Leukeran

chlorambucil

Dosage Form: tablet, film coated
Leukeran®

(chlorambucil)

Tablets

Warning

Leukeran (chlorambucil) can severely suppress bone marrow function. Chlorambucil is a carcinogen in humans. Chlorambucil is probably mutagenic and teratogenic in humans. Chlorambucil produces human infertility (see WARNINGS and PRECAUTIONS).

Leukeran Description

Leukeran (chlorambucil) was first synthesized by Everett et al. It is a bifunctional alkylating agent of the nitrogen mustard type that has been found active against selected human neoplastic diseases. Chlorambucil is known chemically as 4-[bis(2-chlorethyl)amino]benzenebutanoic acid and has the following structural formula:

Chlorambucil hydrolyzes in water and has a pKa of 5.8.

Leukeran (chlorambucil) is available in tablet form for oral administration. Each film-coated tablet contains 2 mg chlorambucil and the inactive ingredients colloidal silicon dioxide, hypromellose, lactose (anhydrous), macrogol/PEG 400, microcrystalline cellulose, red iron oxide, stearic acid, titanium dioxide, and yellow iron oxide.

Leukeran - Clinical Pharmacology

Chlorambucil is rapidly and completely absorbed from the gastrointestinal tract. After single oral doses of 0.6 to 1.2 mg/kg, peak plasma chlorambucil levels (Cmax) are reached within 1 hour and the terminal elimination half-life (t½) of the parent drug is estimated at 1.5 hours. Chlorambucil undergoes rapid metabolism to phenylacetic acid mustard, the major metabolite, and the combined chlorambucil and phenylacetic acid mustard urinary excretion is extremely low — less than 1% in 24 hours. In a study of 12 patients given single oral doses of 0.2 mg/kg of Leukeran, the mean dose (12 mg) adjusted (± SD) plasma chlorambucil Cmax was 492 ± 160 ng/mL, the AUC was 883 ± 329 ng•h/mL, t½ was 1.3 ± 0.5 hours, and the tmax was 0.83 ± 0.53 hours. For the major metabolite, phenylacetic acid mustard, the mean dose (12 mg) adjusted (± SD) plasma Cmax was 306 ± 73 ng/mL, the AUC was 1204 ± 285 ng•h/mL, the t½ was 1.8 ± 0.4 hours, and the tmax was 1.9 ± 0.7 hours.

Chlorambucil and its metabolites are extensively bound to plasma and tissue proteins. In vitro, chlorambucil is 99% bound to plasma proteins, specifically albumin. Cerebrospinal fluid levels of chlorambucil have not been determined. Evidence of human teratogenicity suggests that the drug crosses the placenta.

Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard, which has antineoplastic activity. Chlorambucil and its major metabolite spontaneously degrade in vivo forming monohydroxy and dihydroxy derivatives. After a single dose of radiolabeled chlorambucil (14C), approximately 15% to 60% of the radioactivity appears in the urine after 24 hours. Again, less than 1% of the urinary radioactivity is in the form of chlorambucil or phenylacetic acid mustard. In summary, the pharmacokinetic data suggest that oral chlorambucil undergoes rapid gastrointestinal absorption and plasma clearance and that it is almost completely metabolized, having extremely low urinary excretion.

Indications and Usage for Leukeran

Leukeran (chlorambucil) is indicated in the treatment of chronic lymphatic (lymphocytic) leukemia, malignant lymphomas including lymphosarcoma, giant follicular lymphoma, and Hodgkin’s disease. It is not curative in any of these disorders but may produce clinically useful palliation.

Contraindications

Chlorambucil should not be used in patients whose disease has demonstrated a prior resistance to the agent. Patients who have demonstrated hypersensitivity to chlorambucil should not be given the drug. There may be cross-hypersensitivity (skin rash) between chlorambucil and other alkylating agents.

Warnings

Because of its carcinogenic properties, chlorambucil should not be given to patients with conditions other than chronic lymphatic leukemia or malignant lymphomas. Convulsions, infertility, leukemia, and secondary malignancies have been observed when chlorambucil was employed in the therapy of malignant and non-malignant diseases.

There are many reports of acute leukemia arising in patients with both malignant and non-malignant diseases following chlorambucil treatment. In many instances, these patients also received other chemotherapeutic agents or some form of radiation therapy. The quantitation of the risk of chlorambucil-induction of leukemia or carcinoma in humans is not possible. Evaluation of published reports of leukemia developing in patients who have received chlorambucil (and other alkylating agents) suggests that the risk of leukemogenesis increases with both chronicity of treatment and large cumulative doses. However, it has proved impossible to define a cumulative dose below which there is no risk of the induction of secondary malignancy. The potential benefits from chlorambucil therapy must be weighed on an individual basis against the possible risk of the induction of a secondary malignancy.

Chlorambucil has been shown to cause chromatid or chromosome damage in humans. Both reversible and permanent sterility have been observed in both sexes receiving chlorambucil.

A high incidence of sterility has been documented when chlorambucil is administered to prepubertal and pubertal males. Prolonged or permanent azoospermia has also been observed in adult males. While most reports of gonadal dysfunction secondary to chlorambucil have related to males, the induction of amenorrhea in females with alkylating agents is well documented and chlorambucil is capable of producing amenorrhea. Autopsy studies of the ovaries from women with malignant lymphoma treated with combination chemotherapy including chlorambucil have shown varying degrees of fibrosis, vasculitis, and depletion of primordial follicles.

Rare instances of skin rash progressing to erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome have been reported. Chlorambucil should be discontinued promptly in patients who develop skin reactions.

Pregnancy

Pregnancy Category D. Chlorambucil can cause fetal harm when administered to a pregnant woman. Unilateral renal agenesis has been observed in 2 offspring whose mothers received chlorambucil during the first trimester. Urogenital malformations, including absence of a kidney, were found in fetuses of rats given chlorambucil. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Precautions

General

Many patients develop a slowly progressive lymphopenia during treatment. The lymphocyte count usually rapidly returns to normal levels upon completion of drug therapy. Most patients have some neutropenia after the third week of treatment and this may continue for up to 10 days after the last dose. Subsequently, the neutrophil count usually rapidly returns to normal. Severe neutropenia appears to be related to dosage and usually occurs only in patients who have received a total dosage of 6.5 mg/kg or more in one course of therapy with continuous dosing. About one quarter of all patients receiving the continuous-dose schedule, and one third of those receiving this dosage in 8 weeks or less may be expected to develop severe neutropenia.

While it is not necessary to discontinue chlorambucil at the first evidence of a fall in neutrophil count, it must be remembered that the fall may continue for 10 days after the last dose, and that as the total dose approaches 6.5 mg/kg, there is a risk of causing irreversible bone marrow damage. The dose of chlorambucil should be decreased if leukocyte or platelet counts fall below normal values and should be discontinued for more severe depression.

Chlorambucil should not be given at full dosages before 4 weeks after a full course of radiation therapy or chemotherapy because of the vulnerability of the bone marrow to damage under these conditions. If the pretherapy leukocyte or platelet counts are depressed from bone marrow disease process prior to institution of therapy, the treatment should be instituted at a reduced dosage.

Persistently low neutrophil and platelet counts or peripheral lymphocytosis suggest bone marrow infiltration. If confirmed by bone marrow examination, the daily dosage of chlorambucil should not exceed 0.1 mg/kg. Chlorambucil appears to be relatively free from gastrointestinal side effects or other evidence of toxicity apart from the bone marrow depressant action. In humans, single oral doses of 20 mg or more may produce nausea and vomiting.

