Hycet

hydrocodone bitartrate and acetaminophen

Dosage Form: oral syrup

Warning

HEPATOTOXICITY

ACETAMINOPHEN HAS BEEN ASSOCIATED WITH CASES OF ACUTE LIVER FAILURE, AT TIMES RESULTING IN LIVER TRANSPLANT AND DEATH. MOST OF THE CASES OF LIVER INJURY ARE ASSOCIATED WITH THE USE OF ACETAMINOPHEN AT DOSES THAT EXCEED 4000 MILLIGRAMS PER DAY, AND OFTEN INVOLVE MORE THAN ONE ACETAMINOPHEN-CONTAINING PRODUCT.

Hycet Description

Hydrocodone bitartrate and acetaminophen is supplied in liquid form for oral administration.

WARNING: May be habit-forming (see PRECAUTIONS, Information for Patients/Caregivers, and DRUG ABUSE AND DEPENDENCE).

Hydrocodone bitartrate is an opioid analgesic and antitussive and occurs as fine, white crystals or as a crystalline powder. It is affected by light. The chemical name is 4,5α- epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). It has the following structural formula:

C18H21NO3 • C4H6O6 • 2½ H2O M.W. 494.490

Acetaminophen, 4’-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:

C8H9NO2 MW = 151.16

       

Hycet contains:

		Per 5 mL	Per 15 mL
Hydrocodone Bitartrate	..........................	2.5 mg	7.5 mg
Acetaminophen	..........................	108.0 mg	325.0 mg
Alcohol	..........................	7 %	7 %

In addition, the liquid contains the following inactive ingredients: citric acid anhydrous, ethyl maltol, glycerin, methylparaben, propylene glycol, propylparaben, purified water, saccharin sodium, sorbitol solution, sucrose, with D&C Red #33 and FD&C Red #40 as coloring and natural and artificial flavoring.

Hycet - Clinical Pharmacology

Hydrocodone is a semisynthetic narcotic analgesic and antitussive with multiple actions qualitatively similar to those of codeine. Most of these involve the central nervous system and smooth muscle. The precise mechanism of action of hydrocodone and other opiates is not known, although it is believed to relate to the existence of opiate receptors in the central nervous system. In addition to analgesia, narcotics may produce drowsiness, changes in mood and mental clouding.

The analgesic action of acetaminophen involves peripheral influences, but the specific mechanism is as yet undetermined. Antipyretic activity is mediated through hypothalamic heat regulating centers. Acetaminophen inhibits prostaglandin synthetase. Therapeutic doses of acetaminophen have negligible effects on the cardiovascular or respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing.

Pharmacokinetics

The behavior of the individual components is described below.

Hydrocodone

Following a 10 mg oral dose of hydrocodone administered to five adult male subjects, the mean peak concentration was 23.6 ± 5.2 ng/mL. Maximum serum levels were achieved at 1.3 ± 0.3 hours and the half-life was determined to be 3.8 ± 0.3 hours. Hydrocodone exhibits a complex pattern of metabolism including O-demethylation, N-demethylation and 6-keto reduction to the corresponding 6-α- and 6-β-hydroxymetabolites.

See OVERDOSAGE for toxicity information.

Acetaminophen

Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug.

See OVERDOSAGE for toxicity information.

Indications and Usage for Hycet

Hycet (hydrocodone bitartrate and acetaminophen oral solution) is indicated for the relief of moderate to moderately severe pain.

Contraindications

This product should not be administered to patients who have previously exhibited hypersensitivity to hydrocodone, acetaminophen, or any other component of this product.

Patients known to be hypersensitive to other opioids may exhibit cross-sensitivity to hydrocodone.

Warnings

Hepatotoxicity

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well.

Hypersensitivity/anaphylaxis

There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue Hycet immediately and seek medical care if they experience these symptoms. Do not prescribe Hycet for patients with acetaminophen allergy.

Respiratory Depression

At high doses or in sensitive patients, hydrocodone may produce dose-related respiratory depression by acting directly on the brain stem respiratory center. Hydrocodone also affects the center that controls respiratory rhythm, and may produce irregular and periodic breathing.

Infants may have increased sensitivity to the respiratory depressant effects of opioids (see PRECAUTIONS, Pediatric Use). If use of Hycet in such patients is contemplated, it should be administered cautiously, in substantially reduced initial doses, by personnel experienced in administering opioids to infants, and with intensive monitoring.

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a preexisting increase in intracranial pressure. Furthermore, narcotics produce adverse reactions, which may obscure the clinical course of patients with head injuries.

Acute Abdominal Conditions

The administration of narcotics may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Misuse, Abuse, and Diversion of Opioids

Hycet contains hydrocodone, an opioid agonist, and is a Schedule III controlled substance. Opioid agonists have the potential for being abused and are sought by abusers and people with addiction disorders, and are subject to diversion.

Hycet can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Hycet in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion (see DRUG ABUSE AND DEPENDENCE).

Precautions

General

Special Risk Patients

As with any narcotic analgesic agent, Hycet should be used with caution in elderly or debilitated patients, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind.

Cough Reflex

Hydrocodone suppresses the cough reflex; as with all narcotics, caution should be exercised when Hycet is used postoperatively and in patients with pulmonary disease.

Information for Patients/Caregivers

• Do not take Hycet if you are allergic to any of its ingredients.


• If you develop signs of allergy such as a rash or difficulty breathing, stop taking Hycet and contact your healthcare provider immediately.


• Do not take more than 4000 milligrams of acetaminophen per day. Call your doctor if you took more than the recommended dose.

Hydrocodone, like all narcotics, may impair mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Such tasks should be avoided while taking this product.

Alcohol and other CNS depressants may produce an additive CNS depression, when taken with this combination product, and should be avoided.

Hydrocodone may be habit-forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.

Physicians should instruct patients and caregivers to read the patient information leaflet, which appears as the last section of the labeling.

Laboratory Tests

In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests.

Drug Interactions

Patients receiving narcotics, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants (including alcohol) concomitantly with hydrocodone bitartrate and acetaminophen oral solution may exhibit an additive CNS depression. When combined therapy is contemplated, the dose of one or both agents should be reduced.

The use of MAO inhibitors or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone.

Drug/Laboratory Test Interactions

Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No adequate studies have been conducted in animals to determine whether hydrocodone has a potential for carcinogenesis, mutagenesis, or impairment of fertility.

