Patients with Hepatic Impairment

Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse events. Anusol Plus HC is not recommended in patients with severe hepatic impairment (Child-Pugh C).

5.11 Laboratory Test Interactions

Anusol Plus HC (Bismuth Oxide) absorbs x-rays and may interfere with x-ray diagnostic procedures of the gastrointestinal tract.

Anusol Plus HC (Bismuth Oxide) subcitrate potassium may cause a temporary and harmless darkening of the stool. However, this change does not interfere with standard tests for occult blood.

Metronizadole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide (NAD+ <=> NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

5.12 Development of Drug Resistant Bacteria

Prescribing Anusol Plus HC 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.

5.13 Cutaneous Reactions

Skin and subcutaneous disorders including Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS syndrome (drug rash with eosinophilia and systemic symptoms) have been reported. Discontinue treatment at the first evidence of a cutaneous reaction [see Adverse Reactions (6.2)].

5.14 Drug Interactions

Oral Contraceptives

Concurrent use of Anusol Plus HC (Bismuth Oxide) with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of Anusol Plus HC (Bismuth Oxide). Breakthrough bleeding has been reported. Advise women of child-bearing potential to use a different or additional form of contraception while taking Anusol Plus HC (Bismuth Oxide) [see Drug Interactions (7.4)].

Anticoagulants

Anusol Plus HC (Bismuth Oxide) may alter the anticoagulant effects of warfarin and other oral coumarin anticoagulants. Metronidazole has been reported to potentiate the anticoagulant effect of warfarin, and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. Tetracycline has been shown to depress plasma prothrombin activity. Closely monitor prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests if Anusol Plus HC (Bismuth Oxide) is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Drug Interactions (7.5)].

Lithium

In patients stabilized on relatively high doses of lithium, short-term use of Anusol Plus HC (Bismuth Oxide) may cause elevation of serum lithium concentrations and signs of lithium toxicity due to the interaction between metronidazole and lithium. Monitor serum lithium and serum creatinine concentrations daily for several days after beginning treatment with Anusol Plus HC (Bismuth Oxide) to detect any increase that may precede clinical symptoms of lithium toxicity [see Drug Interactions (7.6)].

Busulfan

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Do not administer Anusol Plus HC (Bismuth Oxide) concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to Anusol Plus HC (Bismuth Oxide) are available, and concomitant administration with busulfan is medically needed, Monitor for busulfan toxicity and busulfan plasma concentrations and adjust the busulfan dose accordingly [see Drug Interactions (7.8)].

6 ADVERSE REACTIONS

Most frequently reported adverse reactions ; abnormal feces, diarrhea, nausea, and headache. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-678-1605 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 safety of Anusol Plus HC (Bismuth Oxide) plus omeprazole (OBMT) to eradicate Helicobacter pylori was assessed in an open-label, randomized, active-controlled clinical trial conducted in North America. The duration of treatment was 10 days with 147 patients exposed to Anusol Plus HC (Bismuth Oxide) plus omeprazole (OBMT) and 152 exposed to control, consisting of omeprazole, amoxicillin, and clarithromycin (OAC). The age of the population in the study ranged from 18 to 75 years, with 59% male patients and 59% Caucasian patients.

Adverse drug reactions were reported in 58% of patients in the OBMT group and 59% of patients in the OAC group. There were no adverse reactions leading to discontinuation of the study during the clinical trial.

Adverse reactions with an incidence of ≥ 5% in OBMT group include abnormal feces, diarrhea, nausea, and headache. Adverse drug reactions with an incidence of ≥ 5% in OAC group include diarrhea, dysgeusia, dyspepsia, nausea and headache.

Table 2 lists adverse reactions with an incidence of ≥ 1%, in either groups (OBMT vs OAC) and in order of decreasing incidence for the OBMT group.

Adverse reactions with an incidence of <1% for OBMT group are: back pain, vomiting, tongue darkening, anxiety, gastritis, gastroenteritis, myalgia, chest pain, increased appetite, blood creatine phosphokinase increased, malaise, somnolence, tachycardia, duodenal ulcer, visual disturbance, weight increased.

6.2 Postmarketing Experience

Additionally, the following adverse reactions, presented by system organ class in alphabetical order, have been identified during post approval use of Anusol Plus HC (Bismuth Oxide). 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.

• Gastrointestinal disorders: abdominal distention, eructation, flatulence
• General disorders and administration site conditions: chest discomfort, fatigue.
• Infections and infestations: candidiasis, pseudomembranous colitis (Clostridium difficile colitis).
• Nervous Systems: peripheral neuropathy.
• Skin and subcutaneous disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome (drug rash with eosinophilia and systemic symptoms)

Metronidazole

Blood and Lymphatic system disorders: Reversible neutropenia (leucopenia) in cases of prolonged treatment; rarely reversible thrombocytopenia however no persistent hematological abnormalities attributable to metronidazole have been observed.

Cardiac disorders: Flattening of the T-wave.

Gastrointestinal disorders: Nausea, vomiting, diarrhea, abdominal pain, constipation, anorexia, metallic taste, furry tongue, glossitis, stomatitis and candida overgrowth.

Hypersensitivity/Immune system disorders: Urticaria, erythematous rash, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever.

Metabolism and nutrition disorders: Pancreatitis.

Nervous system disorders: Convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia.

Dermatologic disorders: Erythematous rash and pruritus.

Renal and urinary disorders: Dysuria, cystitis, polyuria, incontinence, darkened urine, and a sense of pelvic pressure.

Other: Dyspareunia, decrease of libido, proctitis, joint pains.

Tetracycline Hydrochloride

Blood and lymphatic system disorders: Hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, neutropenia, and eosinophilia.

Gastrointestinal disorders: Nausea, vomiting, diarrhea, anorexia, glossitis, black hairy tongue, dysphagia, enterocolitis, inflammatory lesions (with Candida overgrowth) in the anogenital region, esophagitis and esophageal ulceration.

Nervous system disorders: Intracranial hypertension including pseudotumor cerebri, tinnitus, and myasthenic syndrome.

Renal and urinary disorders: Increased BUN.

Skin and subcutaneous tissue disorders: Maculopapular and erythematous rashes, onycholysis, discoloration of the nails, exfoliative dermatitis and photosensitivity have been rarely reported.

Liver: Hepatotoxicity and liver failure.

Hypersensitivity reactions: Urticaria, angioedema, anaphylaxis, Henoch-Schonlein purpura, pericarditis, exacerbation of systemic lupus erythematosus, and serum sickness-like reactions.

