Celemin Hepa

Acetic Acid:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Therapeutic vaginal jelly
• Celemin Hepa (Acetic Acid) reviews

Indications and Usage

Celemin Hepa (Acetic Acid) is indicated as adjunctive therapy in those cases where restoration and maintenance of vaginal acidity is desirable.

Contraindications

None known.

Warnings

No serious adverse reactions or potential safety hazard have been reported with the use of Celemin Hepa (Acetic Acid).

Precautions

General

No special care is required for the safe and effective use of Celemin Hepa .

Drug Interactions

No incidence of drug interactions has been reported with concomitant use of Celemin Hepa (Acetic Acid) and any other medication.

Laboratory Tests

The monitoring of vaginal acidity may be helpful in following the patient's response. (The normal vaginal pH has been shown to be in the range of 4.0 to 5.0)

Carcinogenesis

No long-term studies in animals have been performed to evaluate carcinogenic potential.

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with Celemin Hepa . It is not known whether Celemin Hepa (Acetic Acid) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Celemin Hepa (Acetic Acid) should be given to a pregnant woman only if clearly needed.

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 Celemin Hepa (Acetic Acid) is administered to a nursing woman.

Adverse Reactions

Occasional cases of local stinging and burning have been reported.

Dosage and Administration

The usual dose is one applicator full, administered intra-vaginally, morning and evening. Duration of treatment may be determined by the patient's response to therapy. Each tube has a tamper evident seal at the opening of the tube. Replace cap after each use. To fill applicator screw applicator clockwise onto the tube. Squeeze tube forcing Celemin Hepa (Acetic Acid) jelly into barrel until it is full. Then unscrew applicator counter-clockwise to remove from tube. Lie on your back with knees drawn up. Hold filled applicator by the barrel and gently insert it into the vagina as far as it will comfortably go. Press plunger to empty the contents. Keep the plunger depressed and remove the applicator from vagina. After each use pull applicator apart and wash with warm soapy water, rinse well, dry and reassemble.

How Supplied

50g Tube (NDC 00813-0799-55) with Celemin Hepa (Acetic Acid) applicator.

Keep this and all medication out of the reach of children. In case of accidental overdose, call a doctor or poison control center immediately.

Store at controlled room temperature 59°-86°F (15°-30°C)

Mfg. by:

Pernix Manufacturing

Houston, TX 77099

Mfg. for:

Pharmics, Inc.

Salt Lake City, UT 84119

(801) 966-4138

www.pharmics.com

Revised 05/13

Therapeutic Vaginal Jelly

Directions for using Celemin Hepa (Acetic Acid) applicator.

Each tube has a tamper evident seal at the opening of the tube. Replace cap after each use.

After each use pull applicator apart and wash with warm soapy water, rinse well, dry and reassemble.

Figure Figure Figure

Acetylcysteine:

• 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
• Celemin Hepa (Acetylcysteine) reviews

1 INDICATIONS AND USAGE

Celemin Hepa (Acetylcysteine) is indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen in patients with acute ingestion or from repeated supratherapeutic ingestion (RSI).

Celemin Hepa (Acetylcysteine) is an antidote for acetaminophen overdose indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen in patients with acute ingestion or from repeated supratherapeutic ingestion. (1)

2 DOSAGE AND ADMINISTRATION

Pre-Treatment Assessment Following Acute Ingestion :

Obtain a plasma or serum sample to assay for acetaminophen concentration at least 4 hours after ingestion.

• If the time of acetaminophen ingestion is unknown:
  • Administer a loading dose of Celemin Hepa (Acetylcysteine) immediately.
  • Obtain an acetaminophen concentration to determine the need for continued treatment.
• If the acetaminophen concentration cannot be obtained (or is unavailable or uninterpretable) within the 8-hour time interval after acetaminophen ingestion or there is clinical evidence of acetaminophen toxicity:
  • Administer a loading dose of Celemin Hepa (Acetylcysteine) immediately and continue treatment for a total of 17 doses.
• If the patient presents more than 8 hours after ingestion and the time of acute acetaminophen ingestion is known:
  • Administer a loading dose of Celemin Hepa (Acetylcysteine) immediately.
  • Obtain acetaminophen concentration to determine need for continued treatment.
• If the patient presents less than 8 hours after ingestion and the time of acute acetaminophen ingestion is known and the acetaminophen concentration is known:
  • Use the Rumack-Matthew nomogram (Figure 1) to determine whether or not to initiate treatment with Celemin Hepa (Acetylcysteine). (2.2)

Nomogram for Estimating Potential for Hepatotoxicity from Acute Acetaminophen Ingestion (2.2):

• See the Full Prescribing Information for instructions on how to use the nomogram to determine the need for loading and maintenance dosing.