Children with nephrotic syndrome and patients receiving high pulse doses of chlorambucil may have an increased risk of seizures. As with any potentially epileptogenic drug, caution should be exercised when administering chlorambucil to patients with a history of seizure disorder or head trauma, or who are receiving other potentially epileptogenic drugs.

Administration of live vaccines to immunocompromised patients should be avoided.

Information for Patients

Patients should be informed that the major toxicities of chlorambucil are related to hypersensitivity, drug fever, myelosuppression, hepatotoxicity, infertility, seizures, gastrointestinal toxicity, and secondary malignancies. Patients should never be allowed to take the drug without medical supervision and should consult their physician if they experience skin rash, bleeding, fever, jaundice, persistent cough, seizures, nausea, vomiting, amenorrhea, or unusual lumps/masses. Women of childbearing potential should be advised to avoid becoming pregnant.

Laboratory Tests

Patients must be followed carefully to avoid life-endangering damage to the bone marrow during treatment. Weekly examination of the blood should be made to determine hemoglobin levels, total and differential leukocyte counts, and quantitative platelet counts. Also, during the first 3 to 6 weeks of therapy, it is recommended that white blood cell counts be made 3 or 4 days after each of the weekly complete blood counts. Galton et al have suggested that in following patients it is helpful to plot the blood counts on a chart at the same time that body weight, temperature, spleen size, etc., are recorded. It is considered dangerous to allow a patient to go more than 2 weeks without hematological and clinical examination during treatment.

Drug Interactions

There are no known drug/drug interactions with chlorambucil.

Carcinogenesis, Mutagenesis, Impairment of Fertility

See WARNINGS section for information on carcinogenesis, mutagenesis, and impairment of fertility.

Pregnancy

Teratogenic Effects: Pregnancy Category D: See WARNINGS section.

Nursing Mothers

It is not known whether this drug 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 chlorambucil, 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

The safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of chlorambucil 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.

Adverse Reactions

Hematologic

The most common side effect is bone marrow suppression, anemia, leukopenia, neutropenia, thrombocytopenia, or pancytopenia. Although bone marrow suppression frequently occurs, it is usually reversible if the chlorambucil is withdrawn early enough. However, irreversible bone marrow failure has been reported.

Gastrointestinal

Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral ulceration occur infrequently.

CNS

Tremors, muscular twitching, myoclonia, confusion, agitation, ataxia, flaccid paresis, and hallucinations have been reported as rare adverse experiences to chlorambucil which resolve upon discontinuation of drug. Rare, focal and/or generalized seizures have been reported to occur in both children and adults at both therapeutic daily doses and pulse-dosing regimens, and in acute overdose (see PRECAUTIONS: General).

Dermatologic

Allergic reactions such as urticaria and angioneurotic edema have been reported following initial or subsequent dosing. Skin hypersensitivity (including rare reports of skin rash progressing to erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome) has been reported (see WARNINGS).

Miscellaneous

Other reported adverse reactions include: pulmonary fibrosis, hepatotoxicity and jaundice, drug fever, peripheral neuropathy, interstitial pneumonia, sterile cystitis, infertility, leukemia, and secondary malignancies (see WARNINGS).

Overdosage

Reversible pancytopenia was the main finding of inadvertent overdoses of chlorambucil. Neurological toxicity ranging from agitated behavior and ataxia to multiple grand mal seizures has also occurred. As there is no known antidote, the blood picture should be closely monitored and general supportive measures should be instituted, together with appropriate blood transfusions, if necessary. Chlorambucil is not dialyzable.

Oral LD50 single doses in mice are 123 mg/kg. In rats, a single intraperitoneal dose of 12.5 mg/kg of chlorambucil produces typical nitrogen-mustard effects; these include atrophy of the intestinal mucous membrane and lymphoid tissues, severe lymphopenia becoming maximal in 4 days, anemia, and thrombocytopenia. After this dose, the animals begin to recover within 3 days and appear normal in about a week, although the bone marrow may not become completely normal for about 3 weeks. An intraperitoneal dose of 18.5 mg/kg kills about 50% of the rats with development of convulsions. As much as 50 mg/kg has been given orally to rats as a single dose, with recovery. Such a dose causes bradycardia, excessive salivation, hematuria, convulsions, and respiratory dysfunction.

Leukeran Dosage and Administration

The usual oral dosage is 0.1 to 0.2 mg/kg body weight daily for 3 to 6 weeks as required. This usually amounts to 4 to 10 mg per day for the average patient. The entire daily dose may be given at one time. These dosages are for initiation of therapy or for short courses of treatment. The dosage must be carefully adjusted according to the response of the patient and must be reduced as soon as there is an abrupt fall in the white blood cell count. Patients with Hodgkin’s disease usually require 0.2 mg/kg daily, whereas patients with other lymphomas or chronic lymphocytic leukemia usually require only 0.1 mg/kg daily. When lymphocytic infiltration of the bone marrow is present, or when the bone marrow is hypoplastic, the daily dose should not exceed 0.1 mg/kg (about 6 mg for the average patient).

Alternate schedules for the treatment of chronic lymphocytic leukemia employing intermittent, biweekly, or once-monthly pulse doses of chlorambucil have been reported. Intermittent schedules of chlorambucil begin with an initial single dose of 0.4 mg/kg. Doses are generally increased by 0.1 mg/kg until control of lymphocytosis or toxicity is observed. Subsequent doses are modified to produce mild hematologic toxicity. It is felt that the response rate of chronic lymphocytic leukemia to the biweekly or once-monthly schedule of chlorambucil administration is similar or better to that previously reported with daily administration and that hematologic toxicity was less than or equal to that encountered in studies using daily chlorambucil.

Radiation and cytotoxic drugs render the bone marrow more vulnerable to damage, and chlorambucil should be used with particular caution within 4 weeks of a full course of radiation therapy or chemotherapy. However, small doses of palliative radiation over isolated foci remote from the bone marrow will not usually depress the neutrophil and platelet count. In these cases chlorambucil may be given in the customary dosage.

It is presently felt that short courses of treatment are safer than continuous maintenance therapy, although both methods have been effective. It must be recognized that continuous therapy may give the appearance of “maintenance” in patients who are actually in remission and have no immediate need for further drug. If maintenance dosage is used, it should not exceed 0.1 mg/kg daily and may well be as low as 0.03 mg/kg daily. A typical maintenance dose is 2 mg to 4 mg daily, or less, depending on the status of the blood counts. It may, therefore, be desirable to withdraw the drug after maximal control has been achieved, since intermittent therapy reinstituted at time of relapse may be as effective as continuous treatment.

Procedures for proper handling and disposal of anticancer drugs should be used. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

How is Leukeran Supplied

Leukeran is supplied as brown, film-coated, round, biconvex tablets containing 2 mg chlorambucil in amber glass bottles with child-resistant closures. One side is engraved with “GX EG3” and the other side is engraved with an “L.”

Bottle of 50 (NDC 0173-0635-35).

Store in a refrigerator, 2° to 8°C (36° to 46°F).

REFERENCES

1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32-41.


2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health and Human Services, 1992, US Dept of Health and Human Services, Public Health Service publication NIH 92-2621.


3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1591.


4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.


5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428.


6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263.


7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.


8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2006, GlaxoSmithKline. All rights reserved.

November 2006 RL-2328

Principal Display Panel

NDC 0173-0635-35

Leukeran®

(chlorambucil) Tablets

2 mg

50 Tablets

Each tablet contains 2 mg chlorambucil.

Rx only

WARNING: This drug is only to be taken under close medical supervision. Do not take in larger doses or more frequently or for a longer time than specifically directed by the physician. Periodic blood counts are necessary to determine proper dose and to avoid ill effects.

See prescribing information for Dosage and Administration.

Store in a refrigerator, 2o to 8oC (36o to 46oF). Dispense in tight container as defined in the USP.

Mfd by Heumann Pharma GmbH

90537 Feucht, Germany for

GlaxoSmithKline

RTP, NC 27709

Made in Germany

7000049 Rev. 3/04

Leukeran  chlorambucil  tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0173-0635 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CHLORAMBUCIL (CHLORAMBUCIL) CHLORAMBUCIL 2 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE   HYPROMELLOSES   ANHYDROUS LACTOSE   POLYETHYLENE GLYCOL   CELLULOSE, MICROCRYSTALLINE   FERRIC OXIDE RED   STEARIC ACID   TITANIUM DIOXIDE   FERRIC OXIDE YELLOW

Product Characteristics Color BROWN Score no score Shape ROUND Size 7mm Flavor Imprint Code GX;EG3;L Contains

Packaging # NDC Package Description Multilevel Packaging 1 0173-0635-35 50 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA010669	02/13/1985	06/30/2014

Labeler - GlaxoSmithKline LLC (167380711)

Revised: 10/2011GlaxoSmithKline LLC

More Leukeran resources

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

• Leukeran Concise Consumer Information (Cerner Multum)


• Leukeran MedFacts Consumer Leaflet (Wolters Kluwer)


• Leukeran Monograph (AHFS DI)


• Leukeran Advanced Consumer (Micromedex) - Includes Dosage Information


• Chlorambucil Professional Patient Advice (Wolters Kluwer)

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Inapsine

Generic Name: Droperidol
Class: Anxiolytics, Sedatives, and Hypnotics; Miscellaneous
VA Class: CN205
CAS Number: 548-73-2

• QT Interval Prolongation


• 
  

  QT interval prolongation and/or torsades de pointes (including fatalities) have occurred at doses at or below those recommended, in some cases when no known risk factors were present.¹¹⁴

  
  


• 
  

  Because of potential for serious proarrhythmic effects and death, use only when response to other treatment is unacceptable (due to lack of efficacy or intolerable adverse effects).¹¹⁴

  
  


• 
  

  Prior to administration, obtain 12-lead ECG to exclude the presence of prolonged QT interval (QT_c interval >440 msec in males, >450 msec in females).¹¹⁴

  
  


• 
  

  Do notadminister droperidol if QT interval is prolonged.¹¹⁴

  
  


• 
  

  If potential benefit outweighs risk of serious arrhythmia, monitor for arrhythmia with ECG prior to administration and for 2–3 hours after completion of therapy.¹¹⁴

  
  


• 
  

  Contraindicated in patients with known or suspected QT prolongation, including congenital long QT syndrome.¹¹⁴

  
  


• 
  

  Use with extreme caution in patients at risk for prolonged QT syndrome (e.g., CHF, bradycardia, diuretic use, cardiac hypertrophy, hypokalemia, hypomagnesemia, use of other drugs known to prolong QT interval).¹¹⁴ Other risk factors may include age >65 years, alcohol abuse, and concomitant use of benzodiazepines, volatile anesthetics, or IV opiates.¹¹⁴ (See Prolonged QT Syndrome under Cautions.)

  
  


• 
  

  Initiate droperidol at low dose and increase with caution as needed to achieve desired effect.¹¹⁴

  
  

Introduction

Butyrophenone derivative; structurally similar to haloperidol; pharmacologically similar to haloperidol and phenothiazines.^a

Uses for Inapsine

Nausea and Vomiting Associated with Surgical and Diagnostic Procedures

Reduction of the incidence of nausea and vomiting associated with surgical and diagnostic procedures.^{114 a} Because of the risk of serious, sometimes fatal proarrhythmic effects, use only in patients who fail to respond adequately (because of insufficient efficacy or intolerable adverse effects) to other antiemetic therapy.¹¹⁴ (See Boxed Warning.)

Adjunct to Anesthesia and Neuroleptanalgesia

Has been used preoperatively† and as an adjunct during induction and maintenance of general anesthesia† and as an adjunct to regional anesthesia†; also has been used in combination with an opiate analgesic (e.g., fentanyl) for neuroleptanalgesia† as an anxiolytic and to potentially increase the opiate analgesic effect.^a No longer recommended for these uses because of the risk of serious adverse effects.^{112 113}

Nausea and Vomiting Associated with Cancer Chemotherapy

Has been used effectively alone or in combination antiemetic regimens to prevent and/or reduce cancer chemotherapy-induced nausea and vomiting†, principally that induced by cisplatin.^{100 101 102 103 104 105 106 107}

Delirium

Occasionally used in the management of delirium†;¹⁰⁸ has been effective in the management of agitation (not necessarily delirium) and may be preferred to haloperidol in some delirious patients due to shorter half-life, more rapid onset of effect, and increased sedative effects.^{108 109 110 111}

Inapsine Dosage and Administration

General

• 
  

  Routinely monitor vital signs and ECG.¹¹⁴

  
  

Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer IM or by slow IV injection.^{114 a}

Dosage

Individualize dosage according to the patient’s age, weight, physical status, and underlying pathologic condition.¹¹⁴ Also consider other drugs, type of anesthesia used, and surgical procedure.¹¹⁴

Pediatric Patients

Nausea and Vomiting Associated with Surgical and Diagnostic Procedures

IV or IM

Children 2–12 years of age: Initially, up to 0.1 mg/kg (maximum of 2.5 mg), based on the patient’s age and clinical condition.^{114 116} Administer additional doses with caution and only if potential benefit outweighs potential risk.¹¹⁴

Adults

Nausea and Vomiting Associated with Surgical and Diagnostic Procedures

IV or IM

Initially, up to 2.5 mg.¹¹⁴ Administer additional doses of 1.25 mg with caution to achieve the desired effect, if potential benefit outweighs the potential risk.¹¹⁴

Delirium†

IM

Usually, 5 mg.^{108 110 111}

Prescribing Limits

Pediatric Patients

Nausea and Vomiting Associated with Surgical and Diagnostic Procedures

IV of IM

Children 2–12 years of age: Maximum initial dose of 0.1 mg/kg (up to 2.5 mg) based on age and clinical condition.^{114 116}

Adults

Nausea and Vomiting Associated with Surgical and Diagnostic Procedures

IV or IM

Maximum initial dose: 2.5 mg.¹¹⁴

Special Populations

Geriatric, Debilitated, and High-Risk Patients

Reduce initial dose in geriatric, debilitated, or high-risk patients.¹¹⁴ Carefully adjust subsequent dosage (if needed) according to response and tolerance following the initial dose.¹¹⁴

Cautions for Inapsine

Contraindications

• 
  

  Known or suspected QT interval prolongation (i.e., QT_c interval >440 msec in males, >450 msec in females), including congenital long QT syndrome.¹¹⁴

  
  


• 
  

  Known hypersensitivity to droperidol or any ingredient in the formulation.¹¹⁴

  
  

Warnings/Precautions

Warnings

Prolonged QT Syndrome

QT interval prolongation and serious, sometimes fatal arrhythmias (torsades de pointes, ventricular arrhythmias, cardiac arrest) have occurred.¹¹⁴ (See Boxed Warning.)

ECG monitoring is recommended; do not use if QT interval prolongation is present.¹¹⁴

Use with extreme caution in patients with risk factors for prolonged QT syndrome, including clinically important bradycardia (<50 bpm) or heart disease (e.g., CHF , cardiac hypertrophy); treatment with class I or III antiarrhythmic agents, MAO inhibitors, or other drugs known to prolong the QT interval; electrolyte imbalance (particularly hypomagnesemia or hypokalemia); or treatment with drugs (e.g., diuretics) that may cause electrolyte imbalance.¹¹⁴

Promptly evaluate any signs or symptoms suggestive of irregular cardiac rhythm (e.g., palpitations, syncope).¹¹⁴

Hypotension

Possibility of severe hypotension; parenteral fluids and other supportive measures should be readily available.¹¹⁴

If hypotension occurs, consider possibility of hypovolemia and institute appropriate therapy with IV fluids.¹¹⁴

Consider repositioning patient to improve venous return to the heart when operative conditions permit; however, during spinal and peridural anesthesia, placing the patient into a head-down position may result in a higher level of anesthesia than is desirable and may impair venous return to the heart.¹¹⁴ Because of the possibility of orthostatic hypotension, use care when moving and positioning patients during anesthesia.¹¹⁴

If hypotension is not corrected with fluids or repositioning, consider use of pressor agents, but not epinephrine (may paradoxically decrease BP due to droperidol’s α-adrenergic blockade).¹¹⁴

CNS Depression

CNS depressant effects; monitor vital signs routinely.¹¹⁴

Concurrent Use With Opiate Agonists

When concurrent use of opiates and droperidol is required, administer opiates in reduced dosage.¹¹⁴ Be familiar with each drug, particularly widely differing durations of action.^a

Respiratory depression induced by opiates persists longer than analgesic effects.^a Before ordering opiate analgesics during anesthesia recovery, consider total dosage of administered opiates; if opiates are required during the recovery period, use initially in reduced dosages (as low as one-fourth to one-third of those usually recommended).^a Keep resuscitative equipment and an opiate antagonist readily available to manage apnea.^a

Neuroleptic Malignant Syndrome (NMS)

NMS (altered consciousness, muscular rigidity, autonomic instability) has occurred.¹¹⁴

May be difficult to distinguish NMS from malignant hyperthermia perioperatively; consider prompt dantrolene treatment if increases in temperature, heart rate, and/or carbon dioxide production occur following administration of droperidol.¹¹⁴

General Precautions

Anesthesia

Certain forms of conduction anesthesia (e.g., spinal anesthesia, peridural anesthesia) can alter respiration by blocking intercostal nerves and can cause peripheral vasodilation and hypotension; droperidol also has cardiovascular effects.¹¹⁴

When droperidol is used to supplement these forms of anesthesia, be prepared to manage physiologic alterations involved.¹¹⁴

Hemodynamic Assessments

Droperidol may decrease pulmonary arterial pressure and interfere with interpretation of hemodynamic measurements made during diagnostic or surgical procedures.¹¹²

Monitoring

Monitor ECG and vital signs regularly.¹¹⁴

Effects on EEG

When EEG is used for postoperative monitoring, consider that the EEG pattern returns to normal slowly following droperidol use.¹¹⁴

Pheochromocytoma

Severe hypertension and tachycardia have occurred following droperidol administration in patients with diagnosed or suspected pheochromocytoma.¹¹⁴

Specific Populations

Pregnancy

Category C.¹¹⁴

Use in labor and delivery not recommended.¹¹⁴

Lactation

Not known whether droperidol is distributed into milk.¹¹⁴ Use with caution.¹¹⁴

Pediatric Use

Safety and efficacy not established in children <2 years of age.¹¹⁴

Geriatric Use

Use with caution; reduce initial dose and carefully adjust subsequent dosage.^a

Hepatic Impairment

Use with caution.¹¹⁴

Renal Impairment

Use with caution.¹¹⁴

Common Adverse Effects

Hypotension, tachycardia, dysphoria, postoperative drowsiness, restlessness, hyperactivity, anxiety, extrapyramidal reactions (dystonia, akathisia, oculogyric crisis).^{114 a}

Interactions for Inapsine

Drugs That Prolong QT Interval

Risk of prolonged QT interval and potentially serious or life-threatening arrhythmias.¹¹⁴ Avoid concomitant use of droperidol with drugs known to prolong the QT interval.¹¹⁴

Specific Drugs

Drug	Interaction	Comments
Anesthetics, regional or conduction (e.g., spinal or peridural anesthesia)	Possible altered respiration, peripheral vasodilation, and hypotension.114 (See Anesthesia under Cautions.)	Use with caution114
Antiarrhythmics, class I or III	Possible prolongation of the QT interval; potentially arrhythmogenic114	Avoid concomitant use of droperidol with drugs known to prolong the QT interval114
Antidepressants (e.g., tricyclics)	Potentially arrhythmogenic; some antidepressants known to prolong the QT interval114	Avoid concomitant use of droperidol with drugs known to prolong the QT interval114
Antihistamines known to prolong the QT interval (terfenadine, astemizole [no longer commercially available in US])	Potentially arrhythmogenic114	Avoid concomitant use of droperidol with drugs known to prolong the QT interval114
Antimalarials	Potentially arrhythmogenic; some antimalarials known to prolong the QT interval114	Avoid concomitant use of droperidol with drugs known to prolong the QT interval114
Calcium-channel blocking agents	Potentially arrhythmogenic; some calcium-channel blockers known to prolong the QT interval114	Avoid concomitant use of droperidol with drugs known to prolong the QT interval114
CNS depressants (alcohol, barbiturates, benzodiazepines, general or volatile anesthetics, opiates and other analgesics, sedatives, tranquilizers)	Possible additive or potentiated CNS depression114 a	Reduce initial droperidol dose in patients who have received other CNS depressants, or vice versa114
Cyclobenzaprine	Torsades de pointes, with progression to ventricular fibrillation, reported with concomitant use of droperidol, cyclobenzaprine, and fluoxetine.115 (Possible mechanism: inhibition of cyclobenzaprine metabolism by fluoxetine; droperidol may have contributed to QT interval prolongation and development of torsades de pointes.115 )
Diuretics	Potential for diuretic-induced hypokalemia or hypomagnesemia resulting in prolongation of the QT interval114	Use with caution114
Epinephrine	Possible paradoxical decrease in BP due to droperidol’s α-adrenergic blockade114	Use pressor agents other than epinephrine to treat hypotension that is unresponsive to IV fluids or repositioning of the patient114
Fentanyl	Increased BP reported (with or without preexisting hypertension) when droperidol administered with fentanyl or other parenteral analgesics (increased BP possibly resulted from unexplained changes in sympathetic activity after large doses or due to anesthetic/surgical stimulation during light anesthesia)114
Laxatives	Potential for laxative-induced hypokalemia or hypomagnesemia resulting in prolongation of the QT interval114	Use with caution114
MAO inhibitors	Risk factor for prolonged QT syndrome114	Use concomitantly with extreme caution or do not use114
Mineralocorticoids	Supraphysiologic doses of steroid hormones with mineralocorticoid activity may induce hypokalemia or hypomagnesemia, prolonging the QT interval114	Use with caution114
Neuroleptic agents known to prolong the QT interval (e.g., phenothiazines)	Potentially arrhythmogenic114	Avoid concomitant use of droperidol with drugs known to prolong the QT interval114

Inapsine Pharmacokinetics

Absorption

Onset

Onset occurs within 3–10 minutes following IM or IV administration, but peak effects may not be apparent until 30 minutes.¹¹⁴

Duration

Following IM or IV administration, sedative and tranquilizing effects generally persist for 2–4 hours; alteration of consciousness may persist for up to 12 hours.¹¹⁴

Distribution

Extent

Reportedly crosses the blood-brain barrier and is distributed into the CSF.^a

Reportedly crosses the placenta; not known whether droperidol is distributed into milk.^a

Elimination

Metabolism

Metabolized in the liver.^a

Elimination Route

Droperidol and its metabolites are excreted in urine (10% as unchanged drug) and feces.^a

Stability

Storage

Parenteral

Injection

15–25°C; protect from light.¹¹⁴

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility^HID

Compatible
Dextrose 5% in water
Ringer’s injection, lactated
Sodium chloride 0.9%

Drug Compatibility

Y-Site CompatibilityHID

Compatible
Amifostine
Azithromycin
Aztreonam
Bivalirudin
Bleomycin sulfate
Cladribine
Cisplatin
Cyclophosphamide
Cytarabine
Dexmedetomidine HCl
Docetaxel
Doxorubicin HCl
Doxorubicin HCl liposome injection
Etoposide phosphate
Famotidine
Fenoldopam mesylate
Filgrastim
Fluconazole
Fludarabine phosphate
Gatifloxacin
Gemcitabine HCl
Granisetron HCl
Hetastarch in lactated electrolyte injection (Hextend)
Hydrocortisone sodium succinate
Idarubicin HCl
Linezolid
Melphalan HCl
Meperidine HCl
Metoclopramide HCl
Mitomycin
Ondansetron HCl
Paclitaxel
Potassium chloride
Propofol
Remifentanil HCl
Sargramostim
Teniposide
Thiotepa
Vinblastine sulfate
Vincristine sulfate
Vinorelbine tartrate
Vitamin B complex with C
Incompatible
Allopurinol sodium
Amphotericin B cholesteryl sulfate complex
Cefepime HCl
Fluorouracil
Foscarnet sodium
Furosemide
Leucovorin calcium
Nafcillin sodium
Piperacillin sodium–tazobactam sodium
Variable
Heparin sodium
Methotrexate sodium

ActionsActions

• 
  

  Exhibits strong sedative and tranquilizing effects.^a Potentiates the actions of other CNS depressants but apparently has no analgesic activity.^{114 a}

  
  


• 
  

  Has antiemetic activity.^{114 a}

  
  


• 
  

  Acts principally at CNS subcortical levels;^a may cause extrapyramidal reactions.^{114 a}

  
  


• 
  

  Exhibits some α-adrenergic blocking activity; attenuates the cardiovascular response to sympathomimetic amines (e.g., reduces pressor effect of epinephrine).^{114 a}

  
  


• 
  

  Direct peripheral vasodilatory effects, alone or in conjunction with α-adrenergic blockade, may cause hypotension and decreased peripheral vascular resistance.^{114 a}

  
  


• 
  

  May decrease pulmonary arterial pressure (particularly if abnormally high).^{114 a}

  
  


• 
  

  May reduce the incidence of epinephrine-induced arrhythmias but does not appear to prevent other arrhythmias.^{114 a}

  
  

Advice to Patients

• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses or alcohol use.¹¹⁴

  
  


• 
  

  Importance of avoiding alcohol during therapy due to risk of additive effects.¹¹⁴

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed.¹¹⁴

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹¹⁴ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Droperidol

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection	2.5 mg/mL*	Droperidol Injection (preservative-free)	American Regent, Hospira
			Inapsine (preservative-free in ampuls or with parabens in multiple-dose vials)	Akorn

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

100. Grossman B, Lessin LS, Cohen P. Droperidol prevents nausea and vomiting from cis-platinum. N Engl J Med. 1979; 301:47. [PubMed 449910]

101. Jacobs AJ, Deppe G, Cohen CJ. A comparison of the antiemetic effects of droperidol and prochlorperazine in chemotherapy with cis-platinum. Gynecol Oncol. 1980; 10:55-7. [PubMed 7190532]

102. Wilson J, Weltz M, Solimando D et al. Continuous infusion droperidol: anti-emetic therapy for cis-platinum (DDP) toxicity. Proc Am Soc Clin Oncol. 1981; 22:421.

103. Mason BA, Dambra J, Grossman B et al. Effective control of cisplatin-induced nausea using high-dose steroids and droperidol. Cancer Treat Rep. 1982; 66:243-5. [IDIS 145462] [PubMed 7198937]

104. Brown RE, Gregg RE, Hood JC. Droperidol treatment in streptozocin-induced nausea and vomiting. Drug Intell Clin Pharm. 1982; 16:775-6. [IDIS 157659] [PubMed 6216088]

105. Owens NJ, Schauer AR, Nightingale CH et al. Antiemetic efficacy of prochlorperazine, haloperidol, and droperidol in cisplatin-induced emesis. Clin Pharm. 1984; 3:167-70. [IDIS 182892] [PubMed 6373102]

106. Lewis GO, Bernath AM, Ellison NM et al. Double-blind crossover trial of droperidol, metoclopramide, and prochlorperazine as antiemetics in cisplatin therapy. Clin Pharm. 1984; 3:618-21. [IDIS 193407] [PubMed 6391784]

107. Cersosimo RJ, Bromer R, Hoffer S et al. The antiemetic activity of droperidol administered by intramuscular injection during cisplatin chemotherapy: a pilot study. Drug Intell Clin Pharm. 1985; 19:118-21. [IDIS 195459] [PubMed 4038643]

108. Trzepacz P, Breitbart W, Levenson J et al for the American Psychiatric Association Working Group on Delirium. Practice guideline for the treatment of patients with delirium. Am J Psychiatry. 1999; 156(Supp 5):1-20.

109. Van Leeuwen A, Molders J, Sterkmans P et al. Droperidol in acutely agitated patients. J Nerv Ment Dis. 1977; 164:280-3. [PubMed 321727]

110. Resnick M, Burton B. Droperidol vs haloperidol in the initial management of acutely agitated patients. J Clin Psychiatry. 1984; 45:298-9. [IDIS 188732] [PubMed 6376480]

111. Thomas H, Schwartz E, Petrilli R et al. Droperidol versus haloperidol for chemical restraint of agutated and combative patients. Ann Emerg Med. 1992; 21:407-13. [PubMed 1554179]

112. Ahmed S. Dear healthcare professional letter regarding QT prolongation and torsades de pointes. Emeryville, CA: Akorn Inc.; 2001 Dec 4.

113. FDA strengthens warnings for droperidol. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2001 Dec 5.

114. Taylor Pharmaceuticals. Inapsine (droperidol) injection for intravenous or intramuscular use prescribing information. Decatur, IL; 2001 Nov.

115. Michalets EL, Smith LK, Van Tassel ED. Torsade de pointes resulting from the addition of droperidol to an existing cytochrome P450 drug interaction. Ann Pharmacother. 1998; 32:761-5. [IDIS 408347] [PubMed 9681092]

116. Gunn VL, Nechyba C, eds. The Harriett Lane handbook: a manual for pediatric house officers. 16th ed. Philadelphia, PA: Mosby; 2002:672-3.

a. AHFS drug information 2004. McEvoy GK, ed. Droperidol. Bethesda, MD: American Society of Health-System Pharmacists; 2004:2412-14

HID. Trissel LA. Handbook on injectable drugs. 13th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2005:546-552.

More Inapsine resources

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

• Inapsine Prescribing Information (FDA)


• Inapsine MedFacts Consumer Leaflet (Wolters Kluwer)


• Inapsine Concise Consumer Information (Cerner Multum)


• Inapsine Advanced Consumer (Micromedex) - Includes Dosage Information


• Droperidol Prescribing Information (FDA)


• Droperidol Professional Patient Advice (Wolters Kluwer)

Compare Inapsine with other medications

• Nausea/Vomiting
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Mycil Athlete's Foots Spray

1. Name Of The Medicinal Product

Mycil Athletes Foot Spray

2. Qualitative And Quantitative Composition

Tolnaftate BP 0.12% w/w

3. Pharmaceutical Form

Dry powder spray

4. Clinical Particulars

4.1 Therapeutic Indications

For the adjunctive treatment and prevention of athlete's foot (Tinea Pedis). It is also effective in other conditions, such as dhobie itch (Tinea Cruris) and prickly heat (Miliaria).

4.2 Posology And Method Of Administration

For topical application to the skin.

Wash and thoroughly dry the affected area before spraying liberally morning and night. Continue the treatment for at least a week after the infection has cleared up. Routine use of the spray can help prevent infection.

4.3 Contraindications

Hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Keep all medicines out of the reach of children.

Keep away from eyes.

For external use only.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically significant drug interactions known.

4.6 Pregnancy And Lactation

No special requirements.

4.7 Effects On Ability To Drive And Use Machines

None

4.8 Undesirable Effects

None known

4.9 Overdose

Not applicable

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Tolnaftate is a well established drug substance having potent antifungal properties.

5.2 Pharmacokinetic Properties

Not applicable

5.3 Preclinical Safety Data

There are no preclinical safety data of relevance to the consumer.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Talc, denatured ethanol, bentone 38 V, dimethyl ether.

6.2 Incompatibilities

None known

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Store below 25°C

6.5 Nature And Contents Of Container

Internally lacquered aluminium can fitted with a continuous spray valve and an actuator.

Pack size 150ml

6.6 Special Precautions For Disposal And Other Handling

Caution flammable. Do not use near fire or flame. Pressurised container. Protect from sunlight and do not expose to temperatures exceeding 50°C. Do not pierce or burn, even after use. Do not spray on a naked flame. Do not use near, or place container on, polished or painted surfaces. CFC-free — does not contain CFCs which damage ozone.

7. Marketing Authorisation Holder

Crookes Healthcare Limited

1 Thane Road West

Nottingham NG2 3AA

8. Marketing Authorisation Number(S)

PL 0327/0070

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 27/02/91

10. Date Of Revision Of The Text

November 1995

Methotrexate Tablets B.P. 2.5mg

1. Name Of The Medicinal Product

Methotrexate Tablets B.P. 2.5mg.

2. Qualitative And Quantitative Composition

Active Constituent

Methotrexate Ph EUR 2.5mg.

3. Pharmaceutical Form

Tablet for oral administration.

4. Clinical Particulars

4.1 Therapeutic Indications

Methotrexate is indicated in the treatment of neoplastic disease, such as trophoblastic neoplasms and leukaemia and in the control of severe recalcitrant psoriasis which is not responsive to other forms of therapy.

4.2 Posology And Method Of Administration

ADULTS AND CHILDREN

Antineoplastic Chemotherapy

Methotrexate is active orally and parenterally. Methotrexate Injection B.P. may be given by the intramuscular, intravenous, intra-arterial or intrathecal routes. Dosage is related to the patient's body weight or surface area. Methotrexate has been used with beneficial effect in a wide variety of neoplastic diseases, alone and in combination with other cytotoxic agents.

Choriocarcinoma and Similar Trophoblastic Diseases

Methotrexate is administered orally or intramuscularly in doses of 15-30mg daily for a 5-day course. Such courses may be repeated 3-5 times as required, with rest periods of one or more weeks interposed between courses until any manifesting toxic symptoms subside.

The effectiveness of therapy can be evaluated by 24 hour quantitative analysis of urinary chorionic gonadotrophin hormone (HCG). Combination therapy with other cytotoxic drugs, has also been reported as useful.

Hydatidiform mole may precede or be followed by choriocarcinoma, and Methotrexate has been used in similar doses for the treatment of hydatidiform mole and chorioadenoma destruens.

Breast Carcinoma

Prolonged cyclic combination with Cyclophosphamide, Methotrexate and Fluorouracil has given good results when used as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. Methotrexate dosage was 40mg/m² intravenously on the first and eighth days.

Leukaemia

Acute granulocytic leukaemia is rare in children but common in adults and this form of leukaemia responds poorly to chemotherapy.

Methotrexate is not generally a drug of choice for induction of remission of lymphoblastic leukaemia. Oral Methotrexate 3.3mg/m² daily, and Prednisolone 40-60mg/m² daily for 4-6 weeks has been used. After a remission is attained, Methotrexate in a maintenance dosage of 20-30mg/m² orally or by I.M. injection has been administered twice weekly. Twice weekly doses appear to be more effective than daily drug administration. Alternatively, 2.5mg/kg has been administered I.V. every 14 days.

Meningeal Leukaemia

Some patients with leukaemia are subject to leukaemic invasions of the central nervous system and the CSF should be examined in all leukaemia patients.

Passage of Methotrexate from blood to the cerebrospinal fluid is minimal and for adequate therapy the drug should be administered intrathecally. Methotrexate may be given in a prophylactic regimen in all cases of lymphocytic leukaemia. Methotrexate is administered by intrathecal injection in doses of 200-500 microgram/kg body weight. The administration is at intervals of 2 to 5 days and is usually repeated until the cell count of cerebrospinal fluid returns to normal. At this point one additional dose is advised. Alternatively, Methotrexate 12mg/m² can be given once weekly for 2 weeks, and then once monthly. Large doses may cause convulsions and untoward side effects may occur as with any intrathecal injection, and are commonly neurological in character.

Lymphomas

In Burkitt's Tumour, stages 1-2, Methotrexate has prolonged remissions in some cases. Recommended dosage is 10-25mg per day orally for 4 to 8 days. In stage 3, Methotrexate is commonly given concomitantly with other antitumour agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods, and in stage 3 they respond to combined drug therapy with Methotrexate given in doses of 0.625mg to 2.5mg/kg daily. Hodgkin's Disease responds poorly to Methotrexate and to most types of chemotherapy.

Mycosis Fungoides

Therapy with Methotrexate appears to produce clinical remissions in one half of the cases treated. Recommended dosage is usually 2.5 to 10mg daily by mouth for weeks or months and dosage should be adjusted according to the patient's response and haematological monitoring. Methotrexate has also been given intramuscularly in doses of 50mg once weekly or 25mg twice weekly.

Psoriasis Chemotherapy

Cases of severe uncontrolled psoriasis, unresponsive to conventional therapy, have responded to weekly single, oral, I.M. or I.V. doses of 10-25mg per week, adjusted according to the patient's response. An initial test dose one week prior to initiation of therapy is recommended to detect any idiosyncrasy. A suggested dose range is 5-10mg.

An alternative dosage schedule consists of 2.5 to 5mg of Methotrexate administered orally at 12 hour intervals for 3 doses each week or at 8-hour intervals for 4 doses each week; weekly dosages should not exceed 30mg.

A daily oral dosage schedule of 2 to 5mg administered orally for 5 days followed by a rest period of at least 2 days may also be used. The daily dose should not exceed 6.25mg.

The patient should be fully informed of the risks involved and the clinician should pay particular attention to the appearance of liver toxicity by carrying out liver function tests before starting Methotrexate treatment, and repeating these at 2 to 4 month intervals during therapy. The aim of therapy should be to reduce the dose to the lowest possible level with the longest possible rest period. The use of Methotrexate may permit the return to conventional topical therapy which should be encouraged.

4.3 Contraindications

Significantly impaired renal function.

Significantly impaired hepatic function

Pre-existing blood dyscrasias, such as significant marrow hypoplasia, leukopenia, thrombocytopenia or anaemia.

Methotrexate is contraindicated in pregnancy.

Due to the potential for serious adverse reactions from methotrexate in breast fed infants, breast feeding is contra-indicated in women taking methotrexate.

Patients with a known allergic hypersensitivity to methotrexate should not receive methotrexate.

4.4 Special Warnings And Precautions For Use

WARNINGS

Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy.

Due to the possibility of fatal or severe toxic reactions, the patient should be fully informed by the physician of the risks involved and be under his constant supervision.

Deaths have been reported with the use of Methotrexate in the treatment of psoriasis.

In the treatment of psoriasis, Methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after dermatological consultation.

1. Full blood counts should be closely monitored before, during and after treatment. If a clinically significant drop in white-cell or platelet count develops, methotrexate should be withdrawn immediately. Patients should be advised to report all symptoms or signs suggestive of infection.

2. Methotrexate may be hepatotoxic, particularly at high dosage or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis have been reported. Since changes may occur without previous signs of gastrointestinal or haematological toxicity, it is imperative that hepatic function be determined prior to initiation of treatment and monitored regularly throughout therapy. If substantial hepatic function abnormalities develop, methotrexate dosing should be suspended for at least 2 weeks.Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function. Concomitant use of other drugs with hepatotoxic potential (including alcohol) should be avoided.

3. Methotrexate has been shown to be teratogenic; it has caused foetal death and/or congenital anomalies. Therefore it is not recommended in women of childbearing potential unless there is appropriate medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant psoriatic patients should not receive Methotrexate.

4. Renal function should be closely monitored before, during and after treatment. Caution should be exercised if significant renal impairment is disclosed. Reduce dose of methotrexate in patients with renal impairment. High doses may cause the precipitation of methotrexate or its metabolites in the renal tubules. A high fluid throughput and alkalinisation of the urine to pH 6.5 — 7.0, by oral or intravenous administration of sodium bicarbonate (5 x 625mg tablets every three hours) or acetazolamide (500mg orally four times a day) is recommended as a preventative measure. Methotrexate is excreted primarily by the kidneys. Its use in the presence of impaired renal function may result in accumulation of toxic amounts or even additional renal damage.

5. Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

6. Methotrexate affects gametogenesis during the period of its administration and may result in decreased fertility which is thought to be reversible on discontinuation of therapy. Conception should be avoided during the period of Methotrexate administration and for at least 6 months thereafter. Patients and their partners should be advised to this effect.

7. Methotrexate has some immunosuppressive activity and immunological responses to concurrent vaccination may be decreased. The immunosuppressive effect of Methotrexate should be taken into account when immune responses of patients are important or essential.

8. Pleural effusions and ascites should be drained prior to initiation of methotrexate therapy.

9. Deaths have been reported with the use of methotrexate. Serious adverse reactions including deaths have been reported with concomitant administration of methotrexate (usually in high doses) along with some non-steroidal anti-inflammatory drugs (NSAIDs).

10. Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.

11. Systemic toxicity may occur following intrathecal administration. Blood counts should be monitored closely.

12. A chest X-ray is recommended prior to initiation of methotrexate therapy.

13. If acute methotrexate toxicity occurs, patients may require folinic acid.

4.3 Contraindications

Methotrexate has a high potential toxicity, usually dose related, and should be used only by physicians experienced in antimetabolite chemotherapy, in patients under their constant supervision. The physician should be familiar with the various characteristics of the drug and its established clinical usage.

Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests.

It should be noted that intrathecal doses are transported into the cardiovascular system and may give rise to systemic toxicity. Systemic toxicity of methotrexate may also be enhanced in patients with renal dysfunction, ascites, or other effusions due to prolongation of serum half-life.

Carcinogenesis, mutagenesis, and impairment of fertility:

Animal carcinogenicity studies have demonstrated methotrexate to be free of carcinogenic potential. Although methotrexate has been reported to cause chromosomal damage to animal somatic cells and bone marrow cells in humans, these effects are transient and reversible. In patients treated with methotrexate, evidence is insufficient to permit conclusive evaluation of any increased risk of neoplasia.

Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy. In addition, methotrexate causes, embryotoxicity, abortion and foetal defects in humans. Therefore the possible risks of effects on reproduction should be discussed with patients of childbearing potential (see 'Warnings').

Patients undergoing therapy should be subject to appropriate supervision so that signs or symptoms of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Pretreatment and periodic haematological studies are essential to the use of Methotrexate in chemotherapy because of its common effect of haematopoietic suppression. This may occur abruptly and on apparent safe dosage, and any profound drop in blood cell count indicates immediate stopping of the drug and appropriate therapy. In patients with malignant disease who have pre-existing bone marrow aplasia, leukopenia, thrombocytopenia or anaemia, methotrexate should be used with caution, if at all.

In general, the following laboratory tests are recommended as part of essential clinical evaluation and appropriate monitoring of patients chosen for or receiving Methotrexate therapy: complete haemogram; haematocrit; urinalysis; renal function tests; liver function tests and chest X-ray.

The purpose is to determine any existing organ dysfunction or system impairment. The tests should be performed prior to therapy, at appropriate periods during therapy and after termination of therapy.

Liver biopsy may be considered after cumulative doses> 1.5g have been given, if hepatic impairment is suspected.

Methotrexate is bound in part to serum albumin after absorption, and toxicity may be increased because of displacement by certain drugs such as salicylates, sulphonamides, phenytoin, and some antibacterials such as tetracycline, chloramphenicol and para-aminobenzoic acid. These drugs, especially salicylates and sulphonamides, whether antibacterial, hypoglycaemic or diuretic, should not be given concurrently until the significance of these findings is established.

Vitamin preparations containing folic acid or its derivatives may alter response to Methotrexate.

Methotrexate should be used with extreme caution in the presence of infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age. If profound leukopenia occurs during therapy, bacterial infection may occur or become a threat. Cessation of the drug and appropriate antibiotic therapy is usually indicated. In severe bone marrow depression, blood or platelet transfusions may be necessary.

Since it is reported that Methotrexate may have an immunosuppressive action, this factor must be taken into consideration in evaluating the use of the drug where immune responses in a patient may be important or essential.

In all instances where the use of Methotrexate is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the physician. Reinstitution of Methotrexate therapy should be carried out with caution, with adequate consideration of further need for the drug and alertness as to the possible recurrence of toxicity.

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Methotrexate is extensively protein bound and may be displaced by certain drugs such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, so causing a potential for increased toxicity when used concurrently.

Concomitant use of other drugs with nephrotoxic or hepatotoxic potential (including alcohol) should be avoided.

Vitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate.

Caution should be used when NSAIDs and salicylates are administered concomitantly with methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate and thereby may enhance its toxicity. Concomitant use of NSAIDs and salicylates has been associated with fatal methotrexate toxicity.

However, patients using constant dosage regimens of NSAIDs have received concurrent doses of methotrexate without problems observed.

Renal tubular transport is also diminished by probenecid and penicillins; use of these with methotrexate should be carefully monitored.

Severe bone marrow depression has been reported following the concurrent use of methotrexate and co-trimoxazole or trimethoprim. Concurrent use should probably be avoided.

Methotrexate-induced stomatitis and other toxic effects may be increased by the use of nitrous oxide.

An increased risk of hepatitis has been reported following the use of methotrexate and the acitretin metabolite, etretinate. Consequently, the concomitant use of methotrexate and acitretin should be avoided.

4.6 Pregnancy And Lactation

Abortion, foetal death, and/or congenital anomalies have occurred in pregnant women receiving Methotrexate, especially during the first trimester of pregnancy. Methotrexate is contraindicated in the management of psoriasis or rheumatoid arthritis in pregnant women. Women of childbearing potential should not receive Methotrexate until pregnancy is excluded. For the management of psoriasis or rheumatoid arthritis, Methotrexate therapy in women should be started immediately following a menstrual period and appropriate measures should be taken in men or women to avoid conception during and for at least 6 months following cessation of Methotrexate therapy.