7 DRUG INTERACTIONS

• Methoxyflurane: Risk of fatal renal toxicity; do not co-administer..
• Disulfiram: Psychotic reactions can occur; do not take concurrently or within the last 2 weeks of disulfiram. (4.2, 7.2)
• Alcohol: Abdominal cramps, nausea, vomiting, headaches, and flushing can occur; do not consume during therapy and for at least 3 days afterwards. (4.3, 7.3)
• Oral Contraceptives: Decreased efficacy possibly resulting in pregnancy; use a different or additional form of contraception. (5.14, 7.4)
• Anticoagulants: Potentiation of the anticoagulant effect; Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored. (5.14, 7.5)
• Lithium: Increased lithium serum concentrations; measure serum lithium and serum creatinine concentrations during therapy. (5.14, 7.6)
• Antacids, Multivitamins or Dairy Products: Decreased absorption of Anusol Plus HC (Bismuth Oxide); do not take concomitantly. (7.7)
• Busulfan: Increased busulfan serum concentrations; avoid concomitant use, monitor for busulfan toxicity (7.8)
• CYP inducers and CYP inhibitors: Prolonged or accelerated half-life of metronidazole or concomitant medications; use with caution (7.9, 7.10)

7.1 Methoxyflurane

Do not administer methoxyflurane to patients taking Anusol Plus HC (Bismuth Oxide). The concurrent use of tetracycline hydrochloride, a component of Anusol Plus HC (Bismuth Oxide), with methoxyflurane has been reported to result in fatal renal toxicity.

7.2 Disulfiram

Psychotic reactions have been reported in alcoholic patients who are using metronidazole, a component of Anusol Plus HC and disulfiram concurrently. Anusol Plus HC (Bismuth Oxide) should not be given to patients who have taken disulfiram within the last two weeks.

7.3 Alcohol

Consumption of alcoholic beverages or administration of other products containing propylene glycol during treatment with Anusol Plus HC (Bismuth Oxide) and for at least 3 days afterwards may cause a disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) due to the interaction between alcohol or propylene glycol and metronidazole, a component of Anusol Plus HC (Bismuth Oxide). Discontinue alcoholic beverage or other products containing propylene glycol during and for at least 3 days after therapy with Anusol Plus HC (Bismuth Oxide).

7.4 Oral Contraceptives

Concurrent use of Anusol Plus HC with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of Anusol Plus HC (Bismuth Oxide). Breakthrough bleeding has been reported. Women of child-bearing potential should use a different or additional form of contraception while taking Anusol Plus HC (Bismuth Oxide).

7.5 Anticoagulants

Anusol Plus HC (Bismuth Oxide) may alter the anticoagulant effects of warfarin and other oral coumarin anticoagulants. Metronidazole has been reported to potentiate the anticoagulant effect of warfarin, and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. Tetracycline has been shown to depress plasma prothrombin activity. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if Anusol Plus HC (Bismuth Oxide) is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding.

7.6 Lithium

In patients stabilized on relatively high doses of lithium, short-term use of Anusol Plus HC may cause elevation of serum lithium concentrations and signs of lithium toxicity due to the interaction between metronidazole and lithium. Serum lithium and serum creatinine concentrations should be monitored several days after beginning treatment with Anusol Plus HC (Bismuth Oxide) to detect any increase that may precede clinical symptoms of lithium toxicity.

7.7 Antacids, Multivitamins, or Dairy Products

The absorption of Anusol Plus HC (Bismuth Oxide) may be reduced if administered with antacids containing aluminium, calcium, or magnesium; preparations containing iron, zinc, or sodium bicarbonate; or milk or dairy products due to the interaction between these products and tetracycline. These products should not be consumed concomitantly with Anusol Plus HC (Bismuth Oxide). However, the clinical significance of reduced tetracycline systemic exposure is unknown as the relative contribution of systemic versus local antimicrobial activity against Helicobacter pylori has not been established.

7.8 Busulfan

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Do not administer Anusol Plus HC concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to Anusol Plus HC (Bismuth Oxide) are available, and concomitant administration with busulfan is medically needed, monitor for busulfan toxicity and busulfan plasma concentrations and adjust the busulfan dose accordingly.

7.9 Inhibitors of CYP450 liver enzymes

The simultaneous administration of Anusol Plus HC (Bismuth Oxide) and drugs that inhibit microsomal liver enzymes, such as cimetidine, may result in a prolonged half-life and decreased plasma clearance of metronidazole.

7.10 Inducers of CYP450 liver enzymes

The simultaneous administration of Anusol Plus HC (Bismuth Oxide) and drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma concentrations of metronidazole. Impaired clearance of phenytoin has also been reported in this situation. Monitor phenytoin concentrations during treatment with Anusol Plus HC (Bismuth Oxide).

8 USE IN SPECIFIC POPULATIONS

• Lactation: A woman should pump and discard human milk for the duration of Anusol Plus HC therapy, and for 2 days after therapy ends, (8.2)
• Pediatric Use: Tetracycline may cause permanent discoloration of the teeth. Enamel hypoplasia has also been reported. Do not use in children less than 8 years of age. (5.4, 8.4)

8.1 Pregnancy

Risk Summary

Anusol Plus HC (Bismuth Oxide) is contraindicated in women who are pregnant because treatment of Helicobacter pylori infection can be delayed in pregnant women, and the use of drugs of the tetracycline class during the second and third trimester pregnancy can also cause permanent discoloration of the teeth (yellow-gray brown) and possibly inhibit bone development . Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in the newborn animals. There are maternal risks with high intravenous doses of tetracycline .

Metronidazole usage in pregnancy has been associated with certain congenital anomalies . In animals, no fetotoxicity was observed when metronidazole was orally administered to pregnant mice at approximately 5% of the indicated human dose. There are no human or animal data on the use of Anusol Plus HC (Bismuth Oxide) subcitrate potassium during pregnancy. Although there are data on the separate components, there are no available data on the use of Anusol Plus HC (Bismuth Oxide) in pregnant women.

Clinical Considerations

Maternal Adverse Reactions

Tetracycline administered during pregnancy at high doses (> 2 g IV) was associated with rare but serious cases of maternal hepatotoxicity. This syndrome may result in stillborn or premature birth due to maternal pathology .