Recommended Adult and Pediatric Dosage (2.3):

• Celemin Hepa (Acetylcysteine) is for oral administration only; not for nebulization or intratracheal instillation.
• Loading dose: 140 mg/kg.
• Maintenance doses: 70 mg/kg repeated every 4 hours for a total of 17 doses.
• See Full Prescribing Information for weight-based dosage and preparation and administration instructions.

Repeated Supratherapeutic Acetaminophen Ingestion (2.4):

• Obtain acetaminophen concentration and other laboratory tests to guide treatment; Rumack-Matthew nomogram does not apply.

2.1 Pretreatment Assessment and Testing Following Acute Acetaminophen Ingestion

The following recommendations are related to acute acetaminophen ingestion. For recommendations related to repeated supratherapeutic exposure see Dosage and Administration (2.4) .

• Assess the history and timing of acetaminophen ingestion as an overdose.
  • The reported history of the quantity of acetaminophen ingested as an overdose is often inaccurate and is not a reliable guide to therapy.
• Obtain the following laboratory tests to monitor hepatic and renal function and electrolyte and fluid balance: aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, international normalized ratio (INR), creatinine, blood urea nitrogen (BUN), blood glucose, and electrolytes.
• Obtain a plasma or serum sample to assay for acetaminophen concentration at least 4 hours after ingestion. Acetaminophen concentrations obtained earlier than 4 hours post-ingestion may be misleading as they may not represent maximum acetaminophen concentrations.
• If the time of acute acetaminophen ingestion is unknown:
  • Administer a loading dose of Celemin Hepa (Acetylcysteine) immediately .
  • Obtain an acetaminophen concentration to determine need for continued treatment .
• If the acetaminophen concentration cannot be obtained (or is unavailable or uninterpretable) within the 8-hour time interval after acetaminophen ingestion or there is clinical evidence of acetaminophen toxicity:
  • Administer a loading dose of Celemin Hepa (Acetylcysteine) immediately and continue treatment for a total of 17 doses .
• If the patient presents more than 8 hours after ingestion and the time of acute acetaminophen ingestion is known:
  • Administer a loading dose of Celemin Hepa (Acetylcysteine) immediately .
  • Obtain acetaminophen concentration to determine need for continued treatment .
• If the patient presents less than 8 hours after ingestion and the time of acute acetaminophen ingestion is known and the acetaminophen concentration is known:
  • Use the Rumack-Matthew nomogram (Figure 1) to determine whether or not to initiate treatment with Celemin Hepa (Acetylcysteine) .

2.2 Nomogram for Estimating Potential for Hepatotoxicity from Acute Acetaminophen Ingestion and Need for Celemin Hepa Treatment

If the timing of the acute acetaminophen ingestion is known and the results of the acetaminophen assay are available within 8 hours:

• Refer to the Rumack-Matthew nomogram to determine whether or not to initiate treatment with Celemin Hepa (Acetylcysteine).
• Initiation of Celemin Hepa (Acetylcysteine) depends on the acetaminophen concentration and also the clinical presentation of the patient.

The nomogram may underestimate the hepatotoxicity risk in patients with chronic alcoholism, malnutrition, or CYP2E1 enzyme inducing drugs (e.g., isoniazid), and consideration should be given to treating these patients even if the acetaminophen concentrations are in the nontoxic range.

Loading Dose

For patients whose acetaminophen concentrations are at or above the "possible" toxicity line (dotted line in nomogram):

• Administer a loading dose of Celemin Hepa (Acetylcysteine) .

For patients with an acute overdose due to an extended-release acetaminophen, if the acetaminophen concentration at 4 hours post ingestion is below the possible toxicity line then obtain a second sample for acetaminophen concentration 8 to 10 hours after the acute ingestion. If the second value is at or above the "possible" toxicity line (dotted line in nomogram):

• Administer a loading dose of Celemin Hepa (Acetylcysteine) .

For patients whose values are below the "possible" toxicity line, but time of ingestion was unknown or sample was obtained less than 4 hours after ingestion:

• Administer a loading dose of Celemin Hepa (Acetylcysteine) .

For patients whose values are below the "possible" toxicity line and time of ingestion is known and the sample was obtained more than 4 hours after ingestion, do not administer Celemin Hepa (Acetylcysteine) because there is minimal risk of hepatotoxicity.

Maintenance Dose

Determine need for continued treatment with Celemin Hepa (Acetylcysteine) after the loading dose. Choose ONE of the following based on the acetaminophen concentration:

The acetaminophen concentration is above the possible toxicity line according to the nomogram :

• Continue Celemin Hepa (Acetylcysteine) treatment with the maintenance dose for 17 doses .
• Monitor hepatic and renal function and electrolytes throughout treatment.

The acetaminophen concentration could not be obtained:

• Continue Celemin Hepa (Acetylcysteine) treatment with the maintenance dose for 17 doses .
• Monitor hepatic and renal function and electrolytes throughout treatment.

For patients whose acetaminophen concentration is below the "possible" toxicity line and time of ingestion is known and the sample was obtained more than 4 hours after ingestion:

• Discontinue Celemin Hepa (Acetylcysteine).

The acetaminophen concentration was in the non-toxic range, but time of ingestion was unknown or less than 4 hours:

• Obtain a second sample for acetaminophen concentration and consider the patient's clinical status to decide whether or not to continue Celemin Hepa (Acetylcysteine) treatment.
• If there is any uncertainty as to patient's risk of developing hepatotoxicity, it is recommended to administer a complete treatment course under medical observation with appropriate monitoring.

Continued Therapy After Completion of Loading and Maintenance Doses

In cases of suspected massive overdose, or with concomitant ingestion of other substances, or in patients with preexisting liver disease; the absorption and/or the half-life of acetaminophen may be prolonged. In such cases, consideration should be given to the need for continued treatment with Celemin Hepa (Acetylcysteine) beyond a total of 17 maintenance doses.

Acetaminophen levels and ALT/AST and INR should be checked after the last maintenance dose. If acetaminophen levels are still detectable, or if the ALT/AST are still increasing or the INR remains elevated; the maintenance doses should be continued and the treating physician should contact a US regional poison center at 1-800-222-1222, or alternatively, a "special health professional assistance line for acetaminophen overdose" at 1-800-525-6115 for assistance with dosing recommendations.

2.3 Recommended Dosage and Preparation and Administration Instructions in Adults and Pediatrics for Acute Acetaminophen Ingestion

• Celemin Hepa is for oral administration only; not for nebulization or intratracheal instillation.
• After appropriate preparation and dilution, Celemin Hepa (Acetylcysteine) is interchangeable with 20% Celemin Hepa (Acetylcysteine) solution, when given at the same Celemin Hepa (Acetylcysteine) dosage.
• Adults and Pediatrics: The recommended loading dose of Celemin Hepa (Acetylcysteine) is 140 mg/kg. Administer a first maintenance dose of 70 mg/kg 4 hours after the loading dose. Repeat 70 mg/kg maintenance dose every 4 hours for a total of 17 maintenance doses.

Preparation and Administration Instructions

• Dissolve the appropriate number of 2.5 gram and/or 500 mg Celemin Hepa (Acetylcysteine) effervescent tablets in the volume of water indicated in dosing tables and text below, based upon patient weight.
• Once the tablets are dissolved, administer the oral solution immediately.
• Solutions should be freshly prepared for each dose and utilized within 2 hours.
• If the patient vomits an oral dose of Celemin Hepa (Acetylcysteine) within 1 hour of administration, repeat that dose.
• If the patient is persistently unable to retain the orally administered Celemin Hepa (Acetylcysteine), Celemin Hepa (Acetylcysteine) may be administered by nasoduodenal tube. An intravenous formulation of Celemin Hepa (Acetylcysteine) may also be considered.

Patients Weighing 20 kg and Greater

Tables 1 and 2 provide the weight-based loading and maintenance doses, respectively, of Celemin Hepa (Acetylcysteine) for patients weighing 20 kg and greater. For patients weighing 20 to 59 kg dissolve Celemin Hepa (Acetylcysteine) tablets in 150 mL of water. For patients weighing 60 kg and greater dissolve Celemin Hepa (Acetylcysteine) tablets in 300 mL of water.

Patients Weighing 1 to 19 kg

Dissolve two 2.5 gram Celemin Hepa (Acetylcysteine) effervescent tablets in 100 mL of water to create a 50 mg/mL solution. Calculate the loading and maintenance doses using the patient's kilogram weight:

Loading dose: Calculate the dose by multiplying the patient's kilogram weight by 140 mg/kg and dividing by the concentration of the solution (50 mg/mL). The result is the dose in mL for administration using an oral syringe.

Maintenance dose: Calculate the dose by multiplying the patient's kilogram weight by 70 mg/kg and dividing by the concentration of the solution (50 mg/mL). The result is the dose in mL for administration using an oral syringe.

2.4 Recommendations for Repeated Supratherapeutic Acetaminophen Ingestion

Repeated supratherapeutic acetaminophen ingestion (RSI) is an ingestion of acetaminophen at dosages higher than those recommended for extended periods of time. The risk of hepatotoxicity and the recommendations for treatment of acute acetaminophen ingestion (i.e., the Rumack-Matthew nomogram) do not apply to patients with RSI. Therefore, obtain the following information to guide Celemin Hepa (Acetylcysteine) treatment for RSI.

• Acetaminophen serum or plasma concentrations. A reported history of the quantity of acetaminophen ingested is often inaccurate and is not a reliable guide to therapy.
• Laboratory tests to monitor hepatic and renal function and electrolyte and fluid balance: AST, ALT, bilirubin, INR, creatinine, BUN, blood glucose, and electrolytes.

For specific Celemin Hepa (Acetylcysteine) dosage and administration information in patients with RSI, consider contacting your regional poison center at 1-800-222-1222, or alternatively, a special health professional assistance line for acetaminophen overdose at 1-800-525-6115.

3 DOSAGE FORMS AND STRENGTHS

Celemin Hepa (Acetylcysteine) effervescent tablets are supplied as white, round, flat tablets with a lemon mint flavor in the following dosage strengths:

• 500 mg tablets debossed with "I" on one side.
• 2.5 gram tablets debossed with "O" on one side.

Celemin Hepa (Acetylcysteine) tablets contain the inactive ingredient sodium bicarbonate which may be clinically relevant in some patients .

Effervescent tablets: 500 mg and 2.5 grams (3)

4 CONTRAINDICATIONS

None.

None (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions, Including Urticaria: Discontinue Celemin Hepa unless deemed essential to patient management and the reactions can be otherwise controlled. (5.1)
• Risk of Upper Gastrointestinal Hemorrhage: Consider the risk/benefit for patients at risk of hemorrhage (e.g., those with esophageal varices, peptic ulcers, etc.) versus the risk of developing hepatic toxicity, and treat with Celemin Hepa (Acetylcysteine) accordingly.(5.2)

5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including generalized urticaria have been observed in patients receiving oral Celemin Hepa (Acetylcysteine) for acetaminophen overdose. If hypersensitivity reactions occur, Celemin Hepa (Acetylcysteine) should be discontinued unless it is deemed essential for patient management and the reactions can be otherwise controlled.

5.2 Risk of Upper Gastrointestinal Hemorrhage

Occasionally severe and persistent vomiting occurs as a symptom of acute acetaminophen overdose. Treatment with Celemin Hepa (Acetylcysteine) may aggravate the vomiting and increase the risk of upper gastrointestinal hemorrhage in at risk patients (e.g., those with esophageal varices, peptic ulcers, etc.). Consider the risk/benefit for patients at risk of hemorrhage versus the risk of developing hepatic toxicity, and treat with Celemin Hepa (Acetylcysteine) as needed.

6 ADVERSE REACTIONS

The following adverse reactions are described, or described in greater detail, in other sections of the labeling:

• Hypersensitivity Reactions
• Risk for Upper Gastrointestinal Hemorrhage

The most common adverse reactions have been identified from clinical studies or postmarketing reports of Celemin Hepa (Acetylcysteine). 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.

The most common adverse reactions were nausea, vomiting, other gastrointestinal symptoms, and rash with or without fever.

Most common adverse reactions are nausea and vomiting, other gastrointestinal symptoms, and rash with or without fever. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Arbor Pharmaceuticals LLC at 1- 866-516-4950 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited published case reports and case series on Celemin Hepa use during pregnancy are insufficient to inform a drug-associated risk of birth defects and miscarriage. However, there are clinical considerations . In animal reproduction studies, no teratogenic effects were observed with oral administration of Celemin Hepa (Acetylcysteine) to pregnant rats and rabbits during organogenesis at doses up to 0.6 times the maximum recommended human dose (based on body surface area) of about 560 mg/kg (total dose on first day of treatment) .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Acetaminophen and Celemin Hepa (Acetylcysteine) cross the placenta. Delaying treatment in pregnant women with acetaminophen overdose and potentially toxic acetaminophen plasma levels may increase the risk of maternal and fetal morbidity and mortality.

Data

Animal Data

No teratogenic effects were observed in embryo-fetal development studies in rats at oral doses up to 2000 mg/kg/day (0.6 times the maximum recommended human dose based on body surface area) or in rabbits at oral doses up to 1000 mg/kg/day (0.6 times the maximum recommended human dose based on body surface area) administered during organogenesis.

8.2 Lactation

Risk Summary

There is no information regarding the presence of Celemin Hepa (Acetylcysteine) in human milk, or the effects of Celemin Hepa (Acetylcysteine) on the breastfed infant or on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Celemin Hepa (Acetylcysteine) and any potential adverse effects on the breastfed infant from Celemin Hepa (Acetylcysteine) or from the underlying maternal condition.

8.4 Pediatric Use

Pediatric approval, including dosing, is not based on adequate and well-controlled clinical studies. Pediatric dosing recommendations are based on clinical experience .

8.5 Geriatric Use

Clinical studies of Celemin Hepa (Acetylcysteine) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience with Celemin Hepa (Acetylcysteine) has not identified differences in the responses 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.

8.6 Patients Sensitive to High Sodium Intake

Celemin Hepa (Acetylcysteine) tablets contain sodium. Consider the total sodium content from dietary and non-dietary sources in patients who may be sensitive to excess sodium intake, such as those with congestive heart failure, hypertension, or renal impairment.