Both men and women receiving Methotrexate should be informed of the potential risk of adverse effects on reproduction. Women of childbearing potential should be fully informed of the potential hazard to the foetus should they become pregnant during Methotrexate therapy. In cancer chemotherapy, Methotrexate should not be used in pregnant women or women of childbearing potential who might become pregnant unless the potential benefits to the mother outweigh the possible risks to the foetus.

Defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, and infertility have been reported in patients receiving Methotrexate.

Methotrexate is distributed into breast milk. Because of the potential for serious adverse reactions to Methotrexate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

4.7 Effects On Ability To Drive And Use Machines

Not applicable

4.8 Undesirable Effects

The most common adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal distress. Although very rare, anaphylactic reactions to methotrexate have occurred. Others reported are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions as reported for the various systems are as follows:

Skin:

Stevens-Johnson syndrome, epidermal necrolysis, erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration in psoriatic patients and rarely painful erosion of psoriatic plaques have been reported. The recall phenomenon has been reported in both radiation and solar damaged skin.

Blood:

Bone marrow depression, leukopenia, thrombocytopenia, anaemia, hypogammaglobulinaemia, haemorrhage from various sites, septicaemia.

Alimentary System:

Gingivitis, pharyngitis, stomatitis, anorexia, vomiting, diarrhoea, haematemesis, melaena, gastrointestinal ulceration and bleeding, enteritis, hepatic toxicity resulting in active liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis, or hepatic cirrhosis. In rare cases the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon.

Hepatic:

Hepatic toxicity resulting in significant elevations of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis or cirrhosis or death may occur, usually following chronic administration.

Urogenital System:

Renal failure, azotaemia, cystitis, haematuria, defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, foetal defects, severe nephropathy. Vaginitis, vaginal ulcers, cystitis, haematuria and nephropathy have also been reported.

Pulmonary System:

Infrequently an acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Acute pulmonary oedema has also been reported after oral and intrathecal use. Pulmonary fibrosis is rare. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses.

Central Nervous System:

Headaches, drowsiness, blurred vision, aphasia, hemiparesis and convulsions have occurred possibly related to haemorrhage or to complications from intra-arterial catheterization. Convulsion, paresis, Guillain-Barre syndrome and increased cerebrospinal fluid pressure have followed intrathecal administration.

Other reactions related to, or attributed to the use of Methotrexate such as pneumonitis, metabolic changes, precipitation of diabetes, osteoporotic effects, abnormal changes in tissue cells and even sudden death have been reported.

There have been reports of leukoencephalopathy following intravenous methotrexate in high doses, or low doses following cranial-spinal radiation.

Adverse reactions following intrathecal methotrexate

are generally classified into three groups, acute, subacute, and chronic. The acute form is a chemical arachnoiditis manifested by headache, back or shoulder pain, nuchal rigidity, and fever. The subacute form may include paresis, usually transient, paraplegia, nerve palsies, and cerebellar dysfunction. The chronic form is a leukoencephalopathy manifested by irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia, somnolence, coma, and rarely, death. There is evidence that the combined use of cranial radiation and intrathecal methotrexate increases the incidence of leukoencephalopathy.

Additional reactions related to or attributed to the use of methotrexate such as osteoporosis, abnormal (usually 'megaloblastic') red cell morphology, precipitation of diabetes, other metabolic changes, and sudden death have been reported.

4.9 Overdose

Calcium Folinate (Calcium Leucovorin) is a potent agent for neutralizing the immediate toxic effects of Methotrexate on the haematopoietic system. Where large doses or overdoses are given, Calcium Folinate may be administered by intravenous infusion in doses up to 75mg within 12 hours, followed by 12mg intramuscularly every 6 hours for 4 doses. Where average doses of Methotrexate appear to have an adverse effect 6-12mg of Calcium Folinate may be given intramuscularly every 6 hours for 4 doses. In general, where overdosage is suspected, the dose of Calcium Folinate should be equal to or higher than, the offending dose of Methotrexate and should be administered as soon as possible; preferably within the first hour and certainly within 4 hours after which it may not be effective.

Other supporting therapy such as blood transfusion and renal dialysis may be required. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Methotrexate is an antimetabolite which acts principally by competitively inhibiting the enzyme, dihydrofolate reductase. In the process of DNA synthesis and cellular replication, folic acid must be reduced to tetrahydrofolic acid by this enzyme, and inhibition by Methotrexate interferes with tissue cell reproduction. Actively proliferating tissues such as malignant cells are generally more sensitive to this effect of Methotrexate. It also inhibits antibody synthesis.

Methotrexate also has immunosuppressive activity, in part possibly as a result of inhibition of lymphocyte multiplication. The mechanism(s) of action in the management of rheumatoid arthritis of the drug is not known, although suggested mechanisms have included immunosuppressive and/or anti-inflammatory effect.

5.2 Pharmacokinetic Properties

In doses of 0.1mg (of Methotrexate) per kg, Methotrexate is completely absorbed from the G.I. tract; larger oral doses may be incompletely absorbed. Peak serum concentrations are achieved within 0.5 - 2 hours following I.V. / I.M. or intra-arterial administration. Serum concentrations following oral administration of Methotrexate may be slightly lower than those following I.V. injection.

Methotrexate is actively transported across cell membranes. The drug is widely distributed into body tissues with highest concentrations in the kidneys, gall bladder, spleen, liver and skin. Methotrexate is retained for several weeks in the kidneys and for months in the liver. Sustained serum concentrations and tissue accumulation may result from repeated daily doses. Methotrexate crosses the placental barrier and is distributed into breast milk. Approximately 50% of the drug in the blood is bound to serum proteins.

In one study, Methotrexate had a serum half-life of 2-4 hours following I.M. administration. Following oral doses of 0.06mg/kg or more, the drug had a serum half-life of 2-4 hours, but the serum half-life was reported to be increased to 8-10 hours when oral doses of 0.037mg/kg were given.

Methotrexate does not appear to be appreciably metabolised. The drug is excreted primarily by the kidneys via glomerular filtration and active transport. Small amounts are excreted in the faeces, probably via the bile. Methotrexate has a biphasic excretion pattern. If Methotrexate excretion is impaired accumulation will occur more rapidly in patients with impaired renal function. In addition, simultaneous administration of other weak organic acids such as salicylates may suppress Methotrexate clearance.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Other Constituents

Maize Starch	Ph EUR 30.0mg
Lactose	Ph EUR 41.8mg
Pre gelatinized Starch (Prejel PA5)	Ph EUR 2.5mg
Polysorbate 80	Ph EUR 0.2mg
Microcrystalline Cellulose (AVICEL 101)	Ph EUR 20.0mg
Magnesium Stearate	Ph EUR 3.0mg

There is no overage included in the formulation.

6.2 Incompatibilities

Immediate precipitation or turbidity results when combined with certain concentrations of

Droperidol, Heparin Sodium, Metoclopramide Hydrochloride, Ranitidine Hydrochloride in

Syringe.

6.3 Shelf Life

60 months

6.4 Special Precautions For Storage

There are no specific storage requirements.

6.5 Nature And Contents Of Container

White polyethylene bottle with high density polyethylene screw closure containing 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Faulding Pharmaceuticals Plc

Queensway

Royal Leamington Spa

Warwickshire, CV31 3RW

8. Marketing Authorisation Number(S)

PL 04515/0004

9. Date Of First Authorisation/Renewal Of The Authorisation

9^th September 1985/24^th June 1996

10. Date Of Revision Of The Text

4^th July 2001