Data

Human Data

Tetracycline

Published case reports have described the yellowing of bones and teeth in human infants exposed to tetracycline during the second and third trimester of pregnancy. The yellowing is caused by the direct deposition of tetracycline during the mineralization process. This discoloration is more common during long-term use of the drug but has also been observed following repeated short-term courses. All tetracyclines form a stable calcium complex in any bone forming tissue. A decrease in fibula growth rate was observed in premature infants given oral tetracycline in doses of 25 mg/kg every six hours. The effect resolved when the drug was discontinued. One long-term follow-up study in children exposed to tetracycline in-utero showed no adverse effects on bone growth and development.

Metronidazole

There are published data from case-control studies, cohort studies, and 2 meta-analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero; however, these findings were not confirmed. In addition, more than ten randomized, placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited.

Anusol Plus HC (Bismuth Oxide) subcitrate potassium

There are no human data on the use of Anusol Plus HC (Bismuth Oxide) subcitrate potassium during pregnancy.

Animal Data

Tetracycline

Results of animal studies indicate that tetracycline crosses the placenta, is found in fetal tissues, and can have toxic effects on the developing fetus (often related to reversible retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. Multiple studies of limited design were conducted with pregnant and lactating female rats that resulted in fetuses and neonates with yellow discoloration of bones and teeth.

Metronidazole

Metronidazole crosses the placental barrier. No fetotoxicity was observed when metronidazole was administered orally to pregnant mice at 10 mg/kg/day, approximately 5 percent of the indicated human dose (1500 mg/day) based on body surface area; however in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed. The relationship of these findings to the drug is unknown.

Anusol Plus HC (Bismuth Oxide) subcitrate potassium

Animal reproductive studies have not been conducted with Anusol Plus HC (Bismuth Oxide) subcitrate potassium.

8.2 Lactation

Risk Summary

Two of the individual components of Anusol Plus HC, tetracycline and metronidazole, are present in human milk at concentrations similar to maternal serum levels. It is not known whether Anusol Plus HC (Bismuth Oxide) subcitrate, the third component of Anusol Plus HC (Bismuth Oxide) is present in human milk. It is not known what effect metronidazole, tetracycline or Anusol Plus HC (Bismuth Oxide) has on the breastfed infant or on milk production. Tetracycline binds with calcium in human milk [see Clinical Pharmacology (12.3)]. Data indicate that oral absorption of tetracycline in infants is low due to the calcium binding in human milk. Metronidazole transfers to human milk, and infant serum levels can be close to or comparable to infant therapeutic levels. Because of the potential risk of tumorigenicity shown in animal studies with metronidazole, a woman should pump and discard human milk for the duration of Anusol Plus HC (Bismuth Oxide) therapy, and for 2 days after therapy ends, and feed her infant stored human milk (collected prior to therapy) or formula.

8.4 Pediatric Use

Safety and effectiveness of Anusol Plus HC (Bismuth Oxide) in pediatric patients infected with Helicobacter pylori have not been established.

Tetracycline use in children may cause permanent discoloration of the teeth. Enamel hypoplasia has also been reported. Anusol Plus HC (Bismuth Oxide) should not be used in children up to 8 years of age.

8.5 Geriatric Use

Clinical studies of Anusol Plus HC did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, elderly patients may have a greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapies. Anusol Plus HC (Bismuth Oxide) subcitrate potassium, a component of Anusol Plus HC (Bismuth Oxide), is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, additional monitoring may be required.

8.6 Renal Impairment

The antianabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN). In patients with severe renal impairment, higher serum concentrations of tetracycline may lead to azotemia, hyperphosphatemia, and acidosis.

8.7 Hepatic Impairment

Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in plasma. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse events. Anusol Plus HC (Bismuth Oxide) is not recommended in patients with severe hepatic impairment [see Warnings and Precautions (5.10), Clinical Pharmacology (12.3)].

10 OVERDOSAGE

In case of an overdose, patients should contact a physician, poison control center, or emergency room. The available overdosage information for each of the individual components in Anusol Plus HC (Bismuth Oxide) (Metronidazole, Tetracycline and Anusol Plus HC (Bismuth Oxide) subcitrate potassium) are summarized below:

Metronidazole:

Single oral doses of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia. Metronidazole is dialyzable.

Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day.

Treatment of Overdosage

There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.

Tetracycline:

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

Anusol Plus HC (Bismuth Oxide) subcitrate potassium:

Symptoms of a Anusol Plus HC (Bismuth Oxide) subcitrate potassium overdosage are not known.

11 DESCRIPTION

Anusol Plus HC (Bismuth Oxide) capsules are a combination antimicrobial product containing Anusol Plus HC (Bismuth Oxide) subcitrate potassium, metronidazole, and tetracycline hydrochloride for oral administration. Each size 0 elongated capsule contains:

• Anusol Plus HC (Bismuth Oxide) subcitrate potassium, 140 mg
• metronidazole, 125 mg
• smaller capsule (size 3) containing tetracycline hydrochloride, 125 mg

Tetracycline hydrochloride is encapsulated within a smaller capsule to create a barrier to avoid contact with Anusol Plus HC (Bismuth Oxide) subcitrate potassium.

Each Anusol Plus HC (Bismuth Oxide) capsule contains the following inactive ingredients: Magnesium Stearate NF, Lactose Monohydrate NF, Talc USP, Gelatin USP, and Titanium Dioxide NF, Printed in red ink.

Anusol Plus HC (Bismuth Oxide) subcitrate potassium is a white or almost white powder. It is a soluble, complex Anusol Plus HC (Bismuth Oxide) salt of citric acid. The schematized empirical molecular formula of Anusol Plus HC (Bismuth Oxide) subcitrate potassium is Bi (Citrate)₂K₅●3 H₂O. The equivalent theoretical molecular formula is BiC₁₂H₁₄K₅O₁₇. The molecular mass of the theoretical molecular formula of a single unit of Anusol Plus HC (Bismuth Oxide) subcitrate potassium is 834.71.

Metronidazole is a white to pale yellow crystalline powder. Metronidazole is 2-methyl-5-nitroimidazole-1-ethanol, with a molecular formula of C₆H₉N₃O₃ and the following structural formula:

Tetracycline hydrochloride is a yellow, odorless, crystalline powder. Tetracycline hydrochloride is stable in air, but exposure to strong sunlight causes it to darken. Tetracycline hydrochloride is (4S,4aS,5aS,6S,12aS)-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-penta-hydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrochloride, with a molecular formula of C₂₂H₂₄N₂O₈●HCl and the following structural formula:

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Anusol Plus HC is a combination of antibacterial agents (metronidazole and tetracycline hydrochloride) and Anusol Plus HC (Bismuth Oxide) subcitrate potassium.