Hydrocodone has not demonstrated mutagenic potential using the Ames Salmonella-Microsomal Activation test, the Basc test on Drosophila germ cells, and the Micronucleus test on mouse bone marrow.

No adequate studies have been conducted in animals to determine whether acetaminophen has a potential for carcinogenesis, mutagenesis, or impairment of fertility.

Acetaminophen has not demonstrated mutagenic potential using the Ames Salmonella-Microsomal Activation test, the Basc test on Drosophila germ cells, and the Micronucleus test on mouse bone marrow.

Pregnancy

Teratogenic Effects

Pregnancy Category C

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

Nonteratogenic Effects

Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting and fever. These signs usually appear during the first few days of life. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.

Labor and Delivery

Narcotic analgesics cross the placental barrier. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (see OVERDOSAGE). The effect of hydrocodone, if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Mothers

Acetaminophen is excreted in breast milk in small amounts, but the significance of its effects on nursing infants is not known. It is not known whether hydrocodone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from hydrocodone and acetaminophen, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in the pediatric population below the age of two years have not been established. Use of Hycet in the pediatric population is supported by the evidence from adequate and well controlled studies of hydrocodone and acetaminophen combination products in adults with additional data which support the development of metabolic pathways in children two years of age and over (see DOSAGE AND ADMINISTRATION for pediatric dosage information).

Geriatric Use

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

Hydrocodone and the major metabolites of acetaminophen are known to be substantially excreted by the kidney. Thus the risk of toxic reactions may be greater in patients with impaired renal function due to the accumulation of the parent compound and/or metabolites in the plasma. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hydrocodone may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of hydrocodone bitartrate and acetaminophen oral solution and observed closely.

Adverse Reactions

To request medical information or to report SUSPECTED ADVERSE REACTIONS, contact Éclat Pharmaceuticals, L.L.C. at 877-622-2320 or FDA at 1-800-FDA 1088 or www.fda.gov/medwatch.

Potential effects of high dosage are also listed in the OVERDOSAGE section.

Cardio-renal: Bradycardia, cardiac arrest, circulatory collapse, renal toxicity, renal tubular necrosis, hypotension.

Central Nervous System/Psychiatric: Anxiety, dizziness, drowsiness, dysphoria, euphoria, fear, general malaise, impairment of mental and physical performance, lethargy, light-headedness, mental clouding, mood changes, psychological dependence, sedation, somnolence progressing to stupor or coma.

Endocrine: Hypoglycemic coma.

Gastrointestinal System: Abdominal pain, constipation, gastric distress, heartburn, hepatic necrosis, hepatitis, occult blood loss, nausea, peptic ulcer, and vomiting.

Genitourinary System: Spasm of vesical sphincters, ureteral spasm, and urinary retention.

Hematologic: Agranulocytosis, hemolytic anemia, iron deficiency anemia, prolonged bleeding time, thrombocytopenia.

Hypersensitivity: Allergic reactions.

Musculoskeletal: Skeletal muscle flaccidity.

Respiratory Depression: Acute airway obstruction, apnea, dose-related respiratory depression (see OVERDOSAGE), shortness of breath.

Special Senses: Cases of hearing impairment or permanent loss have been reported predominantly in patients with chronic overdose.

Skin: Cold and clammy skin, diaphoresis, pruritus, rash.

Drug Abuse and Dependence

Misuse, Abuse, and Diversion of Opioids

Hycet contains hydrocodone, an opioid agonist, and is a Schedule III controlled substance. Hycet, and other opioids, used in analgesia can be abused and are subject to criminal diversion.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease utilizing a multidisciplinary approach, but relapse is common.

“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physical dependence usually assumes clinically significant dimensions only after several weeks of continued opioid use, although a mild degree of physical dependence may develop after a few days of opioid therapy. Tolerance, in which increasingly large doses are required in order to produce the same degree of analgesia, is manifested initially by a shortened duration of analgesic effect, and subsequently by decreases in the intensity of analgesia. The rate of development of tolerance varies among patients. Physicians should be aware that abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Hycet, like other opioids, may be diverted for non-medical use. Record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Overdosage

Following an acute overdosage, toxicity may result from hydrocodone or acetaminophen.

Signs and Symptoms

Hydrocodone: Serious overdose with hydrocodone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur.

Acetaminophen: In acetaminophen overdosage: dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.

Treatment

A single or multiple drug overdose with hydrocodone and acetaminophen is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended. Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered.

For hydrocodone overdose, primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The narcotic antagonist naloxone hydrochloride is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to narcotics, including hydrocodone. Since the duration of action of hydrocodone may exceed that of the antagonist, the patient should be kept under continued surveillance, and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. A narcotic antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression.

Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration.

Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose dependent and occurs early in the course of intoxication.

Hycet Dosage and Administration

Dosage should be adjusted according to severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose related.

The usual adult dosage is one tablespoonful every 4 to 6 hours as needed for pain. The total daily dosage for adults should not exceed 6 tablespoonfuls.

The usual dosages for children are given by the table below, and are to be given every 4 to 6 hours as needed for pain. These dosages correspond to an average individual dose of 0.27 mL/kg of Hycet (providing 0.135 mg/kg of hydrocodone bitartrate and 5.85 mg/kg of acetaminophen). Dosing should be based on weight whenever possible.

BODY WEIGHT	APPROXIMATE AGE	DOSE every 4 to 6 hours	MAXIMUM TOTAL DAILY DOSE (6 doses per day)
12 to 15 kg 27 to 34 lbs.	2 to 3 years	¾ teaspoonful = 3.75 mL	4½ teaspoonfuls =22.5 mL
16 to 22 kg 35 to 50 lbs.	4 to 6 years	1 teaspoonful = 5 mL	6 teaspoonfuls = 30 mL
23 to 31 kg 51 to 69 lbs.	7 to 9 years	1½ teaspoonfuls = 7.5 mL	9 teaspoonfuls = 45 mL
32 to 45 kg 70 to 100 lbs.	10 to 13 years	2 teaspoonfuls = 10 mL	12 teaspoonfuls = 60 mL
46 kg and up 101 lbs. and up	14 years to adult	1 Tablespoonful = 15 mL	6 Tablespoonfuls = 90 mL

The total daily dosage for children should not exceed 6 doses per day.

