QUINACRINE Systemic*t

INN:   Mepacrine

 

VA CLASSIFICATION (Primary/Secondary): APIO9/IP100; MSI09

 

For a list of brand names for the articles in this monograph, refer to the General Index.

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

 

*Not commercially available in the U.S. tNot commercially available in Canada.

 

 

Category:             Antiprotozoal; antirheumatic; intrapleural sclerosing agent.

 

 

Indications

Note:  Because quinacrine is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled indications for this product in these countries.

 

Accepted

[Giardiasis (treatment)] ‘—.-Quinacrine is indicated as a primary agent in the treatment of giardiasis caused by Giardia lamblia. Quinacnne also is indicated for patients with metronidazole-resistant giardiasis and patients who should not receive or who cannot tolerate metronidazole. Rare resistant cases of giardiasis may require a combination of quinacrine and metronidazole.

[Lupus erythematosus, discoid (treatment)]1 or

[Lupus erythematosus, subacute cutaneous (treatment)]’—Quinacrine is indi cated in the treatment of discoid and subacute cutaneous lupus erythematosus, particularly in patients who cannot take a chloroquine derivative.

[Pneumothorax (prophylaxis)]’—Quinacrine powder is indicated as a second-line intrapleural sclerosing agent to prevent recurrence of pneumothorax in patients at high risk of recurrence, e.g., patients with cystic fibrosis.

 

Acceptance not established

Quinacrine has been used transcervically for female sterilization. More than 100,000 women, primarily in India, Vietnam, and other developing countries, are reported to have undergone this procedure. Although a number of clinical studies have been published in the past 15 years on the use of quinacrine in female sterilization, no randomized, controlled trials have been reported to date and considerable controversy exists about the appropriateness of its use.

Opponents of the use of quinacrine for female sterilization point to the conclu sions of a 1994 World Health Organization (WHO)—sponsored conference in which it was stated that adequate animal toxicology (including genotoxicity) studies had not yet been performed and that long-term safety concerns had not been addressed. Safety concerns include the possibility of increased risk for reproductive tract cancers, development of abnormal uterine lesions, cc-topic pregnancy, failure of the procedure, and fetal exposure to quinacrine. In addition, concerns have been raised about the failure to meet international protocols on human rights and on testing of human subjects in the clinical trials that have been reported to date.

Advocates of the use of quinacrine in female sterilization feel that the method is safe and effective when performed by individuals with proper training and that it is an appropriate alternative to other methods of female sterilization. They note that no fetal malformations have been attributed to the procedure and that the risk for ectopic pregnancy is similar to that with surgical sterilization and with the use of intrauterine devices. They also state that the rate of cancer in women who underwent the quinacrine procedure has not been found to be higher at a statistically significant level than the rate of cancer in women who did not receive quinacrine. In addition, proponents point to the fact that quinacnne has a long history of oral use with no reports of tumorigenicity.

Some population experts support the use of quinacrine sterilization as an appropriate alternative for women who do not accept surgical methods of female sterilization or other long-acting contraceptive methods. It is crucial, however, that these women are informed of and understand quinacrine’s potential risks and that the procedure may be less effective than some other methods of sterilization.

Quinacrine also has been used as an intrapleural sclerosing agent in the prevention of recurrent malignant pleural effusion. However, more comparative clinical studies need to be done to determine the role of intrapleural quinacrine in this indication.

Unaccepted

Although quinacrine has been used for the treatment of diphyllobothriasis, hymenolepiasis, malaria, and taeniasis, it has been superseded by safer and/or more effective agents (e.g., chloroquine, hydroxychloroquine, praziquantel).

 

tNot included in Canadian product labeling.

 

 

Pharmacology/Pharmacokinetics

Note:  The following information refers to the oral administration of quinacrine, unless otherwise noted.

 

Physicochemical characteristics:

Chemical group—Acridine derivative.

Molecular weight—508.92.

 

Mechanism of action/Effect:

The exact mechanism of antiparasitic action is unknown; however, quinacrine binds to deoxyribonucleic acid (DNA) in Vitro by intercalation between adjacent base pairs, inhibiting transcription and translation to ribonucleic acid (RNA). Quinacnne does not appear to localize to the nucleus of Giardia trophozoites, suggesting that DNA binding may not be the primary mechanism of its antimicrobial action. Fluorescence studies using Giardia suggest that the Outer membrane may be involved.

Quinacnne inhibits succinate oxidation and interferes with electron transport. In addition, by binding to nucleoproteins, quinacrine suppresses the lupus erythematosus cell factor and acts as a strong inhibitor of cholinesterase.

 

Absorption: Absorbed rapidly from the gastrointestinal tract following oral administration. Also absorbed rapidly after intrapleural and intrauterine administration.

 

Distribution: Distributed widely; concentrates in the liver, spleen, lungs, and adrenal glands. Concentration in the liver may be 20,000 times that in the plasma. Also deposited in skin, fingernails, and hair. Cerebrospinal fluid (CSF) concentrations are I to 5% of corresponding plasma concentrations. Lowest concentrations are found in the brain, heart, skeletal muscles, and breast milk.

 

Protein binding: High (80 to 90%).

 

Half-life:                5 to 14 days.

 

Time to peak plasma concentration: 8 to 12 hours.

 

Elimination:

Renal—Less than 11% eliminated in the urine daily; acidification of urine increases urinary excretion of quinacnne by up to 14%; excreted slowly, significant amounts being excreted in the urine for 2 months or more after discontinuation of quinacrine.

Fecal.

Small amounts also excreted in bile, sweat, and saliva.

 

Precautions to Consider

Carcinogenicity/Tumorigenicity

In humans, retrospective analysis of patients administered intrauterine quinacrine has revealed a slight (but not statistically significant) increase in the incidence of cancer compared with a control population, but no evidence of excess cancer risk was found. Tumorigenicity data for orally administered quinacnne in humans have not been reported.

In short-term (up to 30 days) animal studies, conflicting tumorigenicity data have been reported. Studies in female mice and rats have shown that quinacnne (at doses of 30 mg per kg of body weight [mg/kg] and 22.5 mg/kg, respectively) enhanced the growth of implanted tumor cells and decreased the rate of survival. However, other studies in male mice have shown that quinacrine (at doses of 20 to 25 mg/kg) suppressed the growth of transplanted tumors and increased the rate of survival.

Longer-term (8 to 40 weeks) animal studies have demonstrated that quinacrine enhances dose-dependently the development of early-stage hepatic carcino genesis (preneoplastic glutathione S transferase [GST-P].-.positive foci) in the rat and the development of pancreatic carcinogenesis in the hamster.

 

Mutagenicity

Quinacrine was mutagenic in the Salmonella TA 1537 mutagenicity assay. However, no chromosomal abnormalities were observed in mammalian mutagenicity tests with monkeys that had received intrauterine quinacrine for 28 days.

Pregnancy/Reproduction

 

Pregnancy—Quinacrine crosses the placenta and reaches the fetal circulation. There is one case of possible renal agenesis and hydrocephalus in an infant, although normal pregnancies have been reported after quinacrine ingestion during the first 4 weeks of gestation. It is recommended that quinacrine treatment for giardiasis in asymptomatic pregnant women be postponed until after delivery.

Quinacrine was embryo lethal but not teratogenic in rats administered intrauterine quinacrine on gestation day 8 or day 12.

 

Breast-feeding

A small amount of quinacrine is distributed into breast milk. However, problems in humans have not been documented.

 

Pediatrics

Children tolerate quinacrine less well than do adults. Quinacrine may cause vomiting in children due to its bitter taste. The tablets may be crushed and mixed with jam, honey, or chocolate syrup, or put in empty gelatin capsules to mask the taste.

 

Geriatrics

Appropriate studies on the relationship of age to the effects of quinacrine have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date.

 

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.

 

Alcohol or alcohol-containing medications

(quinacrine has been reported to produce a mild disulfiram-like reaction when ingested with alcohol, which may be due to quinacrine’s inhibition of the intermediary metabolism of alcohol; ingestion of alcohol or alcohol-containing medications is not recommended during quinacrine treatment)

Primaquine

(concurrent use with quinacrine may inhibit the metabolism of primaquine or may displace it from tissue-binding sites, thereby increasing serum concentrations and the potential toxicity of pnmaquine; these effects may last for up to 3 months after the last dose of quinacrine is administered; concurrent use of quinacrine and primaquine is contraindicated)

 

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 signifi cance).

 

Except under special circumstances, this medication should not be used when the following medical problems exist:

>> Pelvic pathology, including:

Adnexal masses or tumors or Pelvic inflammatory disease or Uterine anomalies

(transcervical use of quinacrine is contraindicated in women with

adnexal masses or tumors, suspicion of malignancy of the reproductive organs, pelvic inflammatory disease, or uterine anomalies)

>> Psoriasis

(quinacrine is contraindicated in patients with psonasis because it may precipitate a severe attack of psoriasis)

 

Risk-benefit should be considered when the following medical problems exist:

Hypersensitivity to quinacrine

Alcoholism or history of or

 

Hepatic disease

(since quinacnne concentrates in the liver, it should be used with caution in patients with alcoholism or a history of alcoholism, or with hepatic disease)

 

Porphyria

(quinacrine may exacerbate porphyria)

 

Psychosis, history of

 

(quinacnne may cause transitory psychosis)

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 giardiasis:

>>           Stool examinations

        (three stool examinations, taken several days apart, beginning 3 to 4

        weeks following treatment, are recommended to rule Out continued

        infection if symptoms persist; however, all three exams are not necessary

        if the first or second exam is positive; in some successfully treated

        patients, the lactose intolerance brought on by the infection may persist

        for a period of some weeks or months, mimicking the symptoms of

        giardiasis; in cases of treatment failure, alternative medications may be

        used)

      For lupus erythematosus:

>>           Complete blood count

        (bone marrow suppression may develop as a result of prolonged and/or

        high-dose quinacrine therapy; complete blood counts should be obtained

        at least every 6 weeks to monitor hematologic changes; quinacrine should

        be discontinued if significant anemia or cytopenia develops)

      Hepatic function

        (monitoring of hepatic function is recommended)

 

Side/Adverse Effects

Note:  Hepatitis, aplastic anemia, conical edema, and retinopathy are reported to have occurred with prolonged and/or high-dose therapy with quinacrine. However, these side/adverse effects occur rarely, if at all, with short-term therapy such as that used in giardiasis.

 

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 less frequent

Bone marrow suppression (black, tarry stools; blood in urine or stools; cough or hoarseness; fever and chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin; unusual bleeding or bruis ing)—associated with prolonged and/or high-dose treatment; central nervous system (CNS) stimulation (anxiety; depression; hallucinations; irritability; mood or other mental changes; nervousness; nightmares; psychosis); skin rash, redness, itching, or peeling

Note:  Toxic psychosis may occur in 0.1 to 1.5% of patients taking oral quinacrine; it is usually reversible within a few days of stopping quinacrine treatment, but it also may last from 2 to 4 weeks. The total amount of quinacrine ingested before the onset of psychosis ranges from 300 mg to 2.1 grams; pediatric psychosis has been reported for the lower end of this spectrum.

 

In lupus erythematosus, it is recommended that treatment with

quinacrine be stopped if any rash occurs, since a lichenoid rash usually

precedes the development of cytopenia. Incidence rare

Hepatitis (yellow discoloration of eyes and skin); pelvic pain or lower abdominal cramps, severe—with transcervical use only; vision changes

 

Note:  Yellow discoloration of skin, without eye involvement, may be due to the acridine dye characteristics of quinacrine and not to hepatitis. Further patient examination is suggested.

 

Those indicating need for medical attention only if they continue or are bothersome

Incidence more frequent

Changes in menstrual flow—with transcervical use only; dizziness; fever—with intrapleural and transcervical use; gastrointestinal disturbances (abdominal or stomach cramps; diarrhea; loss of appetite; nausea or vomiting); headache—with oral and transcervical use; pelvic pain or lower abdominal cramps, mild to moderate—with transcervical use only; vaginal pruritus—with transcervical use only

 

Incidence less frequent

Chest pain, mild to moderate—with intrapleural use only

 

Those not indicating need for medical attention Incidence more frequent

Yellow discoloration of skin and urine (without eye involvement), and

darkening offingernails and toenails—due to acridine dye characteristics

 

Note:  Yellow discoloration of skin and urine usually appears after I to 2 weeks of oral treatment, and may persist for up to 4 months after discontinuation of treatment. Yellow discoloration with eye involvement may indicate hepatitis; further patient examination is

General Dosing Information

Quinacrine should preferably be taken after meals with a full glass (240 mL) of water, tea, or fruit juice.

 

For patients unable to swallow tablets or unable to tolerate bitter taste, quinacrine tablets may be crushed and mixed with jam, honey, or chocolate syrup immediately before consuming, or placed in empty gelatin capsules to disguise the bitter taste. Quinacrine is not stable in solution; it is converted to an insoluble precipitate.

 

In the treatment of lupus erythematosus, quinacrine dosing may be decreased by 50% if significant gastrointestinal symptoms occur. Also, treatment should be stopped after 8 weeks if no beneficial effects have been observed by this time.

 

 

Oral Dosage Forms

Note:  Because quinacnne is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript I in this monograph reflect the lack of labeled indications for this product in these countries.