12.3 Pharmacokinetics

The pharmacokinetics of the individual components of Anusol Plus HC (Bismuth Oxide), Anusol Plus HC (Bismuth Oxide) subcitrate potassium, metronidazole and tetracycline hydrochloride are summarized below. In addition, two studies on Anusol Plus HC (Bismuth Oxide) were conducted to determine the effect of co-administration on the pharmacokinetics of the components.

Anusol Plus HC (Bismuth Oxide) Subcitrate Potassium (Bismuth)

Absorption and Distribution

Orally absorbed Anusol Plus HC (Bismuth Oxide) is distributed throughout the entire body. Anusol Plus HC (Bismuth Oxide) is highly bound to plasma proteins (>90%).

Metabolism and Excretion

The elimination half-life of Anusol Plus HC (Bismuth Oxide) is approximately 5 days in both blood and urine. Elimination of Anusol Plus HC (Bismuth Oxide) is primarily through urinary and biliary routes. The rate of renal elimination appears to reach steady state 2 weeks after treatment discontinuation with similar rates of elimination at 6 weeks after discontinuation. The average urinary elimination of Anusol Plus HC (Bismuth Oxide) is 2.6% per day in the first two weeks after discontinuation (urine drug concentrations 24 to 250 mcg/mL) suggesting tissue accumulation and slow elimination.

Metronidazole

Absorption and Distribution

Following oral administration, metronidazole is well absorbed, with peak plasma concentrations occurring between 1 and 2 hours after administration. Plasma concentrations of metronidazole are proportional to the administered dose, with oral administration of 500 mg producing a peak plasma concentration of 12 mcg/mL.

Metronidazole appears in the plasma mainly as unchanged compound with lesser quantities of the 2-hydroxymethyl metabolite also present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole also appears in cerebrospinal fluid, saliva, and breast milk in concentration similar to those found in plasma.

Metabolism and Excretion

The average elimination half-life of metronidazole in normal volunteers is 8 hours. The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(β-hydroxyethyl) 2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1.73m².

Decreased renal function does not alter the single dose pharmacokinetics of metronidazole. In patients with decreased liver function, plasma clearance of metronidazole is decreased.

Tetracycline Hydrochloride

Absorption, Distribution, Metabolism and Excretion

Tetracycline hydrochloride is absorbed (60%-90%) in the stomach and upper small intestine. The presence of food, milk or cations may significantly decrease the extent of absorption. In the plasma, tetracycline is bound to plasma proteins in varying degrees. It is concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in biologically active form.

Tetracycline hydrochloride is distributed into most body tissues and fluids. It is distributed into the bile and undergoes varying degrees of enterohepatic recirculation. Tetracycline hydrochloride tends to localize in tumors, necrotic or ischemic tissue, liver and spleen and form tetracycline-calcium orthophosphate complexes at sites of new bone formation or tooth development. Tetracycline readily crosses the placenta and is excreted in high amounts in breast milk.

Anusol Plus HC (Bismuth Oxide) Capsules

A comparative bioavailability study of metronidazole (375 mg), tetracycline hydrochloride (375 mg) and Anusol Plus HC (Bismuth Oxide) subcitrate potassium (420 mg, equivalent to 120 mg Bi₂O₃) administered as Anusol Plus HC (Bismuth Oxide) or as 3 separate capsule formulations administered simultaneously was conducted in healthy male volunteers. The pharmacokinetic parameters for the individual drugs, when administered as separate capsule formulations or as Anusol Plus HC (Bismuth Oxide), are similar as shown in Table 3 .

Effect of Anusol Plus HC (Bismuth Oxide) on the Bioavailability of Tetracycline Hydrochloride

There is an anticipated reduction in tetracycline hydrochloride systemic absorption due to an interaction with Anusol Plus HC (Bismuth Oxide). The effect of a reduced tetracycline hydrochloride systemic exposure, due to an interaction with Anusol Plus HC (Bismuth Oxide), on the clinical efficacy of Anusol Plus HC (Bismuth Oxide) is not thought to be clinically meaningful as the contribution of systemic, as compared to local, antimicrobial activity against Helicobacter pylori has not been established.

Effect of Food on the Bioavailability of Anusol Plus HC (Bismuth Oxide)

The pharmacokinetic parameters for metronidazole, tetracycline hydrochloride and Anusol Plus HC (Bismuth Oxide) were also determined when Anusol Plus HC (Bismuth Oxide) was administered under fasting and fed conditions, as shown in Table 4 . Food reduced the systemic absorption of all three Anusol Plus HC (Bismuth Oxide) components, with AUC values for metronidazole, tetracycline hydrochloride and Anusol Plus HC (Bismuth Oxide) being reduced by 6%, 34% and 60%, respectively. Reduction in the absorption of all three Anusol Plus HC (Bismuth Oxide) components in the presence of food is not considered to be clinically significant. Anusol Plus HC (Bismuth Oxide) should be given after meals and at bedtime, in combination with omeprazole twice a day.

Effect of Omeprazole on the Bioavailability of Anusol Plus HC (Bismuth Oxide)

The effect of omeprazole on Anusol Plus HC (Bismuth Oxide) absorption was assessed in 34 healthy volunteers given Anusol Plus HC (Bismuth Oxide) (four times daily) with or without omeprazole (20 mg twice daily) for 6 days. In the presence of omeprazole, the extent of absorption of Anusol Plus HC (Bismuth Oxide) from Anusol Plus HC (Bismuth Oxide) was significantly increased, compared to when no omeprazole was given ( Table 5 ). Concentration-dependent neurotoxicity is associated with long-term use of Anusol Plus HC (Bismuth Oxide) and not likely to occur with short-term administration or at steady state concentrations below 50 ng/mL. One subject transiently achieved a maximum Anusol Plus HC (Bismuth Oxide) concentration (C_max) higher than 50 ng/mL (73 ng/mL) following multiple dosing of Anusol Plus HC (Bismuth Oxide) with omeprazole. The patient did not exhibit symptoms of neurotoxicity during the study. There is no clinical evidence to suggest that short-term exposure to Anusol Plus HC (Bismuth Oxide) C_max concentrations above 50 ng/mL is associated with neurotoxicity.