It is of utmost importance that the dose of Hycet be administered accurately. A household teaspoon or tablespoon is not an adequate measuring device, especially when one-half or three-fourths of a teaspoonful is to be measured. Given the inexactitude of the household spoon measure and the possibility of using a tablespoon instead of a teaspoon, which could lead to overdosage, it is strongly recommended that care givers obtain and use a calibrated measuring device. Health care providers should recommend a dropper that can measure and deliver the prescribed dose accurately, and instruct care givers to use extreme caution in measuring the dosage.

How is Hycet Supplied

Hycet (hydrocodone bitartrate and acetaminophen oral solution), is a red-colored, tropical fruit punch flavored liquid containing hydrocodone bitartrate (WARNING: may be habit-forming) 7.5 mg and acetaminophen 325 mg per 15 mL, with 7% alcohol. It is supplied in containers of one pint (473 mL).

NDC 76014-001-25.

STORAGE

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

PHARMACIST: Dispense in a tight, light-resistant container with a child-resistant closure.

A Schedule CIII Narcotic.

Distributed by:

Éclat Pharmaceuticals, L.L.C.

699 Trade Center Blvd., Suite A

Chesterfield, MO 63005

www.eclatpharman.com

To request medical information or to report SUSPECTED ADVERSE REACTIONS, contact Éclat Pharmaceuticals, L.L.C. at 877-622-2320.

PATIENT INFORMATION LEAFLET

Hycet

hydrocodone bitartrate and acetaminophen oral solution

7.5 mg/325 mg per 15 mL

Summary

Hycet (pronounced HI-set) is used to relieve moderate to moderately severe pain. You should not take Hycet if you are allergic to hydrocodone or acetaminophen. The most common side effects of Hycet are abdominal pain, dizziness, drowsiness, light-headedness, nausea, shortness of breath, unusual tiredness, and vomiting. Take this medicine as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

Uses

Hycet is an analgesic used to relieve moderate to moderately severe pain. Hycet is a combination product containing hydrocodone (hye-droe-KO-done) bitartrate and acetaminophen (a-seat-a-MIN-oh-fen). Hydrocodone is a narcotic pain reliever and a cough suppressant. Acetaminophen is a non-narcotic pain reliever and fever reducer. A narcotic analgesic and acetaminophen used together may provide better pain relief than either product used alone. If you have any questions, please call your doctor or pharmacist.

General Cautions

• Do not take this drug if you have allergies or unusual reactions to narcotic pain relievers or acetaminophen because it is likely that you may also be allergic to Hycet.


• This product may inhibit your mental and physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Such tasks should be avoided while you are taking this product.


• This medicine may not be right for you. Check with your doctor or pharmacist, if you:
  
  • are pregnant.
  
  
  • are nursing.
  
  
  • are taking other medications: narcotic pain relievers; allergy medicines; antidepressant medicines; acetaminophen-containing medicines or other medicines that cause central nervous system depression, including alcohol.
  
  
  • have other medical problems: a history of drug or alcohol abuse; recent head injury; emphysema, asthma, or other chronic lung disease; liver disease, kidney disease; underactive thyroid, Addison’s disease, enlarged prostate or difficulty urinating.
  
  

Proper Use

Take this medicine as directed by your doctor. Do not share it with anyone else. This medicine can cause drug dependence and has the potential for abuse. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. If you think that this medicine is not working properly after taking it for some time, do not increase the dose. Check with your doctor or pharmacist.

Dosing

The dose of this medication will be different for different patients. Follow the directions provided by your doctor. The following information includes only the average doses of this medication. If your dose is different, do not change doses unless your doctor tells you to do so.

BODY WEIGHT	APPROXIMATE AGE	DOSE every 4 to 6 hours	MAXIMUM TOTAL DAILY DOSE (6 doses per day)
12 to 15 kg 27 to 34 lbs.	2 to 3 years	¾ teaspoonful = 3.75 mL	4½ teaspoonfuls =22.5 mL
16 to 22 kg 35 to 50 lbs.	4 to 6 years	1 teaspoonful = 5 mL	6 teaspoonfuls = 30 mL
23 to 31 kg 51 to 69 lbs.	7 to 9 years	1½ teaspoonfuls = 7.5 mL	9 teaspoonfuls = 45 mL
32 to 45 kg 70 to 100 lbs.	10 to 13 years	2 teaspoonfuls = 10 mL	12 teaspoonfuls = 60 mL
46 kg and up 101 lbs. and up	14 years to adult	1 Tablespoonful = 15 mL	6 Tablespoonfuls = 90 mL

It is very important that Hycet be dosed accurately. A household teaspoon or tablespoon is not an accurate measuring device, especially when one-half or three-fourths of a teaspoonful is to be measured.

Since a household teaspoon is not accurate and can be mixed-up with a tablespoon (which can cause overdosage), it is strongly recommended that you obtain and use a proper measuring device. Ask your doctor or pharmacist for help to find a dropper that can measure the needed dose properly and ask for help if you do not understand how to use the dropper.

Missed Dose

• To avoid a possible overdose, it is important that you do not take more than a single dosage at one time, or that you don’t take doses at intervals less than 4 hours apart.


• If you miss taking a dose of Hycet, take it as soon as you remember. However, make sure to wait at least 4 hours before taking your next dose.


• If you missed taking a dose, and it is almost time for your next dose, skip the missed dose and take your medicine as scheduled.


• Do not double the prescribed dose.

Possible Side Effects

Side effects you may experience include abdominal pain, constipation, difficulty urinating, dizziness, drowsiness, fear, fuzzy thinking, general feeling of discomfort or illness, light-headedness, mood changes, nausea, nervousness, rash, shortness of breath, slower reactions, unusual tiredness, and vomiting.

Call your doctor if these effects continue or are bothersome.

Side effects not listed above may sometimes occur. If you notice any other effects, check with your doctor.

Storage

• Keep out of reach of children.


• Store at room temperature (protect from heat, do not refrigerate).


• Keep in original labeled bottle.


• Discard medicines that are old or no longer needed.


• Even a single overdose of this medicine may be a life-threatening situation. If you suspect that you or someone else may have taken more than the prescribed dose of this medicine, contact your local poison control center or emergency room immediately. This medicine was prescribed for your particular condition. Do not use it for another condition or give the drug to others.


• This leaflet provides a summary of information about Hycet. If you have any questions or concerns, or want more information about Hycet, contact your doctor or pharmacist. Your pharmacist also has a longer leaflet about Hycet that is written for health professionals that you can ask to read.

Distributed by:

Éclat Pharmaceuticals, L.L.C.

699 Trade Center Blvd., Suite A

Chesterfield, MO 63005

www.eclatpharman.com

To request medical information or to report SUSPECTED ADVERSE REACTIONS, contact Éclat Pharmaceuticals, L.L.C. at 877-622-2320.

Code 866E00

Rev. 06/11

PRINCIPAL DISPLAY PANEL

Hycet  hydrocodone bitartrate and acetaminophen  syrup

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 76014-001 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HYDROCODONE BITARTRATE (HYDROCODONE) HYDROCODONE BITARTRATE 7.5 mg  in 15 mL ACETAMINOPHEN (ACETAMINOPHEN) ACETAMINOPHEN 325 mg  in 15 mL

Inactive Ingredients Ingredient Name Strength ANHYDROUS CITRIC ACID   D&C RED NO. 33   ETHYL MALTOL   FD&C RED NO. 40   GLYCERIN   METHYLPARABEN   PROPYLENE GLYCOL   PROPYLPARABEN   SACCHARIN SODIUM   SORBITOL   SUCROSE   WATER

Product Characteristics Color RED Score      Shape Size Flavor FRUIT PUNCH Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 76014-001-25 473 mL In 1 BOTTLE, PLASTIC None 2 76014-001-22 30 mL In 1 BOTTLE, PLASTIC None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA040482	08/01/2011

Labeler - Eclat Pharmaceuticals, LLC (965538205)

Registrant - Mikart, Inc. (030034847)

Establishment
Name	Address	ID/FEI	Operations
Mikart, Inc.		030034847	MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
Mikart, Inc.		013322387	MANUFACTURE

Revised: 08/2011Eclat Pharmaceuticals, LLC

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Hydrea

Generic Name: hydroxyurea (Oral route)

hye-drox-ee-ure-EE-a

Oral route(Capsule)

Treatment of patients with hydroxyurea may be complicated by severe, sometimes life-threatening, adverse effects. Hydroxyurea is mutagenic and clastogenic, and causes cellular transformation to a tumorigenic phenotype which implies a carcinogenic risk to humans. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemias have been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patients’ underlying disease .

Commonly used brand name(s)

In the U.S.

• Droxia


• Hydrea

Available Dosage Forms:

• Capsule


• Tablet

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Antimetabolite

Uses For Hydrea

Hydroxyurea is used to treat skin cancer (melanoma), a cancer of the white blood cells called chronic myelocytic leukemia (CML), and metastatic cancer (cancer that has spread) of the ovaries. This medicine may also be given together with radiation treatment for head and neck cancer (primary squamous cell cancer).

Hydroxyurea is also used in adult patients with sickle cell anemia to prevent painful episodes and reduce the need for blood transfusions. It works by making the red blood cells more flexible.

Hydroxyurea will interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected, other unwanted effects will also occur. Some of these effects may be serious and must be reported to your doctor.

Before you begin treatment with hydroxyurea, you and your doctor should talk about the good this medicine will do as well as the risks of using it.

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

Before Using Hydrea

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

Allergies

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

Pediatric

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

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of hydroxyurea in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require caution and an adjustment in the dose for patients receiving hydroxyurea.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

Breast Feeding

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

Interactions with Medicines

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

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

• Rotavirus Vaccine, Live

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

• Adenovirus Vaccine Type 4, Live


• Adenovirus Vaccine Type 7, Live


• Bacillus of Calmette and Guerin Vaccine, Live


• Didanosine


• Influenza Virus Vaccine, Live


• Measles Virus Vaccine, Live


• Mumps Virus Vaccine, Live


• Rotavirus Vaccine, Live


• Rubella Virus Vaccine, Live


• Smallpox Vaccine


• Stavudine


• Typhoid Vaccine


• Varicella Virus Vaccine


• Yellow Fever Vaccine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

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

• Anemia (low red blood cells) or


• Bone marrow problems or


• Gout, history of or


• Leukopenia (low white blood cells) or


• Thrombocytopenia (low platelets)—May make these conditions worse.

• HIV or AIDS infection with didanosine (Videx®) or stavudine (Zerit®) therapy—May cause side effects to become worse.

• Kidney disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Proper Use of hydroxyurea

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

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

This medicine comes with a patient information insert. Read and follow the instructions in the insert carefully. Ask your doctor if you have any questions.

Hydroxyurea should be handled with care and people who are not taking this medicine should be careful to avoid touching it. To decrease the chance of touching the medicine:

• Wear disposable gloves when handling hydroxyurea or bottles containing hydroxyurea.


• Wash your hands before and after contact with the bottle or capsules.


• If powder from the capsule is spilled, you should wipe it up immediately with a damp disposable towel and discard it in a closed container, such as a plastic bag.


• You should keep medicine away from children and pets.


• You should contact your doctor for instructions on how to dispose of capsules that are past the expiration date.

Dosing

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

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

• For oral dosage form (capsules):
  
  • For cancer of the head and neck, ovaries, or skin:
    
    • Adults—Dose is based on body weight and must be determined by your doctor. The dose is 80 milligrams (mg) per kilogram (kg) of body weight, taken as a single dose every third day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For chronic myelocytic leukemia (CML):
    
    • Adults—Dose is based on body weight and must be determined by your doctor. The dose is 30 milligrams (mg) per kilogram (kg) of body weight per day, taken as a single dose.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For sickle cell anemia:
    
    • Adults—Dose is based on body weight and must be determined by your doctor. The dose is 15 milligrams (mg) per kilogram (kg) of body weight per day, taken as a single dose. Your doctor may increase your dose as needed. However, the dose is usually not more than 35 mg per kg of body weight per day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

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

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

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

Precautions While Using Hydrea

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood tests may be needed to check for unwanted effects.

Make sure your doctor knows if you are pregnant before you use this medicine. Using this medicine while you are pregnant can harm your unborn baby. If you think you have become pregnant while using the medicine, tell your doctor right away.

While you are being treated with hydroxyurea, and after you stop using it, do not have any immunizations (vaccines) without your doctor's approval. Hydroxyurea may lower your body's resistance and there is a chance you might get the infection the vaccine is meant to prevent. In addition, other persons living in your household should not get live vaccines (eg, nasal flu vaccine, measles, mumps, or rubella) since there is a chance they could pass the infection on to you. Also, avoid persons who have had a live vaccine. Do not get close to them and do not stay in the same room with them for very long. If you cannot take these precautions, you should consider wearing a protective face mask that covers the nose and mouth.

Hydroxyurea can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.


• Check with your doctor immediately if you notice any unusual bleeding or bruising; black, tarry stools; blood in the urine or stools; or pinpoint red spots on your skin.


• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.


• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.


• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.


• Avoid contact sports or other situations where bruising or injury could occur.

Using this medicine for a long time may increase your risk of developing cancer of the blood (leukemia). Talk to your doctor if you have concerns about this risk.

This medicine may cause temporary loss of hair in some people. After treatment has ended, normal hair growth should return, although the new hair may be a slightly different color or texture.

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

Hydrea Side Effects

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

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

More common

• Cough or hoarseness


• fever or chills


• lower back or side pain


• painful or difficult urination

Less common

• Black, tarry stools


• blackening of the fingernails and toenails


• blood in the urine or stools


• pinpoint red spots on the skin


• sores in the mouth and on the lips


• unusual bleeding or bruising

Rare

• Confusion


• convulsions (seizures)


• difficulty with urination


• dizziness


• headache


• joint pain


• seeing, hearing, or feeling things that are not there


• swelling of the feet or lower legs

Incidence not known

• Bleeding under the skin


• blisters on the skin


• bluish or pale color on the skin of the fingers or toes


• coldness of the fingers or toes


• crater-like lesions on the skin


• itching skin


• numbness or tingling of the fingers or toes


• pain in the fingers or toes


• unusual tiredness or weakness


• weight loss

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Scaling of the skin on the hands and feet


• severe darkening of skin color


• soreness


• sores in the mouth and on the lips


• swelling of the palms and soles of the feet


• violet flushing of the skin

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

More common

• Diarrhea


• drowsiness


• loss of appetite


• nausea or vomiting

Less common

• Constipation


• redness of skin at the place of irradiation


• skin rash and itching

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

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

See also: Hydrea side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Hydrea resources

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

• Hydrea Prescribing Information (FDA)


• Hydrea Concise Consumer Information (Cerner Multum)


• Hydrea MedFacts Consumer Leaflet (Wolters Kluwer)


• Hydroxyurea Prescribing Information (FDA)


• Hydroxyurea Professional Patient Advice (Wolters Kluwer)


• Hydroxyurea Monograph (AHFS DI)


• Droxia MedFacts Consumer Leaflet (Wolters Kluwer)


• Droxia Prescribing Information (FDA)

Compare Hydrea with other medications

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Hydralazine and Hydrochlorothiazide

Dosage Form: capsules

WARNING:THIS FIXED-COMBINATION DRUG IS NOT INDICATED FOR INITIAL THERAPY OF HYPERTENSION. HYPERTENSION REQUIRES THERAPY TITRATED TO THE INDIVIDUAL PATIENT. IF THE FIXED COMBINATION REPRESENTS THE DOSAGE SO DETERMINED, ITS USE MAY BE MORE CONVENIENT IN PATIENT MANAGEMENT. THE TREATMENT OF HYPERTENSION IS NOT STATIC BUT MUST BE REEVALUATED AS CONDITIONS IN EACH PATIENT WARRANT.

Hydralazine and Hydrochlorothiazide Description

Hydralazine HCl and hydrochlorothiazide is an antihypertensive-diuretic combination available as capsules for oral administration. Hydralazine HCl and hydrochlorothiazide capsules of 25 mg/25 mg contain 25 mg of Hydralazine hydrochloride USP and 25 mg of hydrochlorothiazide USP; capsules of 50 mg/50 mg contain 50 mg of hydralazine hydrochloride USP and 50 mg of hydrochlorothiazide USP; and capsules of 100 mg/50 mg contain 100 mg of hydralazine hydrochloride USP and 50 mg of hydrochlorothiazide USP.

Each capsule also contains the following inactive ingredients: Corn starch, crospovidone, gelatin, lactose monohydrate, pharmaceutical glaze, sodium starch glycolate, stearic acid, talc, and titanium dioxide. In addition, the 25 mg/25 mg capsule contains ammonium hydroxide, ethylene glycol monoethyl ether, propylene glycol and synthetic black iron oxide; the 50 mg/50 mg capsule contains FD&C Blue #1, FD&C Red #40, FD&C Yellow #6, synthetic red iron oxide and pharmaceutical shellac; and the 100 mg/50 mg capsule contains D&C Red #28, D&C Yellow #10, FD&C Blue #1,FD&C Blue #2, FD&C Red #40, propylene glycol and synthetic black iron oxide.

Hydralazine hydrochloride is 1-hydrazinophthalazine monohydrochloride, and its structural formula is:

Hydralazine hydrochloride USP is a white to off-white, odorless crystalline powder. It is soluble in water, slightly soluble in alcohol, and very slightly soluble in ether. It melts at about 275°C, with decomposition, and has a molecular weight of 196.64.

Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, and its structural formula is:

Hydrochlorothiazide USP is a white, or practically white, practically odorless crystalline powder. It is freely soluble in sodium hydroxide solution, inn-butylamine, and in dimethylformamide; sparingly soluble in methanol; slightly soluble in water; and insoluble in ether, in chloroform, and in dilute mineral acids. Its molecular weight is 297.75.

Hydralazine and Hydrochlorothiazide - Clinical Pharmacology

Hydralazine

Although the precise mechanism of action of hydralazine is not fully understood, the major effects are on the cardiovascular system. Hydralazine apparently lowers blood pressure by exerting a peripheral vasodilating effect through a direct relaxation of vascular smooth muscle. Hydralazine, by altering cellular calcium metabolism, interferes with the calcium movements within the vascular smooth muscle that are responsible for initiating or maintaining the contractile state.

The peripheral vasodilating effect of hydralazine results in decreased arterial blood pressure (diastolic more than systolic); decreased peripheral vascular resistance; and an increased heart rate, stroke volume, and cardiac output. The preferential dilatation of arterioles, as compared to veins, minimizes postural hypotension and promotes the increase in cardiac output. Hydralazine usually increases renin activity in plasma, presumably as a result of increased secretion of renin by the renal juxtaglomerular cells in response to reflex sympathetic discharge. This increase in renin activity leads to the production of angiotensin II, which then causes stimulation of aldosterone and consequent sodium reabsorption. Hydralazine also maintains or increases renal and cerebral blood flow.

Hydrochlorothiazide

Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage, all thiazides are approximately equal in their diuretic potency. Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium.

The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not affect normal blood pressure.

Pharmacokinetics

Hydralazine:Hydralazine is rapidly absorbed after oral administration, and peak plasma levels are reached at 1-2 hours. Plasma levels decline with a half-life of 3-7 hours. Binding to human plasma protein is 87%. Plasma levels of hydralazine vary widely among individuals. Hydralazine is subject to polymorphic acetylation; slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of blood pressure. Hydralazine undergoes extensive hepatic metabolism; it is excreted mainly in the form of metabolites in the urine.

Administration of hydralazine with food results in higher levels of the drug in plasma.

Hydrochlorothiazide: Onset of action of thiazides occurs in 2 hours and the peak effect at about 4 hours. The action persists for approximately 6-12 hours. Hydrochlorothiazide is rapidly absorbed, as indicated by peak concentrations 1-2.5 hours after oral administration. Plasma levels of the drug are proportional to dose; the concentration in whole blood is 1.6-1.8 times higher than in plasma. Thiazides are eliminated rapidly by the kidney. After oral administration of 25 to 100 mg doses, 72-97% of the dose is excreted in the urine, indicating dose-independent absorption. Hydrochlorothiazide is eliminated from plasma in a biphasic fashion with a terminal half-life of 10-17 hours. Plasma protein binding is 67.9%. Plasma clearance is 15.9-30.0 L/hr; volume of distribution is 3.6-7.8 L/kg.

Gastrointestinal absorption of hydrochlorothiazide is enhanced when administered with food. Absorption is decreased in patients with congestive heart failure, and the pharmacokinetics are considerably different in these patients.

Indications and Usage for Hydralazine and Hydrochlorothiazide

Hypertension (see boxed WARNING).

Contraindications

Hydralazine

Hypersensitivity to hydralazine; coronary artery disease; mitral valvular rheumatic heart disease.

Hydrochlorothiazide

Anuria; hypersensitivity to this or other sulfonamide-derived drugs.

Warnings

Hydralazine

In a few patients hydralazine may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis. In such patients hydralazine should be discontinued unless the benefit-to-risk determination requires continued antihypertensive therapy with this drug. Signs and symptoms usually regress when the drug is discontinued, but residua have been detected many years later. Long-term treatment with steroids may be necessary. (SeePRECAUTIONS, Laboratory Tests.)

Hydrochlorothiazide

Thiazides should be used with caution in patients with severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte imbalance may precipitate hepatic coma.

Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs.

Sensitivity reactions are more likely to occur in patients with a history of allergy or bronchial asthma.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

GENERAL PRECAUTIONS

Hydralazine: Myocardial stimulation produced by hydralazine can cause anginal attacks and ECG changes indicative of myocardial ischemia. The drug has been implicated in the production of myocardial infarction. It must, therefore, be used with caution in patients with suspected coronary artery disease.

The “hyperdynamic” circulation caused by hydralazine may accentuate specific cardiovascular inadequacies. For example, hydralazine may increase pulmonary artery pressure in patients with mitral valvular disease. The drug may reduce the pressor responses to epinephrine. Postural hypotension may result from hydralazine but is less common than with ganglionic blocking agents. It should be used with caution in patients with cerebral vascular accidents.

In hypertensive patients with normal kidneys who are treated with hydralazine, there is evidence of increased renal blood flow and a maintenance of glomerular filtration rate. In some instances where control values were below normal, improved renal function has been noted after administration of hydralazine. However, as with any antihypertensive agent, hydralazine should be used with caution in patients with advanced renal damage.

Peripheral neuritis, evidenced by paresthesia, numbness, and tingling, has been observed. Published evidence suggests that hydralazine has an antipyridoxine effect and that pyridoxine should be added to the regimen if symptoms develop.

Hydrochlorothiazide:All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance, namely hyponatremia, hypochloremic alkalosis, and hypokalemia (seeLaboratory TestsandDrug/Drug Interactions). Warning signs are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbance, such as nausea or vomiting.

Hypokalemia may develop, especially in cases of brisk diuresis or severe cirrhosis.

Interference with adequate oral intake of electrolytes will also contribute to hypokalemia. Hypokalemia may be avoided or treated by the use of potassium supplements or foods with a high potassium content.

Any chloride deficit is generally mild and usually does not require specific treatment, except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In cases of actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

Latent diabetes may become manifest during thiazide administration (see Drug/Drug Interactions).

The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.

If progressive renal impairment becomes evident, withholding or discontinuing diuretic therapy should be considered.

Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism, such as renal lithiasis, bone resorption and peptic ulceration, have not been seen.

Thiazide diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Information for Patients

Patients should be informed of possible side effects and advised to take the medication regularly and continuously as directed.

Laboratory Tests

Hydralazine:Complete blood counts and antinuclear antibody titer determinations are indicated before and periodically during prolonged therapy with hydralazine even though the patient is asymptomatic. These studies are also indicated if the patient develops arthralgia, fever, chest pain, continued malaise, or other unexplained signs or symptoms. A positive antinuclear antibody titer requires that the physician carefully weigh the implications of the test results against the benefits to be derived from antihypertensive therapy with a combination drug containing hydralazine.

Blood dyscrasias, consisting of reduction in hemoglobin and red cell count, leukopenia, agranulocytosis, and purpura, have been reported. If such abnormalities develop, therapy should be discontinued.

Hydrochlorothiazide: Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids.

Drug Interactions

Hydralazine:MAO inhibitors should be used with caution in patients receiving hydralazine.

When other potent parenteral antihypertensive drugs, such as diazoxide, are used in combination with hydralazine, patients should be continuously observed for several hours for any excessive fall in blood pressure. Profound hypotensive episodes may occur when diazoxide injections and hydralazine are used concomitantly.

Hydrochlorothiazide: Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Hypokalemia may develop during concomitant use of steroids or ACTH.

Insulin requirements in diabetic patients may be increased, decreased, or unchanged.

Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to preclude effectiveness of the pressor agent for therapeutic use.

Thiazides may increase the responsiveness to tubocurarine.

Lithium renal clearance is reduced by thiazides, increasing the risk of lithium toxicity.

There have been rare reports in the literature of hemolytic anemia occurring with the concomitant use of hydrochlorothiazide and methyldopa.

Concurrent administration of some nonsteroidal anti-inflammatory agents may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics.

Drug and/or Laboratory Test Interactions

Thiazides may decrease serum levels of protein-bound iodine without signs of thyroid disturbance. Hydralazine HCl and hydrochlorothiazide should be discontinued before tests for parathyroid function are made (seeGeneral, Hydrochlorothiazide, Calcium excretion).

Carcinogenesis and Mutagenesis and Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies in animals have not been conducted with hydralazine HCl and hydrochlorothiazide.

Hydralazine:In a lifetime study in Swiss albino mice, there was a statistically significant increase in the incidence of lung tumors (adenomas and adenocarcinomas) of both male and female mice given hydralazine continuously in their drinking water at a dosage of about 250 mg/kg per day (about 80 times the maximum recommended human dose). In a 2-year carcinogenicity study of rats given hydralazine by gavage at doses of 15, 30, and 60 mg/kg per day (approximately 5 to 20 times the recommended human daily dose), microscopic examination of the liver revealed a small, but statistically significant, increase in benign neoplastic nodules in male and female rats from the high-dose group and in female rats from the intermediate-dose group. Benign interstitial cell tumors of the testes were also significantly increased in male rats from the high-dose group. The tumors observed are common in aged rats, and a significantly increased incidence was not observed until 18 months of treatment. Hydralazine was shown to be mutagenic in bacterial systems (Gene Mutation and DNA Repair) and in one of two rat and one rabbit hepatocytein vitroDNA repair studies. Additionalin vivoandin vitrostudies using lymphoma cells, germinal cells, and fibroblasts from mice, bone marrow cells from Chinese hamsters and fibroblasts from human cell lines did not demonstrate any mutagenic potential for hydralazine.

The extent to which these findings indicate a risk to man is uncertain. While long-term clinical observation has not suggested that human cancer is associated with hydralazine use, epidemiologic studies have so far been insufficient to arrive at any conclusions.

Fertility studies in animals have not been conducted with hydralazine.

Hydrochlorothiazide: Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses up to approximately 600 mg/kg/day) or in male and female rats (at doses up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic inin vitroassays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 ofSalmonella typhimurium(Ames assay) and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or inin vivoassays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and theDrosophilasex-linked recessive lethal trait gene. Positive test results were obtained only in thein vitroCHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 µg/mL, and in theAspergillus nidulansnondisjunction assay at an unspecified concentration.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses up to 100 and 4 mg/kg/day, respectively, prior to mating, and throughout gestation.

Pregnancy:Teratogenic Effects.Pregnancy Category C

Animal reproduction studies have not been conducted with hydralazine HCl and hydrochlorothiazide.

Hydralazine:Animal studies indicate that hydralazine is teratogenic in mice at 20-30 times the maximum daily human dose of 200-300 mg and possibly in rabbits at 10-15 times the maximum daily human dose, but that it is nonteratogenic in rats. Teratogenic effects observed were cleft palate and malformations of facial and cranial bones.

Hydrochlorothiazide: Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus. There are, however, no adequate and well controlled studies of hydralazine HCl and hydrochlorothiazide in pregnant women. Because animal reproduction studies are not always predictive of human response, this combination drug should be used during pregnancy only if clearly needed.

Nonteratogenic Effects

Hydrochlorothiazide: Thiazides cross the placental barrier and appear in cord blood, and there is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Nursing Mothers

It is not known whether hydralazine is excreted in human milk. Thiazides are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of the combination drug in children have not been established.

Adverse Reactions

Adverse reactions are usually reversible upon reduction of dosage or discontinuation of hydralazine HCl and hydrochlorothiazide. Whenever adverse reactions are moderate or severe, it may be necessary to discontinue the drug.

Hydralazine: The following adverse reactions have been observed, but there has not been enough systematic collection of data to support an estimate of their frequency.

Common

Headache, anorexia, nausea, vomiting, diarrhea, palpitations, tachycardia, angina pectoris.

Less Frequent

Digestive:Constipation, paralytic ileus.

Cardiovascular: Hypotension, paradoxical pressor response, edema.

Respiratory:Dyspnea.

Neurologic: Peripheral neuritis, evidenced by paresthesia, numbness, and tingling; dizziness; tremors; muscle cramps; psychotic reactions characterized by depression, disorientation, or anxiety.

Genitourinary:Difficulty in urination.

Hematologic:Blood dyscrasias, consisting of reduction in hemoglobin and red cell count, leukopenia, agranulocytosis, purpura; lymphadenopathy; splenomegaly.

Hypersensitive Reactions: Rash, urticaria, pruritus, fever, chills, arthralgia, eosinophilia, and rarely, hepatitis.

Other:Nasal congestion, flushing, lacrimation, conjunctivitis.

Hydrochlorothiazide:The following adverse reactions have been observed but there has not been enough systematic collection of data to support an estimate of their frequency. Consequently the reactions are categorized by organ systems and are listed in decreasing order of severity and not frequency.

Digestive:Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, anorexia.

Cardiovascular: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics).

Neurologic: Vertigo, dizziness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, restlessness.

Musculoskeletal: Muscle spasm.

Hematologic:Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.

Metabolic: Hyperglycemia, glycosuria, hyperuricemia.

Hypersensitive Reactions: Necrotizing angitis, Stevens-Johnson syndrome, respiratory distress including pneumonitis and pulmonary edema, purpura, urticaria, rash, photosensitivity.

Overdosage

Acute Toxicity

Oral LD50’s in rats (mg/kg): hydralazine, 173 and 187; hydrochlorothiazide, 2750.

Signs and Symptoms

Hydralazine: Signs and symptoms of overdosage include hypotension, tachycardia, headache, and generalized skin flushing.

Complications can include myocardial ischemia and subsequent myocardial infarction, cardiac arrhythmia and profound shock.

Hydrochlorothiazide: The most prominent feature of poisoning is acute loss of fluid and electrolytes.

Cardiovascular: Tachycardia, hypotension, shock.

Neuromuscular:Weakness, confusion, dizziness, cramps of the calf muscles, paresthesia, fatigue, impairment of consciousness.

Digestive: Nausea, vomiting, thirst.

Renal:Polyuria, oliguria or anuria (due to hemoconcentration).

Laboratory Findings: Hypokalemia, hyponatremia, hypochloremia, alkalosis; increased BUN (especially in patients with renal insufficiency).

Combined Poisoning: Signs and symptoms may be aggravated or modified by concomitant intake of antihypertensive medication, barbiturates, curare, digitalis (hypokalemia), corticosteroids, narcotics, or alcohol.

Treatment

There is no specific antidote.

The gastric contents should be evacuated, taking adequate precautions against aspiration and for protection of the airway. An activated charcoal slurry may be instilled if conditions permit. Dialysis may not be effective for elimination of hydralazine HCl and hydrochlorothiazide because of its plasma protein binding (seeCLINICAL PHARMACOLOGY).

These manipulations may have to be omitted or carried out after cardiovascular status has been stabilized, since they might precipitate cardiac arrhythmias or increase the depth of shock.

Support of the cardiovascular system is of primary importance in suspected hydralazine overdosage. Shock should be treated with plasma expanders. The patient’s legs should be kept raised and lost fluid and electrolytes (potassium, sodium) should be replaced. If possible, vasopressors should not be given, but if a vasopressor is required, care should be taken not to precipitate or aggravate cardiac arrhythmia. Tachycardia responds to beta blockers. Digitalization may be necessary, and renal function should be monitored and supported as required.

Hydralazine and Hydrochlorothiazide Dosage and Administration

Dosage should be determined by individual titration (see boxedWARNING).

The usual dosage is one hydralazine HCl and hydrochlorothiazide capsule twice daily, the strength depending upon individual requirement following titration. For maintenance, the dosage should be adjusted to the lowest effective level.

When necessary, other antihypertensive agents such as sympathetic inhibitors may be added gradually in reduced dosages, and the effects should be watched carefully.

How is Hydralazine and Hydrochlorothiazide Supplied

Hydralazine HCl and hydrochlorothiazide are supplied as two piece hard gelatin capsules, in three dosage strengths:

25 mg hydralazine hydrochloride and 25 mg hydrochlorothiazide capsules are white and imprinted “Par 143”, and are available in bottles of 100 (NDC #49884-143-01), 500 (NDC #49884-143-05) and 1000 (NDC #49884-143-10).

50 mg hydralazine hydrochloride and 50 mg hydrochlorothiazide capsules are white/black and imprinted “Par 144”, and are available in bottles of 100 (NDC #49884-144-01), 500 (NDC #49884-144-05) and 1000 (NDC #49884-144-10).

100 mg hydralazine hydrochloride and 50 mg hydrochlorothiazide capsules are powder blue/light blue and imprinted “Par 145”, and are available in bottles of 100 (NDC #49884-145-01), 500 (NDC #49884-145-05) and 1000 (NDC #49884-145-10).

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

Dispense in a tight, light-resistant container as defined in the USP.

Manufactured by:

PAR PHARMACEUTICAL, INC.

Spring Valley, NY 10977

Revised: 03/05. OS143-01-1-15

PRINCIPAL DISPLAY PANEL – 25MG/25MG 100 CAPSULES

PRINCIPAL DISPLAY PANEL 25MG/25MG 500 CAPSULES

PRINCIPAL DISPLAY PANEL 50MG/50MG 100 CAPSULES

HYDRALAZINE HCL AND HYDROCHLOROTHIAZIDE  hydralazine hydrochloride and hydrochlorothiazide  capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 49884-143 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HYDRALAZINE HYDROCHLORIDE (HYDRALAZINE) HYDRALAZINE HYDROCHLORIDE 25 mg HYDROCHLOROTHIAZIDE (HYDROCHLOROTHIAZIDE) HYDROCHLOROTHIAZIDE 25 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color WHITE Score no score Shape CAPSULE Size 16mm Flavor Imprint Code Par;143 Contains

Packaging # NDC Package Description Multilevel Packaging 1 49884-143-01 100 CAPSULE In 1 BOTTLE None 2 49884-143-05 500 CAPSULE In 1 BOTTLE None 3 49884-143-10 1000 CAPSULE In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA088957	10/21/1985	10/29/2009

HYDRALAZINE HCL AND HYDROCHLOROTHIAZIDE  hydralazine hydrochloride and hydrochlorothiazide  capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 49884-144 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HYDRALAZINE HYDROCHLORIDE (HYDRALAZINE) HYDRALAZINE HYDROCHLORIDE 50 mg HYDROCHLOROTHIAZIDE (HYDROCHLOROTHIAZIDE) HYDROCHLOROTHIAZIDE 50 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color WHITE (White) , BLACK (Black) Score no score Shape CAPSULE Size 18mm Flavor Imprint Code Par;144 Contains

Packaging # NDC Package Description Multilevel Packaging 1 49884-144-01 100 CAPSULE In 1 BOTTLE None 2 49884-144-05 500 CAPSULE In 1 BOTTLE None 3 49884-144-10 1000 CAPSULE In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA088946	10/21/1985	10/29/2009

HYDRALAZINE HCL AND HYDROCHLOROTHIAZIDE  hydralazine hydrochloride and hydrochlorothiazide  capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 49884-145 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HYDRALAZINE HYDROCHLORIDE (HYDRALAZINE) HYDRALAZINE HYDROCHLORIDE 100 mg HYDROCHLOROTHIAZIDE (HYDROCHLOROTHIAZIDE) HYDROCHLOROTHIAZIDE 50 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color BLUE Score no score Shape CAPSULE Size 19mm Flavor Imprint Code Par;145 Contains

Packaging # NDC Package Description Multilevel Packaging 1 49884-145-01 100 CAPSULE In 1 BOTTLE None 2 49884-145-05 500 CAPSULE In 1 BOTTLE None 3 49884-145-10 1000 CAPSULE In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA088961	10/21/1985	10/29/2009

Labeler - Par Pharmaceutical, Inc. (092733690)

Registrant - Par Pharmaceutical, Inc. (092733690)

Revised: 10/2009Par Pharmaceutical, Inc.

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