 

QUINACRINE HYDROCHLORIDE TABLETS

 

Usual adult and adolescent dose:

[Giardiasis (treatment)] 1— Oral, 100 mg three times a day for five to seven days.

[Lupus erythematosus (treatment)]1­Oral, 100 mg once a day for the first one to two months. For maintenance,

the dose may be decreased to 25 to 50 mg once a day several times a week, although occasional management with 100 to 200 mg once a day may be needed.

 

Usual pediatric dose:

[Giardiasis (treatment)]’— Oral, 2 mg per kg of body weight three times a day for five to seven days.

[Lupus erythematosus (treatment)] 1— Oral, I to 2 mg per kg of body weight, up to 100 mg, per day.

 

Usual pediatric prescribing limits:

300 mg per day for giardiasis; 100 mg per day for lupus erythematosus.

Strength(s) usually available:

U.S.— Not commercially available.

Canada— Not commercially available.

 

Packaging and storage:

Store below 40 ‘C (104 ‘F), preferably between 15 and 30 ‘C (59 and 86 ‘F) in a tight, light-resistant container.

 

Preparation of dosage form:

For patients who cannot take oral solids—Tablets may be crushed and mixed with jam, honey, or chocolate syrup, or placed in empty gelatin capsules to disguise the bitter taste. Quinacrine is not stable in solution; it is converted to an insoluble precipitate.

 

Auxiliary labeling:

• Take after meals with liquids.

• Continue medicine for full time of treatment.

 

Parenteral Dosage Forms

Note:  Because quinacrine is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled indications for this product in these countries.

 

QUINACRINE HYDROCHLORIDE POWDER FOR INSTILLATION

 

Usual adult and adolescent dose:

[Pneumothorax (treatment)]

Intrapleural, 100 mg instilled once a day for three or four consecutive days.

 

Usual pediatric dose:

[Pneumothorax] ‘—Safety, efficacy, and dosing have not been established.

 

Strength(s) usually available:

U.S.— Not commercially available.

Canada— Not commercially available.

suggested.

 

Overdose

For specific information on the agents used in the management of quinacnne

overdose, see:

•   Barbiturates (Systemic) monograph;

•      Benzodiazepines (Systemic) monograph; and/or

•      Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic)

monograph (vasopressor agents).

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

In order of occurrence— Seizures; hypotension; cardiac arrhythmias; cardiovascular collapse

 

Treatment of overdose

Recommended treatment consists of the following:

To decrease absorption—Evacuating the stomach by gastric lavage or induction of emesis.

Specific treatment— Controlling seizures with benzodiazepines or ultra-short—acting barbiturates.

Treating shock by administration of fluids and vasopressors. Administering ammonium chloride, 8 grams daily in divided doses for adults,

to acidify the urine and promote excretion of quinacrine by up to 14%. Supportive care—Administering supportive measures, such as maintaining an

open airway, breathing, and circulation. Observing closely for at least 6 hours those patients who have survived the acute phase and are asymptomatic. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

 

 

Patient Consultation

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

In  providing consultation, consider emphasizing the following selected informa tion (>> = major clinical significance):

 

Before using this medication

>>           Conditions affecting use, especially:

Hypersensitivity to quinacrine

Pregnancy—Quinacrine crosses the placenta

Breast-feeding—Quinacrine is distributed into breast milk

Use in children—Children tolerate quinacrine less well than do adults

Other medicine, especially primaquine

Other medical problems, especially pelvic pathology (for transcervical use), psoriasis, and a history of psychosis

 

Proper use of this medication

For oral use only:

Taking after meals with a full glass (240 mL) of water, tea, or fruit juice

Crushing tablets and mixing with jam, honey, or chocolate syrup immediately before consuming, or placing in empty gelatin capsules to disguise bitter taste for patients unable to swallow tablets or unable to tolerate bitter taste

Compliance with full course of therapy

Proper dosing

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

Proper storage

 

Precautions while using this medication

Periodic visits to physician to check progress after treatment

 

Checking with physician if no improvement within a few days

>              Caution if dizziness occurs

 

Side/adverse effects

Signs of potential side effects, especially bone marrow depression, CNS stimulation, skin rash, redness, itching, or peeling, hepatitis, severe pelvic pain or lower abdominal cramps (for transcervical use), and vision changes

Yellow discoloration of skin and urine (without eye involvement) and darkening of fingernails and toenails, due to dye-like characteristics of quinacrine, may be alarming to patient although medically insignificant

Preparation of dosage form:

Compounding is required.

 

^tNot included in Canadian product labeling.

 

 

Revised: 04/29/99