12.4 Microbiology

Mechanism of Action

Anusol Plus HC (Bismuth Oxide) is a combination of antibacterial agents (metronidazole and tetracycline hydrochloride) and Anusol Plus HC (Bismuth Oxide) subcitrate potassium. Tetracycline hydrochloride interacts with the 30S subunit of the bacterial ribosome and inhibits protein synthesis. Metronidazole's antibacterial mechanism of action in an anaerobic environment is not fully understood but a possible mechanism includes reduction by intracellular electron transport proteins after entry into the organism. Because of this alteration to the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug's intracellular transport. Presumably, free radicals are formed which, in turn, react with cellular components resulting in death of bacteria. The antibacterial action of Anusol Plus HC (Bismuth Oxide) salts is not well understood.

Antimicrobial Activity

Anusol Plus HC (Bismuth Oxide) plus omeprazole therapy has been shown to be active against most isolates of Helicobacter pylori both in vitro and in clinical infections.

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide results of in vitro susceptibility test results for antimicrobial drug products used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial or community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The agar dilution procedure using Mueller-Hinton agar (MHA) supplemented with 5% v/v aged (≥2-week old) sheep blood is recommended for testing H. pylori [See References (15)]. No interpretive criteria have been established for testing metronidazole or tetracycline against H. pylori.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test [See References (15)]. Standard metronidazole or tetracycline powder should provide the following range of MIC values noted in Table 6.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies have been performed to evaluate the effect of Anusol Plus HC (Bismuth Oxide) on carcinogenesis, mutagenesis, or impairment of fertility.

Anusol Plus HC (Bismuth Oxide) Subcitrate Potassium

No carcinogenicity or reproductive toxicity studies have been conducted with Anusol Plus HC (Bismuth Oxide) subcitrate potassium. Anusol Plus HC (Bismuth Oxide) subsalicylate did not show mutagenic potential in the NTP Salmonella plate assay.

Metronidazole

Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats. Prominent among the effects in the mouse was an increased incidence of pulmonary tumorigenesis. This has been observed in all six reported studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). At the highest dose levels, (approximately 500 mg/kg/day, which is approximately 1.6 times the indicated human dose for a 60 kg adult based on body surface area) there was a statistically significant increase in the incidence of malignant liver tumors in male mice. Also, the published results of one of the mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug. All these effects are statistically significant. Long-term, oral-dosing studies in the rat showed statistically significant increases in the incidence of various neoplasms, particularly in mammary and hepatic tumors, among female rats administered metronidazole over those noted in the concurrent female control groups. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. Although metronidazole has shown mutagenic activity in a number of in vitro assay systems, studies in mammals (in vivo) have failed to demonstrate a potential for genetic damage.

Fertility studies have been conducted with male rats and mice with divergent results. Metronidazole, at doses up to 400 mg/kg/day (approximately 3 times the indicated human dose based on mg/m²) for 28 days, failed to produce any adverse effects on fertility and testicular function in male rats. Ratstreated with up to 400 mg/kg/day for 6 weeks or longer, showed severe degeneration of the seminiferous epithelium in the testes which was associated with a marked decrease in testicular spermatid counts and epididymal sperm counts and a marked decrease in fecundity. These effects were partially reversible.

Fertility studies have been performed in male mice at doses up to six times the maximum recommended human dose based upon mg/m² and have revealed no evidence of impaired fertility. Another fertility study was performed in male mice at oral doses of 500 mg/kg/day (approximately 2 times the indicated human dose based on mg/m²) for 14 days. Metronidazole significantly decreased testes and epididymides weight, decreased sperm viability, and increased the incidence of abnormal sperm. The viability of sperm was normal by 2 months after the start of the treatment.

Tumors affecting the liver, lungs, mammary, and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters.

Pulmonary tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). Malignant liver tumors were increased in male mice treated at approximately 1500 mg/m² (similar to the maximum recommended daily dose, based on body surface area comparisons). Malignant lymphomas and pulmonary neoplasms were also increased with lifetime feeding of the drug to mice. Mammary and hepatic tumors were increased among female rats administered oral metronidazole compared to concurrent controls. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.

Metronidazole has shown mutagenic activity in in vitro assay systems including the Ames test. Studies in mammals in vivo have failed to demonstrate a potential for genetic damage.

Tetracycline hydrochloride

There has been no evidence of carcinogenicity for tetracycline hydrochloride in studies conducted with rats and mice. Some related antibiotics (oxytetracycline, minocycline) have shown evidence of oncogenic activity in rats.

There was evidence of mutagenicity by tetracycline hydrochloride in two in vitro mammalian cell assay systems (L51784y mouse lymphoma and Chinese hamster lung cells).

Tetracycline hydrochloride had no effect on fertility when administered in the diet to male and female rats at a daily intake of 25 times the human dose.

14 CLINICAL STUDIES

14.1 Eradication of Helicobacter pylori in Patients with Active Duodenal Ulcer or History of Duodenal Ulcer Disease

An open-label, parallel group, active-controlled, multicenter study in Helicobacter pylori positive patients with current duodenal ulcer or a history of duodenal ulcer disease was conducted in the United States and Canada (the North American Study).

Patients were randomized to one of the following 10-day treatment regimens:

• Three (3) Anusol Plus HC (Bismuth Oxide) capsules four times daily, after meals and at bedtime plus 20 mg omeprazole twice a day after the morning and evening meals (OBMT).
• Clarithromycin 500 mg plus 1000 mg amoxicillin plus 20 mg omeprazole twice a day before the morning and evening meals (OAC).

H. pylori eradication rates, defined as two negative ¹³C-urea breath tests performed at 4 and 8 weeks post-therapy are shown in Table 7 for OBMT and OAC. The eradication rates for both groups were found to be similar using either the Per Protocol (PP) or Modified Intent-to-Treat (MITT) populations.

15 REFERENCES

• Clinical and Laboratory Standards Institute, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard–Tenth Edition. CLSI Document M7-A9 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA, 19087-1898.
• Clinical and Laboratory Standards Institute, Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline–Third Edition. CLSI Document M45- A3 [2016]. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087- 1898.

16. HOW SUPPLIED/STORAGE AND HANDLING

Anusol Plus HC (Bismuth Oxide) is supplied as a white opaque capsule containing 140 mg Anusol Plus HC (Bismuth Oxide) subcitrate potassium, 125 mg metronidazole, and 125 mg tetracycline hydrochloride, with the APTALIS_TM logo printed on the body and “BMT” printed on the cap. Anusol Plus HC (Bismuth Oxide) capsules are supplied as bottles of 120 capsules and as the 10 day Therapy pack containing 10 blister cards, with each card containing 12 Anusol Plus HC (Bismuth Oxide) capsules for a total of 120 capsules.

