Medication Guide App

Piperazine (Systemic )


VA CLASSIFICATION
Primary: AP200
{23}
Commonly used brand name(s): Entacyl.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anthelmintic (systemic){07}

Indications

Accepted

Ascariasis (treatment) or
Enterobiasis (treatment)—Piperazine is indicated as alternative treatment for ascariasis caused by Ascaris lumbricoides (roundworm) and enterobiasis (oxyuriasis) caused by Enterobius vermicularis (pinworm). Piperazine is especially useful in the treatment of partial intestinal obstruction caused by Ascaris worms, {05} {12} {13} {14} {16} {17} {25} {27} {33} {34} {35} which is a condition primarily seen in children. {35} The use of albendazole, flubendazole, {33} mebendazole, or pyrantel pamoate is generally preferred in the treatment of ascariasis and enterobiasis {01} {05} {07} {08} {10} {11} {12} {13} {14} {16} {17} {18} {19} {20} {21} {25} {27} {28} {29} {33} because they are effective in single doses. {33}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Piperazine adipate: 416.45 {04}
    Piperazine citrate: 642.66 {02} {04}

Mechanism of action/Effect:

Piperazine blocks the response of the worm muscle (best studied in Ascaris ) to acetylcholine, presumably by causing hyperpolarization of nerve endings, resulting in flaccid paralysis of the worm. {05} {07} {39} While the worm is paralyzed, it is dislodged from the intestinal lumen and expelled live from the body by normal intestinal peristalsis. {05}

Absorption:

Rapidly absorbed from the gastrointestinal tract. {05} {07} {19}



Biotransformation:

Approximately 25% is metabolized in the liver. {08} {16} Piperazine is nitrosated to form N-mononitrosopiperazine (MNPz) in gastric juice {19} {22} {26} and further metabolized to N-nitroso-3-hydroxypyrrolidine (NHPYR). {22}

Half-life:

Plasma half-life is highly variable. {08}

Time to peak concentration:

2 to 4 hours. {19}

Elimination:
    Renal—Approximately 20% is excreted unchanged in the urine {05} within 24 hours. {03} {15}


Precautions to Consider

Cross-sensitivity and/or related problems

There has been a report of cross-reactivity between piperazine and ethylenediamine, a substance used as a stabilizer in topical creams. Piperazine can cause a contact allergy that could be life-threatening in a person who has been sensitized to ethylenediamine either by topical application or by occupational exposure. {06} Although rare, adverse dermatologic problems also may occur due to the cross-sensitivity of these two medications. {20} {24}

Carcinogenicity

A potentially carcinogenic nitrosamine derivative, N-mononitrosopiperazine (MNPz), has been found in gastric juice and urine of volunteers given therapeutic doses of piperazine. However, the significance of this finding is unknown. {19} {22} {26}

Tumorigenicity

Tumorigenicity/Mutagenicity

Studies have not been done to determine the tumorigenicity or mutagenicity of piperazine. {09} {16}

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies in humans have not been done. {01} {07} Piperazine has been used without apparent adverse effects during pregnancy. {05} {20} In three cases of first-trimester exposures to piperazine by pregnant women, no malformations were seen in the fetuses. {30} {31} However, because a study showed that orally administered piperazine undergoes partial conversion to a potentially carcinogenic nitrosamine derivative, {19} {22} {26} it is recommended that piperazine be given to pregnant women only if clearly indicated and then only if alternative medications are not available. {19}



Studies in animals (rats and pigs) have failed to demonstrate any teratogenic effects of piperazine on the fetus. {30} {31}

Breast-feeding

Piperazine is thought to be distributed into breast milk {16} but no definitive information is available. {16} {31} However, problems in humans have not been documented. {32}

Pediatrics

Appropriate studies on the relationship of age to the effects of piperazine have not been performed in the pediatric population. No pediatrics-specific problems have been documented to date. However, because of piperazine's potential neurotoxicity, {01} {07} {37}it should be used with caution in children. Prolonged or repeated treatment with piperazine in children should be avoided. {07}


Geriatrics


No information is available on the relationship of age to the effects of piperazine in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Phenothiazines, such as chlorpromazine    (high doses of piperazine may enhance the effects of phenothiazines, such as chlorpromazine, and increase the risk of seizures; {08} {09} concurrent use is not recommended {19})


» Pyrantel    (pyrantel may antagonize the anthelmintic effects of piperazine; {08} {09} {16} concurrent use is not recommended {08} {16})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Hepatic function impairment    (because piperazine is partially metabolized in the liver, accumulation of piperazine may occur, with an increased incidence of side effects {01} {05} {08} {13} {17} {19} {25})


Hypersensitivity reactions to piperazine and its salts, history of{01}{07}{19}{20}
» Renal function impairment    (urinary excretion is the primary route of elimination of piperazine; therefore, high concentrations of piperazine may accumulate in patients with renal dysfunction, resulting in neurotoxicity {01} {05} {07} {08} {13} {17} {19} {20} {25})


» Seizure disorders, especially a history of epilepsy{01}{07}{08}{13}{17}{19}{25}    (seizures may be exacerbated {08} {19})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


For ascariasis
» Stool examinations    (may be required prior to treatment and approximately 2 weeks following treatment with piperazine to determine efficacy or proof of cure {13} {41})


For enterobiasis
» Perianal examinations    (cellophane tape swabbing of the perianal area to detect the presence of eggs may be required prior to treatment to confirm the diagnosis of enterobiasis; swabbing is done again 1 week following treatment with piperazine, especially in patients with persisting symptoms; swabbing should be done every morning on awakening prior to defecation and bathing for at least 5 {40}days to determine efficacy or proof of cure; perianal examinations may also be required to detect the presence of adult worms in the perianal area {14})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Blurring of vision{07}{43}
    
central nervous system (CNS) toxicity such as ataxia (clumsiness), choreiform movement (irregular, twisting movement especially of the face and extremities), or paresthesia (crawling or tingling sensation of the skin)
    
hypersensitivity (fever; joint pain; skin rash or itching){06}{07}{08}{19}{20}{25}{42}
    




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
CNS effects (dizziness; drowsiness; headache; muscle weakness; tremors){07}{19}{25}
    
gastrointestinal disturbances (abdominal cramps or pain; diarrhea; nausea; vomiting){05}{07}{09}{18}{19}{20}{21}{25}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Muscle weakness of the extremities, transient{08}
    
respiratory depression (difficulty in breathing){05}{08}{20}
    
seizures{05}{08}{20}


Treatment of overdose
Recommended treatment consists of the following:


To decrease absorption:
Emesis or gastric lavage may be performed within a few hours of ingestion. {08}



Specific treatment:
Symptomatic treatment may be given. {08}



Supportive care:
Supportive measures such as maintaining an open airway, respiration, and circulation may be administered. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation. {08}



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Piperazine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to piperazine or its salt, or ethylenediamine {01} {06} {07} {08} {19} {20} {25}

Pregnancy—Piperazine partially converts to a potentially carcinogenic nitrosamine derivative; {19} {22} {26} therefore its use in pregnant women is recommended only if clearly indicated and then only if alternative drugs are not available {19}





Use in children—Cautious and short-term use is recommended because of potential neurotoxic effects {01} {07}

Other medications, especially phenothiazines such as chlorpromazine, {08} {09} {19} and pyrantel {08} {09} {16}
Other medical problems, especially hepatic or renal function impairment and seizure disorders, such as epilepsy {01} {07} {08} {13} {17} {19} {25}

Proper use of this medication
No special preparations or added measures (e.g., dietary restrictions or fasting, concurrent medications, purging, or cleansing enemas) are required before, during, or immediately after therapy {05} {07} {19} {28}

Taking on full or empty stomach as directed by physician {14} {19}

Proper administration

For granules for oral solution dosage form
Dissolving contents of 1 packet of granules in 57 mL (about 2 ounces) of water, milk, or fruit juice {01}

Drinking all of liquid to get the full dose of the medication
» Importance of not taking more medication than the amount recommended {07}

» Compliance with full course of therapy

» Repeating treatment program in 1 to 2 weeks for heavy infection {01} {05} {07} {08} {13} {16} {19}

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

For enterobiasis
Treating all household members simultaneously {05} {11} {12} {14}

Precautions while using this medication
Regular visits to physician to check progress

Checking with physician if no improvement after the full course of treatment or if symptoms persist

For enterobiasis
Washing (not shaking) all bedding and nightclothes after treatment to prevent reinfection {13}


Side/adverse effects
Signs of potential side effects, especially blurring of vision, CNS toxicity, and hypersensitivity


General Dosing Information
Patients who are heavily infected with helminths may require a second treatment. {01} {05} {07} {08} {13} {16} {19}

For enterobiasis
Because of the high probability of transfer of pinworms, it is often recommended that all members of the household be treated concurrently. Retreatment is recommended 1 to 2 weeks following initial treatment. {01} {05} {07} {08} {10} {11} {13} {16}


Oral Dosage Forms

PIPERAZINE ADIPATE GRANULES FOR ORAL SOLUTION{01}{36}{42}

Usual adult and adolescent dose
Ascariasis or
Enterobiasis
Patients weighing 41 kg of body weight and over: Oral, 2 grams three times a day for one day. Treatment may be repeated in two weeks. {01}

Patients weighing less than 41 kg of body weight: See Usual pediatric dose. {01}


Usual pediatric dose
Ascariasis or
Enterobiasis
Infants and children up to 2 years of age: Dosage has not been established.

Children 2 to 8 years of age (13.5 to 27.5 kg of body weight): Oral, 2 grams once a day for one day. Treatment may be repeated in two weeks. {01}

Children 8 to 14 years of age (27.5 to 41 kg of body weight): Oral, 2 grams two times a day for one day. Treatment may be repeated in two weeks. {01}

Children 14 years of age and over (41 kg of body weight and over): See Usual adult and adolescent dose. {01}


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


2 grams per packet (Rx) [Entacyl (sodium <19.2 mg)]{01}{38}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.


PIPERAZINE ADIPATE ORAL SUSPENSION{01}{36}{42}

Usual adult and adolescent dose
Ascariasis or
Enterobiasis
Oral, 1.8 grams every four hours for a total of three doses in one day. Treatment may be repeated in two weeks. {01} {43} {44}


Usual pediatric dose
Ascariasis or
Enterobiasis
Infants and children up to 2 years of age: Oral, 600 mg (0.6 gram) every four hours for a total of three doses in one day. Treatment may be repeated in two weeks. {01} {43} {44}

Children 2 to 8 years of age: Oral, 1.2 grams every six hours for a total of two doses in one day. Treatment may be repeated in two weeks. {01} {43} {44}

Children 8 to 14 years of age: Oral, 1.2 grams every four hours for a total of three doses in one day. Treatment may be repeated in two weeks. {01} {43} {44}

Children 14 years of age and over: See Usual adult and adolescent dose. {01}


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


600 mg per 5 mL (Rx) [Entacyl (sodium <0.8 mg)]{01}{38}
{01}
Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from freezing.

Auxiliary labeling:
   • Shake well.


PIPERAZINE CITRATE TABLETS USP{07}{36}

Note: The dosing and strength of the dosage form available are expressed in terms of piperazine hexahydrate.


Usual adult and adolescent dose
Ascariasis
Oral, 3.5 grams (hexahydrate) per day for two consecutive days. Treatment may be repeated after one week for heavy infection. {07}

Enterobiasis
Oral, 65 mg per kg of body weight per day for seven consecutive days. Treatment may be repeated after one week for heavy infection. {05} {07}


Usual adult prescribing limits
{05}{07}Ascariasis: Up to 3.5 grams per day.

Enterobiasis: Up to 2.5 grams per day.

Usual pediatric dose
Ascariasis
Oral, 75 mg per kg of body weight per day for two consecutive days. Treatment may be repeated after one week for heavy infection. {07}

Enterobiasis
See Usual adult and adolescent dose. {07}


Usual pediatric prescribing limits {07}
Ascariasis: Up to 3.5 grams per day.

Enterobiasis: Up to 2.5 grams per day.

Strength(s) usually available
U.S.—


250 mg (hexahydrate) (275.75 mg piperazine citrate anhydrous) (Rx)[Generic]{07}

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a tight container.



Revised: 11/21/1996



References
  1. Entacyl product monograph (Glaxo—Canada), Rec 11/13/92.
  1. The United States pharmacopeia. The national formulary. USP 22nd revision (January 1, 1990). NF 17th ed (January 1,1990). Rockville, MD: The United States Pharmacopeial Convention, Inc., 1990: 1089.
  1. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 29th ed. London: The Pharmaceutical Press, 1989: 63.
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1996. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1995: 552.
  1. Gilman AG, Rall TW, Nies AS, Taylor P, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990: 967.
  1. Cork MJ, Cooke NJ, Mellor E. Pruritus ani, piperazine and thrombocytopenia (Drug Points). Br Med J 1990; 301: 1398.
  1. Piperazine citrate tablets package insert (Richlyn Laboratories, Inc.—US), Rev 5/72, Rec 11/92.
  1. WHO Model Prescribing Information: Drugs used in parasitic diseases. Geneva: World Health Organization, 1990: 90-1.
  1. Dukes MNG, editor. Meyler's side effects of drugs. An encyclopedia of adverse reactions and interactions. 10th ed. Amsterdam: Elsevier, 1984: 591-8.
  1. Speight TM, editor. Avery's drug treatment. Principles and practice of clinical pharmacology and therapeutics. 3rd ed. Auckland: ADIS Press, 1987: 732-811.
  1. Anandan JV. Parasitic infections. In: Koda-Kimble MA, Young LY, editors. Applied therapeutics: the clinical use of drugs. Vancouver: Applied Therapeutics, Inc., 1992; 1-15.
  1. Rakel RE, editor. Conn's current therapy 1992. Philadelphia: W.B. Saunders Company, 1992: 479-86.
  1. Blumenthal DS. Intestinal nematodes. In: Wyngaarden JB, Smith Jr LH, editors. Cecil's textbook of medicine. Philadelphia: WB Saunders Company, 1988: 406-9.
  1. Brown HW, Neva FA. Basic clinical parasitology. 5th ed. Norwalk, CT: Appleton-Century-Crofts, 1983: 105-42.
  1. Fletcher KA, Evans DAP, Kelly JA. Urinary piperazine excretion in healthy Caucasians. Ann Trop Med Parasitol 1982; 76: 77-82.
  1. Katz M. Anthelmintics: current concepts in the treatment of helminthic infections. Drugs 1986 Oct; 32(4): 358-71.
  1. Plorde JJ, Ramsey PG. Nematodes, cestodes and hermaphroditic trematodes. In: Wilson JD, Braunwald E, Isselbacher KJ, et al., editors. Harrison's principles of internal medicine. New York: McGraw-Hill, Inc.,1991: 817-31.
  1. Nanivadekar AS, Gadgil SD, Apte VV. Efficacy of levamisole, mebendazole, piperazine and pyrantel in roundworm infection: by national anthelmintic study group. J Postgrad Med 1984 Jul; 30(3): 144-52.
  1. Goldsmith RS. Clinical pharmacology of the anthelmintic drugs. In: Katzung BG, editor. Basic and clinical pharmacology. Norwalk, CT: Appleton and Lange, 1992: 748-65.
  1. Van Reken DE, Pearson RD. Antiparasitic agents. In: Mandell GL, Douglas Jr RG, Bennett JE, editors. Principles and practice of infectious diseases. New York: Churchill Livingstone, Inc., 1990: 398-427.
  1. Nanivadekar AS, Gadgil SD, Apte VV. A comparative evaluation of mebendazole, piperazine and pyrantel in threadworm infection: anthelmintic study group on enterobiasis. Indian Pediatr 1984 Aug; 21(8): 623-8.
  1. Tricker AR, Kumar R, Siddiqi M, et al. Endogenous formation of N-nitrosamines from piperazine and their urinary excretion following anthelmintic treatment with piperazine citrate. Carcinogenesis 1991; 12(9): 1595-9.
  1. VA Medication Classification System. USP DI 1993: 2862.
  1. Harman RRM. Ethylenediamine and piperazine sensitivity. Br Med J 1983; 287: 463-4.
  1. Markell EK, Voge M, John DT. Medical parasitology. 7th ed. Philadelphia: WB Saunders Company, 1992: 261-93.
  1. Bellander BTD, Hagmar LE, Osterdahl BG. Nitrosation of piperazine in the stomach. Lancet 1981; 2: 372.
  1. Warren KS, Mahmoud AAF. Algorithms in the diagnosis and management of exotic diseases XXII: ascariasis and toxocariasis. J Infect Dis 1977; 135: 868-72.
  1. Schwartzwelder C, Miller JH, Sappenfield RW. The effective use of piperazine for the treatment of human helminthiasis. Gastroenterology 1957; 33: 87-96.
  1. Neva FA. Parasitic diseases of the GI tract in the United States. Dis-A-Month 1972 Jun: 2-44.
  1. Koren G, editor. Maternal-fetal toxicology. A clinicians' guide. New York: Marcel Dekker, Inc., 1990: 41.
  1. Briggs GG, Freeman RK, Yaffe SJ. A reference guide to fetal and neonatal risk. Drugs in pregnancy and lactation. 3rd ed. Baltimore: Williams & Wilkins, 1990: 514.
  1. Panel comment, 5/93.
  1. Panel comment, 5/93.
  1. Panel comment, 5/93.
  1. Panel comment, 5/93.
  1. Reviewers' consensus on monograph revision of 8/93.
  1. Conners GP. Piperazine neurotoxicity: worm wobble revisited. J Emerg Med 1995; 13(3): 341-3.
  1. Entacyl (Roberts). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 31st ed. Ottawa: Canadian Pharmaceutical Association, 1996: 485.
  1. Panel comment, 9/96.
  1. Gorbach SL, Bartlett JG, Blacklow NR. Infectious diseases. Philadelphia: W. B. Saunders Company, 1992: 2004-5.
  1. Panel comment, 9/96.
  1. Reviewers' consensus on monograph revision of 9/96.
  1. Panel comment, 9/96.
  1. Panel comment, 9/96.
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