At the recommended dosage an average sized adult (60 kg) may receive a total of 7 grams of sodium (304.3 mEq) on the first day of treatment, 5.3 grams of sodium (230.4 mEq) on the second day of treatment, and 4.4 grams of sodium (191.3 mEq) on the third day of treatment.

If sodium intake is a concern, please refer to Table 3 for the amount of sodium in each tablet and to Tables 1 and 2 for the recommended dosage in adults and pediatrics based on body weight in order to calculate the amount of sodium administered to an individual patient .

11 DESCRIPTION

Celemin Hepa (Acetylcysteine) is an antidote for the treatment of acetaminophen overdose. It is the N-acetyl derivative of the naturally-occurring amino acid, cysteine. Celemin Hepa (Acetylcysteine) is a white crystalline powder that is freely soluble in water, alcohol, practically insoluble in chloroform and in ether with the molecular formula C₅H₉NO₃S, a molecular weight of 163.2, and chemical name of N-acetyl-L-cysteine. Celemin Hepa (Acetylcysteine) has the following structural formula:

Celemin Hepa (Acetylcysteine) (acetylcysteine) effervescent tablets for oral solution contain 500 mg or 2.5 grams of Celemin Hepa (Acetylcysteine). The following are inactive ingredients: sodium bicarbonate, maltodextrin, lemon flavor, sucralose, peppermint flavor, and edetate disodium.

The amount of sodium in each tablet of Celemin Hepa (Acetylcysteine) is shown in Table 3.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Celemin Hepa has been shown to reduce the extent of liver injury following acetaminophen overdose. Acetaminophen doses of 150 mg/kg or greater have been associated with hepatotoxicity. Celemin Hepa (Acetylcysteine) probably protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite of acetaminophen.

12.3 Pharmacokinetics

Absorption

After administration of a single oral dose of 11 grams of Celemin Hepa (Acetylcysteine) (dissolved in 300 mL of water) to 29 healthy adult subjects, the mean C_max (CV%) was 26.5 (29) mcg/mL and mean (CV) AUC_inf was 186 (29) hr∙mcg/mL. The median (range) time to reach C_max (T_max) was 2 (1 to 3.5) hours.

Distribution

The steady-state volume of distribution (V_d) following administration of an intravenous dose of Celemin Hepa (Acetylcysteine) was 0.47 liter/kg. The protein binding for Celemin Hepa (Acetylcysteine) ranges from 66% to 87 %.

Elimination

Metabolism

Celemin Hepa (Acetylcysteine) (i.e., N-acetylcysteine) undergoes extensive first pass metabolism and is postulated to form cysteine and disulfides (N,N-diacetylcysteine and N-acetylcysteine). Cysteine is further metabolized to form glutathione and other metabolites.

Excretion

After a single oral dose of [³⁵S]-acetylcysteine 100 mg, between 13 to 38% of the total radioactivity administered was recovered in urine within 24 hours. In a separate study, renal clearance was estimated to be approximately 30% of total body clearance.

In healthy subjects given a single oral dose of 11 grams of Celemin Hepa (Acetylcysteine), the mean (CV%) terminal plasma half-life (T_1/2) was 18.1 (22%) hours.

Specific Populations

Hepatic Impairment

Following a 600 mg intravenous dose of Celemin Hepa (Acetylcysteine) to subjects with mild (Child Pugh Class A, n=1), moderate (Child-Pugh Class B, n=4) or severe (Child-Pugh Class C; n=4) hepatic impairment and 6 healthy matched controls, mean T_1/2 increased by 80%. Also, the mean CL decreased by 30% and the systemic Celemin Hepa (Acetylcysteine) exposure (mean AUC) increased 1.6-fold in subjects with hepatic impairment compared to subjects with normal hepatic function. These changes are not considered to be clinically meaningful.

Renal Impairment

Hemodialysis may remove some of total Celemin Hepa (Acetylcysteine).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies in laboratory animals have not been performed with Celemin Hepa (Acetylcysteine).

Mutagenesis

Celemin Hepa (Acetylcysteine) was negative in the Ames test.

Impairment of Fertility

In a fertility study of Celemin Hepa (Acetylcysteine) in rats, intravenous administration of 1000 mg/kg/day (0.3 times the recommended human oral dose based on body surface area) caused a profound reduction of fertility in females, which was correlated with morphological changes in oocytes and severe impairment of implantation (18 of 20 mated females had no implantations). The reversibility of this effect was not evaluated. No effects on fertility were observed in female rats at intravenous doses up to 300 mg/kg/day (0.1 times the recommended human oral dose based on body surface area), or in male rats at intravenous doses up to 1000 mg/kg/day. Mating was unaffected in this study.

In a reproduction study of Celemin Hepa (Acetylcysteine), male rats were treated orally for 15 weeks prior to mating and during the mating period. A slight non-dose related reduction in fertility was observed at oral doses of 500 and 1000 mg/kg/day (0.1 and 0.3 times the recommended human dose, respectively, based on body surface area).

16 HOW SUPPLIED/STORAGE AND HANDLING

Celemin Hepa (Acetylcysteine) effervescent tablets are supplied as white, round, flat tablets with a lemon mint smell packaged in 2-count peelable foil blister packs in the following dosage strengths:

• 500 mg tablets debossed with "I" on one side; Each carton containing 2-count blister packs (24338-700-02)
  • NDC 24338-700-10: 10 pack carton containing 20 tablets
• 2.5 gram tablets debossed with "O" on one side; Each carton containing 2-count blister packs (24338-725-02)
  • NDC 24338-725-10: 10 pack carton containing 20 tablets

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) Protect from moisture. Store tablets in original blister package until use.

Dilutions of Celemin Hepa (Acetylcysteine) should be used freshly prepared and utilized within two hours.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions, including generalized urticaria may occur and to report any signs or symptoms to their healthcare provider immediately .

Manufactured for:

arbor

PHARMACEUTICALS, LLC

Atlanta, GA 30328

Made in Switzerland by Alpex Pharma SA.

CET-PI-02

Rev. 04/2017

Glycine:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Im-1453
• Celemin Hepa (Glycine) reviews

INDICATIONS AND USAGE

1.5% Celemin Hepa (Glycine) Irrigation, USP is indicated for use as irrigating fluid during transurethral prostatic resection and other transurethral surgical procedures.

CONTRAINDICATIONS

NOT FOR INJECTION BY USUAL PARENTERAL ROUTES.

Do not use in patients with anuria.

WARNINGS

FOR UROLOGIC IRRIGATION ONLY.

Solutions for urologic irrigation must be used with caution in patients with severe cardiopulmonary or renal dysfunction. Irrigating fluids used during transurethral prostatectomy have been demonstrated to enter the systemic circulation in relatively large volumes. Thus, Celemin Hepa (Glycine) irrigating solution must be regarded as a systemic drug. Absorption of large amounts of fluids containing Celemin Hepa (Glycine) may significantly alter cardiopulmonary and renal dynamics.

Do not heat container over 66°C (150°F).

PRECAUTIONS

Cardiovascular status, especially of the patient with cardiac disease, should be carefully observed before and during transurethral resection of the prostate when using Celemin Hepa (Glycine) irrigating solution, because the quantity of fluid absorbed into the systemic circulation by opened prostatic veins may produce significant expansion of the extracellular fluid and lead to fulminating congestive heart failure. Shift of sodium free intracellular fluid into the extracellular compartment following systemic absorption of solution may lower serum sodium concentration and aggravate pre-existing hyponatremia.

Care should be exercised if impaired liver function is known or suspected. Under such conditions, ammonia resulting from metabolism of Celemin Hepa (Glycine) may accumulate in the blood.

Aseptic technique is essential with the use of sterile solutions for irrigation. The administration set should be attached promptly. Unused portions should be discarded and a fresh container of appropriate size used for the start-up of each cycle or repeat procedure.

Do not administer unless solution is clear, seal is intact and container is undamaged. Discard unused portion.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with Celemin Hepa (Glycine) Irrigation, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

Nursing Mothers: Caution should be exercised when Celemin Hepa (Glycine) Irrigation, USP is administered to a nursing woman.

Pregnancy: Teratogenic Effects.

Pregnancy Category C. Animal reproduction studies have not been conducted with Celemin Hepa (Glycine) Irrigation, USP. It is also not known whether Celemin Hepa (Glycine) Irrigation, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Celemin Hepa (Glycine) Irrigation, USP should be given to a pregnant woman only if clearly needed.

Pediatric Use: The safety and effectiveness of Celemin Hepa (Glycine) Irrigation have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use.

ADVERSE REACTIONS

Adverse reactions may result from intravascular absorption of Celemin Hepa (Glycine). Large intravenous doses of Celemin Hepa (Glycine) are known to cause salivation, nausea and lightheadedness. Other consequences of absorption of urologic irrigating solutions include fluid and electrolyte disturbances such as acidosis, electrolyte loss, marked diuresis, urinary retention, edema, dryness of mouth, thirst, dehydration, coma from hyponatremia, secondary hyponatremia due to fluid overload, and hyper- ammonemia with resultant coma and/or encephalopathy; cardiovascular disorders such as hypotension, tachycardia, angina-like pains; pulmonary disorders such as pulmonary congestion; and other general reactions such as blurred vision, convulsions, nausea, vomiting, rhinitis, chills, vertigo, backache, transient blindness and urticaria. Allergic reactions from Celemin Hepa (Glycine) are unknown or exceedingly rare.

Should any adverse reaction occur, discontinue the irrigant, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.

OVERDOSAGE

In the event of overhydration or solute overload, re-evaluate the patient and institute appropriate corrective measures. See WARNINGS, PRECAUTIONS and ADVERSE REACTIONS.

DOSAGE AND ADMINISTRATION

1.5% Celemin Hepa (Glycine) Irrigation, USP should be administered only by transurethral instillation with appropriate urologic instrumentation. A disposable irrigation set should be used. The total volume of solution used for irrigation is solely at the discretion of the surgeon.

Height of container(s) above the operating table in excess of 60 cm (approx. 2 ft.) has been reported to increase intravascular absorption of the irrigating fluid.

Drug Interactions

Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store.

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

HOW SUPPLIED

1.5% Celemin Hepa (Glycine) Irrigation, USP is supplied in single-dose 3000 mL flexible irrigation container ( List No. 7974).

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. Store at 20 to 25°C (68 to 77°F).

Revised: October 2004

©Hospira 2004 EN-0577 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

IM-1453

2

HDPE

TO OPEN TEAR AT NOTCH

DO NOT REMOVE FROM OVERWRAP UNTIL READY FOR USE. AFTER REMOVING

THE OVERWRAP, CHECK FOR MINUTE LEAKS BY SQUEEZING CONTAINER FIRMLY.

IF LEAKS ARE FOUND, DISCARD SOLUTION AS STERILITY MAY BE IMPAIRED.

RECOMMENDED STORAGE: ROOM TEMPERATURE (25°C). AVOID EXCESSIVE

HEAT. PROTECT FROM FREEZING. SEE INSERT.

98-4321-R14-3/98

L-Alanine:

• Celemin Hepa (L-Alanine) reviews

Indication: Used for protein synthesis.

Is an important source of energy for muscle tissue, the brain and central nervous system; strengthens the immune system by producing antibodies; helps in the metabolism of sugars and organic acids.

L-Arginine:

• Celemin Hepa (L-Arginine) reviews

Indication: Used for nutritional supplementation, also for treating dietary shortage or imbalance.

Studies have shown that is has improved immune responses to bacteria, viruses and tumor cells; promotes wound healing and regeneration of the liver; causes the release of growth hormones; considered crucial for optimal muscle growth and tissue repair.

L-Histidine:

• Celemin Hepa (L-Histidine) reviews

Indication: The actions of supplemental Celemin Hepa (L-Histidine) are entirely unclear. It may have some immunomodulatory as well as antioxidant activity. Celemin Hepa (L-Histidine) may be indicated for use in some with rheumatoid arthritis. It is not indicated for treatment of anemia or uremia or for lowering serum cholesterol.

Is found abundantly in hemoglobin; has been used in the treatment of rheumatoid arthritis, allergic diseases, ulcers and anemia. A deficiency can cause poor hearing.

L-Isoleucine:

• Celemin Hepa (L-Isoleucine) reviews

Indication: The branched-chain amino acids may have antihepatic encephalopathy activity in some. They may also have anticatabolic and antitardive dyskinesia activity.

They provide ingredients for the manufacturing of other essential biochemical components in the body, some of which are utilized for the production of energy, stimulants to the upper brain and helping you to be more alert.

L-Leucine:

• Celemin Hepa (L-Leucine) reviews

Indication: Indicated to assist in the prevention of the breakdown of muscle proteins that sometimes occur after trauma or severe stress.

An essential amino acid. (Claim) Leucine helps with the regulation of blood-sugar levels, the growth and repair of muscle tissue (such as bones, skin and muscles), growth hormone production, wound healing as well as energy regulation. It can assist to prevent the breakdown of muscle proteins that sometimes occur after trauma or severe stress. It may also be beneficial for individuals with phenylketonuria - a condition in which the body cannot metabolize the amino acid phenylalanine

L-Lysine Acetate:

• Celemin Hepa (L-Lysine Acetate) reviews

Indication: Supplemental Celemin Hepa (L-Lysine Acetate) has putative anti-herpes simplex virus activity. There is preliminary research suggesting that it may have some anti-osteoporotic activity.

Insures the adequate absorption of calcium; helps form collagen ( which makes up bone cartilage & connective tissues); aids in the production of antibodies, hormones & enzymes. Recent studies have shown that Lysine may be effective against herpes by improving the balance of nutrients that reduce viral growth. A deficiency may result in tiredness, inability to concentrate, irritability, bloodshot eyes, retarded growth, hair loss, anemia & reproductive problems.

L-Methionine:

• Celemin Hepa (L-Methionine) reviews

Indication: Used for protein synthesis including the formation of SAMe, L-homocysteine, L-cysteine, taurine, and sulfate.

Celemin Hepa (L-Methionine) is a principle supplier of sulfur which prevents disorders of the hair, skin and nails; helps lower cholesterol levels by increasing the liver's production of lecithin; reduces liver fat and protects the kidneys; a natural chelating agent for heavy metals; regulates the formation of ammonia and creates ammonia-free urine which reduces bladder irritation; influences hair follicles and promotes hair growth. Celemin Hepa (L-Methionine) may protect against the toxic effects of hepatotoxins, such as acetaminophen. Methionine may have antioxidant activity.

L-Phenylalanine:

• Celemin Hepa (L-Phenylalanine) reviews

Indication: Celemin Hepa (L-Phenylalanine) may be helpful in some with depression. It may also be useful in the treatment of vitiligo. There is some evidence that Celemin Hepa (L-Phenylalanine) may exacerbate tardive dyskinesia in some schizophrenic patients and in some who have used neuroleptic drugs.

Used by the brain to produce Norepinephrine, a chemical that transmits signals between nerve cells and the brain; keeps you awake and alert; reduces hunger pains; functions as an antidepressant and helps improve memory.

L-Proline:

• Celemin Hepa (L-Proline) reviews

Indication: Celemin Hepa (L-Proline) is extremely important for the proper functioning of joints and tendons and also helps maintain and strengthen heart muscles.

Celemin Hepa (L-Proline) is a major amino acid found in cartilage and is important for maintaining youthful skin as well as repair of muscle, connective tissue and skin damage. It is also essential for the immune system, and for necessary balance of this formula. It is an essential component of collagen and is important for proper functioning of joints and tendons. Celemin Hepa (L-Proline) is extremely important for the proper functioning of joints and tendons. Helps maintain and strengthen heart muscles.

L-Serine:

• Celemin Hepa (L-Serine) reviews

Indication: Used as a natural moisturizing agent in some cosmetics and skin care products.

Serine is classified as a nutritionally non-essential amino acid. Serine is critical for the production of the body's proteins, enzymes and muscle tissue. Serine is needed for the proper metabolism of fats and fatty acids. It also helps in the production of antibodies. Serine is used as a natural moisturizing agent in some cosmetics and skin care products. The main source of essential amino acids is from the diet, non-essential amino acids are normally synthesize by humans and other mammals from common intermediates.

L-Threonine:

• Celemin Hepa (L-Threonine) reviews

Indication: Celemin Hepa (L-Threonine) makes up collagen, elastin, and enamel protein. It aids proper fat metabolism in the liver, helps the digestive and intestinal tracts function more smoothly, and assists in metabolism and assimilation.

Celemin Hepa (L-Threonine) is an essential amino acid that helps to maintain the proper protein balance in the body. It is important for the formation of collagen, elastin, and tooth enamel, and aids liver and lipotropic function when combined with aspartic acid and methionine.

L-Tryptophan:

• Celemin Hepa (L-Tryptophan) reviews

Indication: Tryptophan may be useful in increasing serotonin production, promoting healthy sleep, managing depression by enhancing mental and emotional well-being, managing pain tolerance, and managing weight.

Tryptophan is critical for the production of the body's proteins, enzymes and muscle tissue. It is also essential for the production of niacin, the synthesis of the neurotransmitter serotonin and melatonin. Tryptophan supplements can be used as natural relaxants to help relieve insomnia. Tryptophan can also reduce anxiety and depression and has been shown to reduce the intensity of migraine headaches. Other promising indications include the relief of chronic pain, reduction of impulsivity or mania and the treatment of obsessive or compulsive disorders. Tryptophan also appears to help the immune system and can reduce the risk of cardiac spasms. Tryptophan deficiencies may lead to coronary artery spasms. Tryptophan is used as an essential nutrient in infant formulas and intravenous feeding. Tryptophan is marketed as a prescription drug (Tryptan) for those who do not seem to respond well to conventional antidepressants. It may also be used to treat those afflicted with seasonal affective disorder (a winter-onset depression). Tryptopan serves as the precursor for the synthesis of serotonin (5-hydroxytryptamine, 5-HT) and melatonin (N-acetyl-5-methoxytryptamine).

L-Valine:

• Celemin Hepa (L-Valine) reviews

Indication: Promotes mental vigor, muscle coordination, and calm emotions. May also be of use in a minority of patients with hepatic encephalopathy and in some with phenylketonuria.

Celemin Hepa (L-Valine) is a branched-chain essential amino acid (BCAA) that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. Valine is one of three branched-chain amino acids (the others are leucine and isoleucine) that enhance energy, increase endurance, and aid in muscle tissue recovery and repair. This group also lowers elevated blood sugar levels and increases growth hormone production. Supplemental valine should always be combined with isoleucine and leucine at a respective milligram ratio of 2:1:2. It is an essential amino acid found in proteins; important for optimal growth in infants and for growth in children and nitrogen balance in adults. The lack of Celemin Hepa (L-Valine) may influence the growth of body, cause neuropathic obstacle, anaemia. It has wide applications in the field of pharmaceutical and food industry.