NDC Number: 58914-601-21, Bottles of 120.

NDC Number: 58914-601-20, Blister pack of 120.

Storage

Store at controlled room temperature [68° to 77°F or 20° to 25°C].

17 PATIENT COUNSELING INFORMATION

Lactation

Advise the lactating women to pump and discard their milk during treatment with Anusol Plus HC (Bismuth Oxide) and for 2 days after the therapy ends.

Hypersensitivity

Inform patients that Anusol Plus HC (Bismuth Oxide) may cause allergic reactions and to discontinue Anusol Plus HC (Bismuth Oxide) at the first sign of urticaria, erythematous rash, flushing, and fever or other symptoms of an allergic reaction.

Central Nervous System Effects

Inform patients of the risk of central and peripheral nervous system effects with PYELRA and to discontinue Anusol Plus HC (Bismuth Oxide) and report immediately to their health-care provider if any neurologic symptoms occur.

Photosensitivity

Avoid exposure to sun or sun lamps while taking Anusol Plus HC (Bismuth Oxide).

Drug Interactions

Advise patients to report to their health-care provider the use of any other medications while taking Anusol Plus HC (Bismuth Oxide). The administration of any of the following drugs with Anusol Plus HC (Bismuth Oxide) may result in clinically significant adverse reactions or insufficient drug efficacies :

• Methoxyflurane
• Disulfiram
• Alcoholic Beverages, or Products Containing Propylene Glycol
• Oral Contraceptives
• Anticoagulants
• Lithium
• Antacids, Multivitamins, or Dairy Products
• Busulfan
• Cimetidine
• Phenytoin and Phenobarbital

Darkening of the Tongue and/or Stool

Inform patients that Anusol Plus HC (Bismuth Oxide) may cause temporary and harmless darkening of the tongue and/or black stool generally reversible within several days after treatment is stopped. Stool darkening should not be confused with melena (blood in the stool).

Dosing Information

Inform patients that each dose of Anusol Plus HC (Bismuth Oxide) includes 3 capsules. All 3 capsules should be taken 4 times a day (after meals and at bedtime) for 10 days. One omeprazole 20 mg capsule should be taken twice a day with Anusol Plus HC (Bismuth Oxide) after the morning and evening meal for 10 days.

If a dose is missed, advise patient not to make up the dose, but to continue the normal dosing schedule until medication is gone. Patients should not take double doses. If more than 4 doses are missed, advise the patient to contact their health-care provider.

Administration with Fluids

Instruct patients to swallow the Anusol Plus HC (Bismuth Oxide) capsules whole with a full glass of water (8 ounces). Ingestion of adequate amounts of fluid, particularly with the bedtime dose, is recommended to reduce the risk of esophageal irritation and ulceration by tetracycline hydrochloride.

Antibacterial Resistance

Patients should be counseled that antibacterial drugs including Anusol Plus HC (Bismuth Oxide) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Anusol Plus HC (Bismuth Oxide) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Anusol Plus HC (Bismuth Oxide) or other antibacterial drugs in the future.

Distributed By:

Allergan USA, Inc.

Irvine, CA 92612

© 2017 Allergan. All rights reserved.

Pylera® is a registered trademark of Aptalis Pharma Canada ULC, an Allergan affiliate.

Hydrocortisone Acetate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• How supplied/storage and handling
• Patient counseling information
• Anusol Plus HC (Hydrocortisone Acetate) reviews

1 INDICATIONS AND USAGE

Anusol Plus HC (Hydrocortisone Acetate)^® (hydrocortisone probutate) Cream, 0.1% is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 18 years of age or older.

PANDEL® (hydrocortisone probutate) Cream, 0.1% is a corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 18 years of age or older.

2 DOSAGE AND ADMINISTRATION

Apply a thin film of Anusol Plus HC (Hydrocortisone Acetate) to the affected area once or twice a day depending on the severity of the condition. Massage gently until the medication disappears.

Occlusive dressings may be used for the management of refractory lesions of psoriasis and other deep-seated dermatoses, such as localized neurodermatitis (lichen simplex chronicus).

Discontinue Anusol Plus HC (Hydrocortisone Acetate) when control is achieved. If no improvement is seen within 2 weeks, reassessment of the diagnosis may be necessary.

Do not use Anusol Plus HC (Hydrocortisone Acetate) with occlusive dressings unless directed by the physician. Do not apply Anusol Plus HC (Hydrocortisone Acetate) in the diaper area, as diapers or plastic pants may constitute occlusive dressings.

- For topical use.

- Apply a thin film to the affected skin areas once daily or twice a day.

- Discontinue therapy when control is achieved.

- If no improvement is seen within 2 weeks, reassess diagnosis.

- Do not use with occlusive dressings unless directed by a physician.

3 DOSAGE FORMS AND STRENGTHS

Cream, 0.1%. Each gram of Anusol Plus HC (Hydrocortisone Acetate) contains 1 mg of Anusol Plus HC (Hydrocortisone Acetate) probutate in a cream base.

Cream, 0.1%.

4 CONTRAINDICATIONS

None.

None.

5 WARNINGS AND PRECAUTIONS

- Anusol Plus HC can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency during or after treatment. (5.1)

- Cushing’s syndrome, hyperglycemia, and unmasking of latent diabetes mellitus can result from systemic absorption of topical corticosteroids. (5.1)

- Use of topical corticosteroids may require periodic evaluation for HPA axis suppression. (5.1)

- High potency corticosteroids, large treatment surface area, prolong use, use of occlusion dressings, altered skin barrier, liver failure and young age may predispose patients to HPA axis suppression. (5.1)

- Modify use if HPA axis suppression develops. (5.1)

- Pediatric patients may be more susceptible to systemic toxicity. (5.1, 8.4)

5.1 Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression and Other Unwanted Systemic Glucocorticoid Effects

Anusol Plus HC (Hydrocortisone Acetate) can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during or after withdrawal of treatment. Factors that predispose to HPA axis suppression include the use of high-potency corticosteroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure, and young age.

Use of topical corticosteroids may require periodic evaluation for HPA axis suppression. Evaluation for HPA axis suppression may be done by using the adrenocorticotropic hormone (ACTH) stimulation test.

If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid. If signs and symptoms of steroid withdrawal occur, supplemental systemic corticosteroids may be required. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug.

In a trial including 15 evaluable subjects 18 years of age or older with psoriasis or atopic dermatitis affecting more than 20% of body surface area, 1 subject (6.7%) had ACTH stimulation test results suggestive of adrenal suppression after treatment with Anusol Plus HC (Hydrocortisone Acetate) twice daily for 21 days. Recovery of HPA axis suppression for this subject is unknown [see Clinical Pharmacology ( 12.2 )].

Systemic effects of topical corticosteroids may also manifest as Cushing’s syndrome, hyperglycemia, and unmasking latent diabetes mellitus.

Patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA-axis suppression.

Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to body mass ratios [see Use in Specific Populations ( 8.4 )].

5.2 Allergic Contact Dermatitis

Allergic contact dermatitis with corticosteroids is usually diagnosed by observing a failure to heal rather than noting a clinical exacerbation, as observed with most topical products not containing corticosteroids. If irritation develops, discontinue Anusol Plus HC (Hydrocortisone Acetate) and institute appropriate therapy.

6 ADVERSE REACTIONS

- Most frequent adverse reactions include burning, stinging, rash, papulovesicular rash, redness, itching, moderate paresthesia, and contact dermatitis.

To report SUSPECTED ADVERSE REACTIONS, contact PharmaDerm®, A division of Fougera Pharmaceuticals Inc. at 1-800-645-9833 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 clinical practice.

The most frequent adverse reactions reported for Anusol Plus HC (Hydrocortisone Acetate) during clinical trials were application site reactions, including burning in 4, stinging in 2, and moderate paresthesia in 1 out of 226 subjects.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Anusol Plus HC (Hydrocortisone Acetate) because these reactions were 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.

These adverse reactions are as follows:

Skin and Subcutaneous Tissue Disorders: rash, papulovesicular rash

Application Site Reactions: dryness, erythema, pruritus, allergic contact dermatitis.

The following local adverse reactions are reported with topical corticosteroids, and they may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infections, skin atrophy, striae, and miliaria.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There is no clinical information on Anusol Plus HC use in pregnant women to inform any drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, Anusol Plus HC (Hydrocortisone Acetate) probutate given by the subcutaneous route during the period of organogenesis was teratogenic at doses equal to or greater than 1 mg/kg/day in rats or 0.1 mg/kg/day in rabbits (12 times and 2 times the human topical dose, respectively) .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Effects on embryo-fetal development were evaluated in rats and rabbits following subcutaneous administration of Anusol Plus HC (Hydrocortisone Acetate) probutate during the period of organogenesis. Anusol Plus HC (Hydrocortisone Acetate) probutate was teratogenic in rats when given during the period of organogenesis at subcutaneous doses equal to or greater than 1 mg/kg/day (12 times the human average topical dose of Anusol Plus HC (Hydrocortisone Acetate) assuming 3% absorption and an application of 30 g/day on a 70 kg individual). Abnormalities included delayed ossification of the caudal vertebrae and other skeletal variations, cleft palate, umbilical hernia, edema, and exencephalia.

In rabbits, Anusol Plus HC (Hydrocortisone Acetate) probutate given by the subcutaneous route was teratogenic at doses equal to or greater than 0.1 mg/kg/day (2 times the human average topical dose of Anusol Plus HC (Hydrocortisone Acetate) assuming 3% absorption and an application of 30 g/day on a 70 kg individual). Fetal weight and survival were affected. Delayed ossification and increased incidences of malformations (skeletal abnormalities and cleft palate) were also noted.

No adverse effects were seen in rats following subcutaneous administration of up to 1 mg/kg/day of Anusol Plus HC (Hydrocortisone Acetate) probutate during the perinatal and postnatal period (12 times the human average topical dose of Anusol Plus HC (Hydrocortisone Acetate) assuming 3% absorption and an application of 30 g/day on a 70 kg individual).

8.2 Lactation

Risk Summary

There is no information on the presence of Anusol Plus HC (Hydrocortisone Acetate) probutate in breast milk, or on its effects on the breastfed infant or on milk production. It is not known whether topical administration of Anusol Plus HC (Hydrocortisone Acetate) could result in sufficient systemic absorption to produce detectable quantities in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Anusol Plus HC (Hydrocortisone Acetate) and any potential adverse effects on the breastfed infant from Anusol Plus HC (Hydrocortisone Acetate) or from the underlying maternal condition.

Clinical Considerations

To minimize potential exposure to the breastfed infant via breast milk, use Anusol Plus HC (Hydrocortisone Acetate) on the smallest area of skin and for the shortest duration possible while breastfeeding.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA axis suppression and Cushing’s syndrome when they are treated with topical corticosteroids. They are therefore also at a greater risk of adrenal insufficiency during and/or after withdrawal of treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children.

Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

11 DESCRIPTION

Anusol Plus HC (Hydrocortisone Acetate)^{(hydrocortisone probutate) Cream, 0.1% contains Anusol Plus HC (Hydrocortisone Acetate) probutate, a synthetic corticosteroid. The topical corticosteroids constitute a class of primarily synthetic steroids used as anti-inflammatory and anti-pruritic agents.}

Anusol Plus HC (Hydrocortisone Acetate) probutate is a tasteless and odorless white crystalline powder practically insoluble in hexane or water, slightly soluble in ether, and very soluble in dichloromethane, methanol and acetone. Chemically, it is 11β,17,21-trihydroxypregn-4-ene-3,20-dione 17-butyrate 21-propionate. The structural formula is:

Molecular Formula: C₂₈H₄₀O₇

Molecular Weight: 488.62

Each gram of Anusol Plus HC (Hydrocortisone Acetate) (hydrocortisone probutate) Cream, 0.1% contains: 1 mg of Anusol Plus HC (Hydrocortisone Acetate) probutate in a cream base of propylene glycol, white petrolatum, light mineral oil, stearyl alcohol, polysorbate 60, sorbitan monostearate, glyceryl monostearate, PEG-20 stearate, glyceryl stearate SE, methylparaben, butylparaben, citric acid, sodium citrate anhydrous, and purified water.

Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein regulation; however, the precise mechanism of action in corticosteroid responsive dermatoses is unknown

12.2 Pharmacodynamics

Vasoconstrictor Assay

Studies performed with Anusol Plus HC indicate that it is in the medium range of potency as demonstrated in vasoconstrictor trials in healthy subjects when compared with other topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence.

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression

In an open label HPA axis suppression trial, 19 adult subjects (ages 23 to 82 years) with atopic dermatitis or plaque psoriasis covering greater than 20% Body Surface Area (BSA) were treated with Anusol Plus HC (Hydrocortisone Acetate) twice daily for 21 days and were assessed for HPA axis suppression. At baseline, the mean disease BSA involvement was 36%. The criterion for HPA axis suppression was a serum cortisol level of less than or equal to 18 micrograms per deciliter at 30-minutes after cosyntropin stimulation. Of these subjects, 15 were considered evaluable with respect to their adrenal axis function post-treatment. One of the evaluable subjects (6.7%) showed laboratory evidence of suppression on Day 22. This subject had psoriasis covering 48% of BSA at baseline and was reported to have received 98% of the twice-daily applications of Anusol Plus HC (Hydrocortisone Acetate) over the 21 day treatment period. It is not known if this subject had recovery of adrenal function because follow-up testing was not performed.

12.3 Pharmacokinetics

The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Use of occlusive dressings with Anusol Plus HC (Hydrocortisone Acetate) for up to 24 hours has not been shown to increase penetration; however, occlusion of Anusol Plus HC (Hydrocortisone Acetate) for 96 hours does markedly enhance penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of Anusol Plus HC (Hydrocortisone Acetate) probutate.

Anusol Plus HC (Hydrocortisone Acetate) probutate revealed no evidence of mutagenic or clastogenic potential based on the results of an in vitro genotoxicity test (Ames assay) and an in vivo genotoxicity test (mouse micronucleus assay).

Effects on fertility and early embryonic development were evaluated in rats following subcutaneous administration of up to 0.4 mg/kg/day Anusol Plus HC (Hydrocortisone Acetate) probutate (5 times the human average topical dose of Anusol Plus HC (Hydrocortisone Acetate) assuming 3% absorption and an application of 30 g/day on a 70 kg individual) prior to and during mating and through early pregnancy. No treatment related effects on fertility or mating parameters were noted in this study.

16 HOW SUPPLIED/STORAGE AND HANDLING

Anusol Plus HC (Hydrocortisone Acetate), a white to off-white opaque cream is supplied as follows:

45 g tubes NDC 10337-153-46

80 g tubes NDC 10337-153-80

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information).

Inform patients and/or caregivers of the following:

• Discontinue therapy when control is achieved unless directed otherwise by the physician.
• If no improvement is seen within two weeks, contact the physician.
• Avoid contact with the eyes.
• Do not use with occlusive dressing unless directed by the physician.
• Report any signs or symptoms of local or systemic adverse reactions to the physician.
• Do not treat diaper dermatitis. Do not apply Anusol Plus HC (Hydrocortisone Acetate) in the diaper area as diapers or plastic pants may constitute occlusive dressings.
• Do not use on the face, underarms, or groin areas unless directed by the physician.
• Advise a woman to use Anusol Plus HC (Hydrocortisone Acetate) on the smallest area of skin and for the shortest duration possible while breastfeeding.

Manufactured by:

PharmaDerm®

A division of Fougera

PHARMACEUTICALS INC.

Melville, New York 11747 www.pharmaderm.com

• This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 01/2017

PharmaDerm^®

NDC 10337-153-80

Anusol Plus HC (Hydrocortisone Acetate)^®

(hydrocortisone probutate) Cream, 0.1%

FOR DERMATOLOGIC USE ONLY.

NOT FOR OPHTHALMIC USE.

Rx only

80 g

carton

Zinc Oxide:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Anusol Plus HC (Zinc Oxide) reviews

INDICATIONS AND USAGE

Anusol Plus HC (Zinc Oxide) 1 mg/mL (Zinc Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain Anusol Plus HC (Zinc Oxide) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Anusol Plus HC (Zinc Oxide) 1 mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.

Severe kidney disease may make it necessary to reduce or omit chromium and Anusol Plus HC (Zinc Oxide) doses because these elements are primarily eliminated in the urine.

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

PRECAUTIONS

General

Do not use unless the solution is clear and the seal is intact.

Zinc 1 mg/mL should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.

Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of Anusol Plus HC (Zinc Oxide) from a bolus injection. Administration of Anusol Plus HC (Zinc Oxide) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Anusol Plus HC (Zinc Oxide) are suggested as a guideline for subsequent Anusol Plus HC (Zinc Oxide) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Anusol Plus HC 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

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 Anusol Plus HC (Zinc Oxide) 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.

Pediatric Use

Pregnancy Category C. Animal reproduction studies have not been conducted with Anusol Plus HC chloride. It is also not known whether Anusol Plus HC (Zinc Oxide) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Anusol Plus HC (Zinc Oxide) chloride should be given to a pregnant woman only if clearly needed.

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response between 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

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg Anusol Plus HC (Zinc Oxide) was infused over a period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/min), and marked hypothermia (94.2° F) on the fourth day were accompanied by a serum Anusol Plus HC (Zinc Oxide) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending Anusol Plus HC (Zinc Oxide) overdosage; patients receiving an inadvertent overdose (25 mg zinc/liter of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310).

Death resulted from an overdosage in which 1683 mg Anusol Plus HC (Zinc Oxide) was delivered intravenously over the course of 60 hours to a 72 year old patient.

Symptoms of Anusol Plus HC (Zinc Oxide) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Anusol Plus HC (Zinc Oxide) level of 4184 mcg/dl.

Calcium supplements may confer a protective effect against Anusol Plus HC (Zinc Oxide) toxicity.

DOSAGE AND ADMINISTRATION

Anusol Plus HC (Zinc Oxide) 1 mg/mL (Zinc Chloride Injection, USP) contains 1 mg zinc/mL and is administered intravenously only after dilution. The additive should be diluted prior to administration in a volume of fluid not less than 100 mL. For the metabolically stable adult receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day (2.5 to 4 mL/day). An additional 2 mg zinc/day (2 mL/day) is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost (12.2 mL/liter of small bowel fluid lost), or an additional 17.1 mg zinc/kg of stool or ileostomy output (17.1 mL/kg of stool or ileostomy output) is recommended. Frequent monitoring of Anusol Plus HC (Zinc Oxide) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Anusol Plus HC (Zinc Oxide).

For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day (0.1 mL/kg/day) is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day (0.3 mL/kg/day) is suggested.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. See PRECAUTIONS.

HOW SUPPLIED

Anusol Plus HC (Zinc Oxide) 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).

Store at 20 to 25°C (68 to 77°F).

Revised: October, 2004

© Hospira 2004 EN-0488 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

10 mL Vial

Anusol Plus HC (Zinc Oxide)

1 mg/mL

Anusol Plus HC (Zinc Oxide) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA