Estroplan

Dosage Form: FOR ANIMAL USE ONLY

Prostaglandin Analogue For Cattle

Equivalent to 250 mcg cloprostenol/mL

CAUTION: Federal (U.S.A.) law restricts this drug to use by or on the order of a licensed veterinarian.

DESCRIPTION:

Estroplan (cloprostenol sodium) injection is a synthetic prostaglandin analogue structurally related to prostaglandin F2α (PGF2α). Each mL of the colorless aqueous solution contains 263 mcg of cloprostenol sodium (equivalent to 250 mcg of cloprostenol), chlorocresol 1.0 mg as a bactericide, citric acid anhydrous 0.66 mg, sodium citrate 5.03 mg, sodium chloride 6.76 mg. The pH is adjusted, as necessary, with sodium hydroxide or citric acid.

ACTION:

Estroplan injection causes functional and morphological regression of the corpus luteum (luteolysis) in cattle. In normal, nonpregnant cycling animals this effect on the life span of the corpus luteum usually results in estrus 2 to 5 days after treatment. In animals with prolonged luteal function (pyometra, mummified fetus, and luteal cysts) the induced luteolysis usually results in resolution of the condition and return to cyclicity. Pregnant animals may abort depending on the stage of gestation.

INDICATIONS:

For intramuscular use to induce luteolysis in beef and dairy cattle. The luteolytic action of Estroplan injection can be utilized to manipulate the estrous cycle to better fit certain management practices, to terminate pregnancies resulting from mismatings and to treat certain conditions associated with prolonged luteal function.

RECOMMENDED USES:

Unobserved or Non-detected Estrus

Cows which are not detected in estrus, although ovarian cyclicity continues, can be treated with Estroplan if a mature corpus luteum is present. Estrus is expected to occur 2 to 5 days following injection, at which time animals may be inseminated. Treated cattle should be inseminated at the usual time following detection of estrus. If estrus detection is not desirable or possible, treated animals may be inseminated twice at about 72 and 96 hours post injection.

Pyometra Or Chronic Endometritis

Damage to the reproductive tract at calving or post partum retention of the placenta often leads to infection and inflammation of the uterus (endometritis). Under certain circumstances, this may progress into chronic endometritis with the uterus becoming distended with purulent matter. This condition, commonly referred to as pyometra, is characterized by a lack of cyclical estrus behavior and the presence of a persistent corpus luteum. Induction of luteolysis with Estroplan usually results in evacuation of the uterus and a return to normal cyclical activity within 14 days after treatment. After 14 days post treatment, recovery rate of treated animals will not be different than that of untreated cattle.

Mummified Fetus

Death of the conceptus during gestation may be followed by its degeneration and dehydration. Induction of luteolysis with Estroplan usually results in expulsion of the mummified fetus from the uterus. (Manual assistance may be necessary to remove the fetus from the vagina.) Normal cyclical activity usually follows.

Luteal Cysts

A cow may be noncyclic due to the presence of a luteal cyst (a single, anovulatory follicle with a thickened wall which is accompanied by no external signs and by no changes in palpable consistency of the uterus). Treatment with Estroplan can restore normal ovarian activity by causing regression of the luteal cyst.

Pregnancies From Mismating

Unwanted pregnancies can be safely and efficiently terminated from 1 week after mating until about five months of gestation. The induced abortion is normally uncomplicated and the fetus and placenta are usually expelled about four to five days after the injection with the reproductive tract returning to normal soon after the abortion. The ability of Estroplan to induce abortion decreases beyond the fifth month of gestation while the risk of dystocia and its consequences increases. Estroplan has not been sufficiently tested under feedlot conditions; therefore recommendations cannot be made for its use in heifers placed in feedlots.

Controlled Breeding

The luteolytic action of Estroplan can be utilized to schedule estrus and ovulation for an individual cycling animal or a group of animals. This allows control of the time at which cycling cows or heifers can be bred. Estroplan can be incorporated into a controlled breeding program by the following methods:

1. Single Estroplan Injection

Only animals with a mature corpus luteum should be treated to obtain maximum response to the single injection. However, not all cycling cattle should be treated since a mature corpus luteum is present for only 11 to 12 days of the 21-day cycle.

Prior to treatment, cattle should be examined rectally and found to be anatomically normal, be non-pregnant and have a mature corpus luteum. If these criteria are met, estrus is expected to occur two to five days following injection, at which time animals may be inseminated. Treated cattle should be inseminated at the usual time following detection of estrus. If estrus detection is not desirable or possible, treated animals may be inseminated either once at about 72 hours or twice at about 72 and 96 hours post injection.

With a single injection program, it may be desirable to assess the cyclicity status of the herd before Estroplan treatment. This can be accomplished by heat detecting and breeding at the usual time following detection of estrus for a 6-day period, all prior to injection. If by the sixth day the cyclicity status appears normal (approximately 25 - 30% detected in estrus), all cattle not already inseminated should be palpated for normality, non-pregnancy, and cyclicity, then injected with Estroplan. Breeding should then be continued at the usual time following signs of estrus on the seventh and eighth day. On the ninth and tenth day breeding may continue at the usual time following detection of estrus or all cattle not already inseminated may be bred either once on the ninth day (at about 72 hours post injection) or on both the ninth and tenth day (at about 72 and 96 hours post injection).

2. Double Estroplan Injections

Prior to treatment, cattle should be examined rectally and found to be anatomically normal, non-pregnant, and cycling (the presence of a mature corpus luteum is not necessary when the first injection of a double injection regimen is given). A second injection should be given 11 days after the first injection. In normal, cycling cattle, estrus is expected 2 to 5 days following the second injection. Treated cattle should be inseminated at the usual time following detection of estrus. If estrus detection is not desirable or possible, treated animals may be inseminated either once at about 72 hours or twice at about 72 and 96 hours following the second Estroplan injection.

Many animals will come into estrus following the first injection; these animals can be inseminated at the usual time following detected estrus. Animals not inseminated should receive a second injection 11 days after the first injection. Animals receiving both injections may be inseminated at the usual time following detection of estrus or may be inseminated either once at about 72 hours or twice at about 72 and 96 hours post second injection.

Any controlled breeding program recommended should be completed by either:

-    Observing animals (especially during the third week after injection) and inseminating or hand mating any animals returning to estrus,

or

-    Turning in clean-up bull(s) 5 to 7 days after the last injection of Estroplan to cover any animals returning to estrus.

REQUIREMENTS FOR CONTROLLED BREEDING PROGRAMS:

A variety of programs can be designed to best meet the needs of individual management systems. A controlled breeding program should be selected which is appropriate for the existing circumstances and management practices.

Before a controlled breeding program is planned the producer’s objectives must be examined and he must be made aware of the projected results and limitations. The producer and his consulting veterinarian should review the operation’s breeding history, herd health and nutritional status and agree that a controlled breeding program is practical in the producer’s specific situation. For any successful controlled breeding program:

- cows and heifers must be normal, nonpregnant, and cycling (rectal palpation should be performed).

- cattle must be in a fit and thrifty breeding condition and on an adequate or increasing plane of nutrition.

- proper program planning and record keeping are essential.

- if artificial insemination is being used it must be performed by competent inseminators using high quality semen.

It is important to understand that Estroplan is effective only in animals with a mature corpus luteum (ovulation must have occurred at least 5 days prior to treatment). This must be considered when breeding is intended following a single Estroplan injection.

SAFETY AND TOXICITY:

At 50 and 100 times the recommended dose, mild side effects may be detected in some cattle. These include increased uneasiness, slight frothing, and milk let-down.

CONTRAINDICATIONS:

Estroplan should not be administered to a pregnant animal whose calf is not to be aborted.

WARNINGS:

For animal use only.

Women of child-bearing age, asthmatics, and persons with bronchial and other respiratory problems should exercise extreme caution when handling this product. In the early stages women may be unaware of their pregnancies.

Estroplan injection is readily absorbed through the skin and may cause abortion and/or bronchospasms: direct contact with the skin should therefore be avoided. Accidental spillage on the skin should be washed off immediately with soap and water.

For a copy of the Material Safety Data Sheet (MSDS) call 1.800.542.8916.

To report adverse reactions call AgriLabs at 1.800.542.8916.

PRECAUTIONS:

There is no effect on fertility following the single or double dosage regimen when breeding occurs at induced estrus or at 72 and 96 hours post treatment. Conception rates may be lower than expected in those fixed time breeding programs which omit the second insemination (i.e. the insemination at or near 96 hours). This is especially true if a fixed time insemination is used following a single Estroplan injection.

As with all parenteral products, careful aseptic techniques should be employed to decrease the possibility of post injection bacterial infection. Antibiotic therapy should be employed at the first sign of infection.

DOSAGE AND ADMINISTRATION:

2mL of Estroplan injection (500 mcg of cloprostenol) should be administered by INTRAMUSCULAR INJECTION for all indications in both beef and dairy cattle.

STORAGE CONDITIONS:

1. Protect from light.

2. Store in carton.

3. Store at controlled room temperature 20°-25°C (68°-77°F).

HOW SUPPLIED:

20 mL and 100 mL multidose vials

ANADA 200-310, approved by FDA

Made in Australia

Manufactured by:

Parnell Technologies Pty Ltd

4/476 Gardeners Road

Alexandria NSW 2015 Australia

Owner of the trademark Estroplan

Distributed by:

Agri Laboratories, Ltd.

P.O. BOX 3103 St. Joseph, MO 64503

1.800.542.8916

www.agrilabs.com

PRINCIPAL DISPLAY PANEL - 20 mL Vial

Estroplan

(cloprostenol sodium)

injection

Equivalent to 250 mcg cloprostenol/mL

CAUTION: Federal (U.S.A.) law restricts this drug to use by or on the order of a licensed veterinarian.

20 mL 10 doses

ANADA 200-310, Approved by FDA

Made in Australia

Distributed by: AgriLabs

Manufactured by: Parnell

Principal Display Panel - 20 mL Carton

Estroplan

(cloprostenol sodium)

injection

An analogue of prostagandin F2α for intramuscular injection in beef and dairy cattle.

Equivalent to 250 mcg cloprostenol/mL

CAUTION: Federal (U.S.A.) law restricts this drug to use by or on the order of a licensed veterinarian.

FOR ANIMAL USE ONLY

20 mL 10 doses

ANADA 200-310, Approved by FDA

Distributed by: AgriLabs

Manufactured by: Parnell

Made in Australia

Principal Display Panel - 100 mL Vial

Estroplan

(cloprostenol sodium)

injection

NDC 57561-009-02

Equivalent to 250 mcg cloprostenol/mL

CAUTION: Federal (U.S.A.) law restricts this drug to use by or on the order of a licensed veterinarian.

100 mL 50 doses

ANADA 200-310, Approved by FDA

Made in Australia

Distributed by: AgriLabs

Manufactured by: Parnell

Principal Display Panel - 100 mL Carton

Estroplan

(cloprostenol sodium)

injection

NDC 57561-009-02

An analogue of prostagandin F2α for intramuscular injection in beef and dairy cattle.

Equivalent to 250 mcg cloprostenol/mL

CAUTION: Federal (U.S.A.) law restricts this drug to use by or on the order of a licensed veterinarian.

FOR ANIMAL USE ONLY

100 mL 50 doses

ANADA 200-310, Approved by FDA

Distributed by: AgriLabs

Manufactured by: Parnell

Made in Australia

Estroplan  cloprostenol sodium  injection, solution

Product Information Product Type PRESCRIPTION ANIMAL DRUG NDC Product Code (Source) 57561-009 Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength cloprostenol sodium (cloprostenol) cloprostenol 250 ug  in 1 mL

Inactive Ingredients Ingredient Name Strength chlorocresol 1 mg  in 1 mL citric acid anhydrous 0.66 mg  in 1 mL sodium citrate 5.03 mg  in 1 mL sodium chloride 6.76 mg  in 1 mL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 57561-009-01 1 VIAL In 1 CARTON contains a VIAL, MULTI-DOSE 1 20 mL In 1 VIAL, MULTI-DOSE This package is contained within the CARTON (57561-009-01) 2 57561-009-02 1 VIAL In 1 CARTON contains a VIAL, MULTI-DOSE 2 100 mL In 1 VIAL, MULTI-DOSE This package is contained within the CARTON (57561-009-02)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANADA	ANADA200310	04/13/2010

Labeler - Agri Laboratories, Ltd. (155594450)

Revised: 04/2010Agri Laboratories, Ltd.

Methotrexate Injection 100mg / ml

1. Name Of The Medicinal Product

Methotrexate Injection 100mg/ml.

2. Qualitative And Quantitative Composition

Active Constituent
Methotrexate	BP.		100mg
Other Constituents
Sodium Hydroxide	BP	QS
Water for Injections	BP	to	1.0ml

There is a 5 % manufacturing overage included in the formulation.

3. Pharmaceutical Form

Sterile solution of Methotrexate in Water for Injections.

4. Clinical Particulars

4.1 Therapeutic Indications

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

Methotrexate Injection B.P. may be given by the intramuscular, intravenous, intra-arterial, intrathecal routes.

NOTE : Methotrexate Injection B.P 1g in 10ml and 5g in 50ml are hypertonic and therefore are not suitable for intrathecal use. The 500mg in 20ml should not be administered by the intrathecal route.

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.

Note: Methotrexate Injection B.P, 1g in 10ml and 5g in 50ml are hypertonic and thus it is not recommended for intrathecal use.

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 hours 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 dosage 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.

NOTE : Methotrexate Injection B.P 1g in 10ml and 5g in 50ml are not recommended for intrathecal use and the 500mg in 20ml is not recommended for intrathecal use.

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, and 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.

Because of 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.

Because of 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.

PRECAUTIONS

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
Sodium Hydroxide	BP	QS
Water for Injections	BP	to	1.0ml

There is a 5 % manufacturing 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

30 months

6.4 Special Precautions For Storage

Store below 25°C. Protect from light and freezing.

Unused portions of opened vials or prepared infusions if not used immediately must be stored at 2-8°C for no longer than 24 hours from the time of opening or preparation.

6.5 Nature And Contents Of Container

Conventional Glass Vials (1g/10ml and 5g/50ml):

Type I glass vial, 10ml, 20mm, 1704 rubber closure, aluminium seal with plastic 'flip-off' top in single vial packs.

Type I glass vial, 50ml, 20mm, 1704 rubber closure, aluminium seal with plastic 'flip-off' top in single vial packs.

Onco-Tain^TM Vials (1g/10ml and 5g/50ml):

Clear Type I Onco-Tain^TM vial, 10ml, 20mm, 1704 rubber closure, aluminium seal with plastic 'flip-off' top in single vial packs.

Clear Type I Onco-Tain^TM vial, 50ml, 20mm, 1704 rubber closure, aluminium seal with plastic 'flip-off' top in single vial packs.

Shell Glass Vials (1g/10ml and 5g/50ml):

Clear Type I shell glass vial, 10ml, 15mm, west type 4405/50 rubber closure in single vial packs.

Clear Type I shell glass vial, 50ml, 27mm, west type 4405/50 rubber closure in single vial packs.

Not all presentations and pack sizes listed above may be marketed.

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 04515/0038

9. Date Of First Authorisation/Renewal Of The Authorisation

13^th March 1987/7^th June 1994

10. Date Of Revision Of The Text

12^th July 2000

Actigall

Generic Name: ursodiol (Oral route)

ur-soe-DYE-ol

Commonly used brand name(s)

In the U.S.

• Actigall


• Urso


• Urso 250


• Urso Forte

Available Dosage Forms:

• Tablet


• Capsule

Therapeutic Class: Gastrointestinal Agent

Pharmacologic Class: Bile Acid

Uses For Actigall

Ursodiol is used in the treatment of gallstone disease. It is taken by mouth to dissolve the gallstones.

Ursodiol is used in patients with gallstones who do not need to have their gallbladders removed or in those in whom surgery should be avoided because of other medical problems. However, ursodiol works only in those patients whose gallstones are made of cholesterol and works best when these stones are small and of the “floating” type.

Ursodiol is also used to help prevent gallstones in patients who are on rapid weight-loss programs.

Ursodiol is also used in patients with cirrhosis of the liver. Cirrhosis causes a patient's liver to have problems and not work properly.

Ursodiol is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, ursodiol is used in certain patients with the following medical conditions:

• Chronic liver disease


• Liver transplant (to help reduce the risk of rejection)

Before Using Actigall

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

Allergies

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

Pediatric

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

Geriatric

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

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

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

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

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

• Ascites (accumulation of fluid in the abdominal cavity) or


• Bleeding varices (veins that enlarge and bleed) or


• Hepatic encephalopathy (brain disease due to liver failure) or


• Liver damage (from not having a certain chemical in your liver to break down a substance called lithocholate) or


• Liver problems—May make these conditions worse .

• Biliary tract problems or


• Pancreatitis (inflammation of pancreas)—These conditions may make it necessary to have surgery since treatment with ursodiol would take too long.

Proper Use of ursodiol

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

Take ursodiol with meals for best results, unless otherwise directed by your doctor.

Take ursodiol for the full time of treatment, even if you begin to feel better. If you stop taking this medicine too soon, the gallstones may not dissolve as fast or may not dissolve at all.

It is thought that body weight and the kind of diet the patient follows may affect how fast the stones dissolve and whether new stones will form. However, check with your doctor before going on any diet.

Ursodiol forte tablet can be broken in halves to provide recommended dosage. To break the tablet easily, place the tablet on a flat surface with the scored section on top. Hold the tablet with your thumbs placed close to the groove then apply gentle pressure until it breaks apart. Swallow each segment with water. Do not chew .

Half-tablets can be used for up to 28 days when kept in the medicine bottle. Due to the bitter taste, segments should be stored separately .

Dosing

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

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

• For oral dosage form (capsules or tablets):
  
  • For gallstone disease:
    
    • Adults and children 12 years of age and older—The dose is based on body weight and must be determined by your doctor. The usual dose is 8 to 10 milligrams (mg) per kilogram (kg) (3.6 to 4.5 mg per pound) of body weight a day, divided into two or three doses. Each dose is usually taken with a meal.
    
    
    • Children up to 12 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  • For prevention of gallstones during rapid weight loss:
    
    • Adults—Oral, 300 mg two times a day.
    
    
    • Children up to 12 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  • For cirrhosis of the liver:
    
    • Adults—The dose is based on body weight and must be determined by your doctor. The usual dose is 13 to 15 milligrams (mg) per kilogram (kg) (5.85 to 6.75 mg per pound) of body weight a day, divided into two to four doses. Each dose should be taken with a meal.
    
    
    • Children up to 12 years of age—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

Call your doctor or pharmacist for instructions.

If you miss a dose of this medicine, take it as soon as possible or double your next dose.

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

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

Precautions While Using Actigall

It is important that your doctor check your progress at regular visits. Laboratory tests will have to be done every few months while you are taking this medicine to make sure that the gallstones are dissolving and your liver is working properly.

Do not take aluminum-containing antacids (e.g., ALternaGEL®, Maalox®), cholestyramine (Questran®), colestipol (Colestid®), clofibrate (Atromid-S®), or estrogen or birth control pills while taking ursodiol. To do so may keep ursodiol from working properly. Before using these medicines, check with your doctor first .

Check with your doctor immediately if severe abdominal or stomach pain, especially toward the upper right side, or severe nausea and vomiting occur. These symptoms may mean that you have other medical problems or that your gallstone condition needs your doctor's attention.

Actigall Side Effects

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

Check with your doctor as soon as possible if any of the following side effects occur:

More common

• Bladder pain


• bloody or cloudy urine


• difficult, burning, or painful urination


• dizziness


• fast heartbeat


• frequent urge to urinate


• indigestion


• lower back or side pain


• severe nausea


• shortness of breath


• skin rash or itching over the entire body


• stomach pain


• vomiting


• weakness


• wheezing

Less common

• Black, tarry stools


• blood in vomit


• chest pain


• chills


• cough


• fever


• painful or difficult urination


• severe or continuing stomach pain


• sore throat


• sores, ulcers, or white spots on lips or in mouth


• swollen glands


• unusual bleeding or bruising


• unusual tiredness or weakness

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

• Diarrhea

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

More common

• Back pain


• body aches or pain


• congestion


• constipation


• cough producing mucus


• difficulty in breathing


• dryness or soreness of throat


• ear congestion


• general feeling of discomfort or illness


• hair loss


• headache


• heartburn


• loss of appetite


• loss of voice


• muscle aches and pains


• muscle or bone pain


• muscle stiffness


• nasal congestion


• nausea


• pain, swelling, or redness in joints


• runny nose


• shivering


• sneezing


• sweating


• tightness in chest


• trouble in swallowing


• trouble sleeping


• voice changes

Less common or rare

• Worsening psoriasis

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

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

See also: Actigall side effects (in more detail)

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

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

More Actigall resources

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

• Actigall Concise Consumer Information (Cerner Multum)


• Actigall Prescribing Information (FDA)


• Actigall MedFacts Consumer Leaflet (Wolters Kluwer)


• Ursodiol Prescribing Information (FDA)


• Ursodiol Professional Patient Advice (Wolters Kluwer)


• Ursodiol Monograph (AHFS DI)


• Urso Prescribing Information (FDA)

Compare Actigall with other medications

• Biliary Cirrhosis
• Gallbladder Disease
• Nonalcoholic Fatty Liver Disease

Nalex-A

Generic Name: chlorpheniramine, phenyltoloxamine, and phenylephrine (klor fen IR a meen/fen ill toe LOX a meen/fen ill EFF rin)

Brand Names: C-Hist-SR, Chlortox, Comhist, Linhist-L.A., Nalex-A

What is Nalex-A (chlorpheniramine, phenyltoloxamine, and phenylephrine)?

Chlorpheniramine and phenyltoloxamine are antihistamines. They block the effects of the naturally occurring chemical histamine in the body. Chlorpheniramine and phenyltoloxamine prevent sneezing; itchy, watery eyes and nose; and other symptoms of allergies and hay fever.

Phenylephrine is a decongestant. It constricts (shrinks) blood vessels (veins and arteries). This reduces the blood flow to certain areas and allows nasal passages to open up.

Chlorpheniramine, phenyltoloxamine, and phenylephrine is used to treat nasal congestion and sinusitis (inflammation of the sinuses) associated with allergies, hay fever, and the common cold.

Chlorpheniramine, phenyltoloxamine, and phenylephrine may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Nalex-A (chlorpheniramine, phenyltoloxamine, and phenylephrine)?

Use caution when driving, operating machinery, or performing other hazardous activities. Chlorpheniramine, phenyltoloxamine, and phenylephrine may cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities. Use alcohol cautiously. Alcohol may increase drowsiness and dizziness while taking chlorpheniramine, phenyltoloxamine, and phenylephrine.

Do not take more of this medication than is recommended. If your symptoms do not improve, or if they worsen, talk to your doctor.

Who should not take Nalex-A (chlorpheniramine, phenyltoloxamine, and phenylephrine)?

Do not take chlorpheniramine, phenyltoloxamine, and phenylephrine if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Before taking this medication, tell your doctor if you have

• kidney disease,


• liver disease,


• 
  

  diabetes,

  
  


• 
  

  glaucoma,

  
  


• 
  

  heart disease or high blood pressure,

  
  


• 
  

  thyroid disease,

  
  


• 
  

  emphysema or chronic bronchitis, or

  
  


• 
  

  difficulty urinating or an enlarged prostate.

  
  

You may not be able to take chlorpheniramine, phenyltoloxamine, and phenylephrine, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

Chlorpheniramine, phenyltoloxamine, and phenylephrine is in the FDA pregnancy category B. This means that it is unlikely to harm an unborn baby. Do not take this medication without first talking to your doctor if you are pregnant. This medication passes into breast milk and may harm a nursing baby. Do not take this medication without first talking to your doctor if you are breast-feeding a baby. If you are over 60 years of age, you may be more likely to experience side effects from chlorpheniramine, phenyltoloxamine, and phenylephrine. You may require a lower dose of this medication. Read the package label for directions or consult your doctor or pharmacist before treating a child with this medication. Children are more susceptible than adults to the effects of medicines and may have unusual reactions.

How should I take Nalex-A (chlorpheniramine, phenyltoloxamine, and phenylephrine)?

Take chlorpheniramine, phenyltoloxamine, and phenylephrine exactly as directed. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water. Do not crush, chew, or break the long-acting or sustained-release forms of this medication. Swallow it whole. If you are unsure of the formulation of the medicine, ask your pharmacist for help.

If you cannot swallow the tablets or capsules, look for a liquid form of the medication.

Do not take more of this medication than is recommended. An overdose of this medication can cause serious harm.

Do not take chlorpheniramine, phenyltoloxamine, and phenylephrine for longer than 7 days in a row. If your symptoms do not improve, if they get worse, or if you have a fever, talk to your doctor.

Store chlorpheniramine, phenyltoloxamine, and phenylephrine at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take a double dose of this medication.

What happens if I overdose?

Seek emergency medical attention.

Symptoms of a chlorpheniramine, phenyltoloxamine, and phenylephrine overdose include a dry mouth, large pupils, flushing, nausea, and vomiting.

What should I avoid while taking Nalex-A (chlorpheniramine, phenyltoloxamine, and phenylephrine)?

Use caution when driving, operating machinery, or performing other hazardous activities. Chlorpheniramine, phenyltoloxamine, and phenylephrine may cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities. Use alcohol cautiously. Alcohol may increase drowsiness and dizziness while taking chlorpheniramine, phenyltoloxamine, and phenylephrine.

Chlorpheniramine, phenyltoloxamine, and phenylephrine may increase the effects of other drugs that cause drowsiness, including antidepressants, alcohol, other antihistamines, pain relievers, anxiety medicines, seizure medicines, and muscle relaxants. Dangerous sedation, dizziness, or drowsiness may occur if chlorpheniramine, phenyltoloxamine, and phenylephrine is taken with any of these medications.

Nalex-A (chlorpheniramine, phenyltoloxamine, and phenylephrine) side effects

Serious side effects are unlikely to occur. Stop taking chlorpheniramine, phenyltoloxamine, and phenylephrine and seek emergency medical attention if you experience an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives).

Other, less serious side effects may be more likely to occur. Continue to take chlorpheniramine, phenyltoloxamine, and phenylephrine and talk to your doctor or try another similar medication if you experience

• 
  

  dryness of the eyes, nose, and mouth;

  
  


• 
  

  drowsiness or dizziness;

  
  


• 
  

  blurred vision;

  
  


• 
  

  difficulty urinating; or

  
  


• 
  

  excitation in children.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Nalex-A (chlorpheniramine, phenyltoloxamine, and phenylephrine)?

Do not take chlorpheniramine, phenyltoloxamine, and phenylephrine if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Do not take other over-the-counter cough, cold, allergy, diet, pain, or sleep medications while taking chlorpheniramine, phenyltoloxamine, and phenylephrine without first talking to your pharmacist or doctor. Other medications may also contain chlorpheniramine, phenyltoloxamine, phenylephrine, or other similar drugs, and you may accidentally take too much of these medicines.

Chlorpheniramine, phenyltoloxamine, and phenylephrine may increase the effects of other drugs that cause drowsiness, including antidepressants, alcohol, other antihistamines, pain relievers, anxiety medicines, seizure medicines, and muscle relaxants. Dangerous sedation, dizziness, or drowsiness may occur if chlorpheniramine, phenyltoloxamine, and phenylephrine is taken with any of these medications.

Drugs other than those listed here may also interact with chlorpheniramine, phenyltoloxamine, and phenylephrine. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines, including herbal products.

More Nalex-A resources

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

• Nalex-A Controlled-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Comhist MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Nalex-A with other medications

• Cold Symptoms
• Nasal Congestion
• Sinus Symptoms

Where can I get more information?

• Your pharmacist has additional information about chlorpheniramine, phenyltoloxamine, and phenylephrine written for health professionals that you may read.

See also: Nalex-A side effects (in more detail)

Tilade

Generic Name: Nedocromil Sodium
Class: Mast-cell Stabilizers
ATC Class: R01AC07
VA Class: RE101
Chemical Name: 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano(3,2-g)quinoline-2,8-dicarboxylic acid disodium salt
Molecular Formula: C₁₉H₁₇NO₇•2Na
CAS Number: 69049-74-7

Introduction

Mast cell stabilizer; a pyranoquinoline dicarboxylic acid derivative.^{1 2 3 4 5 6 7 9 10 11 1 2 3 9 10 11}

Uses for Tilade

Asthma

Used as an adjunct in the overall management of mild to moderate bronchial asthma.^{1 2 3 4 5 9 10 11 a}

For prophylaxis only; not indicated for reversal of acute bronchospasm, including status asthmaticus.^{a 1 9 10} (See Acute Bronchospasm under Warnings.)

Tilade Dosage and Administration

General

• 
  

  Initially, administer concurrently with patient’s existing maintenance dosages of β-adrenergic agonists, theophylline, and/or corticosteroids.^{a 1 2 4 5} Once clinical response is observed and asthma adequately controlled, gradual reduction in concomitant therapy may be possible.^{a 1 2 4 5}

  
  

Administration

Oral Inhalation

Administer by oral inhalation using an oral aerosol inhaler.¹

Shake inhaler well before use.^{1 8} Actuate aerosol inhaler 3 times prior to the initial use or if it has not been used for >7 days.^a

Exhale slowly and completely, invert the inhaler, place the mouthpiece of the inhaler well into the mouth, and close the lips around it.⁸ Inhale slowly and deeply through the mouth while actuating the inhaler.⁸ Hold breath for 5–10 seconds, withdraw the mouthpiece, and exhale slowly.^{2 8}

Avoid spraying in eyes.^a

Clean inhaler twice weekly. Remove metal canister and cap and rinse plastic mouthpiece in hot running water. Allow to dry overnight in a warm place.^{a 8}

Optimal therapeutic effect is dependent upon administration at regular intervals, even during symptom-free periods.^a

Dosage

Available as nedocromil sodium, dosage expressed in terms of the salt.^{a 1}

The dose of nedocromil sodium is expressed as the amount delivered from the actuator of the inhaler per metered spray.^a

Oral inhalation aerosol delivers 2 mg from the valve and 1.75 mg from the actuator per metered spray.^a Each aerosol canister delivers ≥104 metered sprays.^{a 1}

Pediatric Patients

Asthma

Oral Inhalation

Children ≥6 years of age: 3.5 mg (2 inhalations) 4 times daily at regular intervals (14 mg/day).¹

Less frequent administration may be effective if asthma is well controlled at this dose (e.g., patients only need occasional β-agonist therapy and are not experiencing serious exacerbations).^a

Adults

Asthma

Oral Inhalation

3.5 mg (2 inhalations) 4 times daily at regular intervals (14 mg/day).¹

Less frequent administration may be effective if asthma is well controlled at this dose (e.g., patients only need occasional β-agonist therapy and are not experiencing serious exacerbations).^a

Prescribing Limits

Pediatric Patients

Asthma

Oral Inhalation

Children ≥6 years of age: Maximum 3.5 mg (2 inhalations) 4 times daily (14 mg/day).¹

Adults

Asthma

Oral Inhalation

Maximum 3.5 mg (2 inhalations) 4 times daily (14 mg/day).^{a 1}

Special Populations

No special population dosage recommendations at this time.^a

Cautions for Tilade

Contraindications

Known hypersensitivity to nedocromil or any ingredient in the formulation.^a

Warnings/Precautions

Warnings

Acute Bronchospasm

Nedocromil is not a bronchodilator; do not use for reversal of acute bronchospasm, especially status asthmaticus.^{1 9 10 a}

Use should generally be continued during acute exacerbations, unless patient becomes intolerant to use of inhaled dosage forms.^a

Bronchospasm, possibly life-threatening, may occur immediately after administration.^a If this occurs, discontinue nedocromil and institute alternative therapy.^a

General Precautions

Concomitant Corticosteroid Dosage

Role of nedocromil as a corticosteroid-sparing agent in patients receiving oral or inhaled corticosteroids not defined.^a Monitor patients closely if systemic or inhaled corticosteroids are reduced.^a

Specific Populations

Pregnancy

Category B.^a

Lactation

Not known if nedocromil is distributed into milk.^a Caution is advised if nedocromil is used.^a

Pediatric Use

Safety and efficacy not established in children <6 years of age.^a

Common Adverse Effects

Unpleasant taste, coughing, pharyngitis, rhinitis, upper respiratory infection, dyspnea, bronchospasm, sinusitis, nausea, vomiting, headache, chest pain, fever, viral infection.^a

Interactions for Tilade

No formal drug interaction studies to date.^a

Tilade Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is 8 and 17% for single and multiple inhaled doses, respectively.^a

Onset

Full therapeutic effect may not be obtained for ≥1 week.^a

Distribution

Plasma Protein Binding

89%.^a

Elimination

Elimination Route

Excreted principally in urine as unchanged drug.^a

Half-life

3.3 hours.^a

Special Populations

Pharmacokinetics in children 6–11 years of age appear similar to those in adults.^a

Stability

Storage

Oral Inhalation

Aerosol, Solution for Inhalation

2–30°C.^a Do not freeze.^a

Temperatures >120°F may cause aerosol canister to burst.^a

Actions

• 
  

  Inhibits acute bronchoconstrictor response and delayed inflammatory response.^{a 1 2 6 9 10 11}

  
  


• 
  

  In vitro, inhibits eosinophils, neutrophils, macrophages, mast cells, monocytes, platelets,^{a 1 2 3 9 10 11} histamine, leukotriene C₄, and prostaglandin D₂.^{a 1 2 3 5 6}

  
  


• 
  

  Inhibits bronchoconstriction caused by sulfur dioxide, inhaled neurokinin A, various antigens, exercise, cold air, fog, and adenosine monophosphate.^a

  
  


• 
  

  Exhibits no bronchodilator, antihistamine, or corticosteroid activity.^a

  
  


• 
  

  Exhibits cough suppression resulting from inhibition of neuronal reflexes in airways.^{2 6 9 10}

  
  

Advice to Patients

• 
  

  Importance of providing patient a copy of manufacturer’s patient information.^a

  
  


• 
  

  Importance of adequate understanding of proper storage, preparation, disposal, and inhalation technique.^a

  
  


• 
  

  Importance of adherence to dosing schedules, even during symptom-free periods, and of not changing dose unless otherwise instructed by a clinician.^a

  
  


• 
  

  Importance of notifying physician immediately if symptoms do not improve or condition worsens.^a

  
  


• 
  

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

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^a

  
  


• 
  

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

  
  

Preparations

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

Nedocromil Sodium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral Inhalation	Aerosol	1.75 mg/metered spray (from the mouthpiece)	Tilade Inhaler (with chlorofluorohydrocarbon propellants)	Monarch

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, 1959-2010, Selected Revisions May 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Aventis. Tilade (nedocromil sodium) inhalation aerosol prescribing information. Kansas City, MO; 1999 Oct.

2. Gonzalez JP, Brogden RN. Nedocromil sodium: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of reversible obstructive airways disease. Drugs. 1987; 34:560-77. [IDIS 236663] [PubMed 2826101]

3. Rebuck AS, Kesten S, Boulet LP et al. A 3-month evaluation of the efficacy of nedocromil sodium in asthma: a randomized, double-blind, placebo-controlled trial of nedocromil sodium conducted by a Canadian multicenter study group. J Allergy Clin Immunol. 1990; 85:612-7. [IDIS 314389] [PubMed 2155958]

4. Callaghan B, Teo NC, Clancy L. Effects of the addition of nedocromil sodium to maintenance bronchodilator therapy in the management of chronic asthma. Chest. 1992; 101:787-92. [IDIS 293018] [PubMed 1311666]

5. Cherniack RM, Wasserman SI, Ramsdell JW et al. A double-blind multicenter group comparative study of the efficacy and safety of nedocromil sodium in the management of asthma. Chest. 1990; 97:1299-1306. [IDIS 289144] [PubMed 2161328]

6. Tandon MK. Double-blind crossover study of nedocromil sodium in partially reversible chronic obstructive airways disease. Chest. 1993; 103:105-10. [IDIS 308235] [PubMed 8380266]

7. Morton AR, Ogle SL, Fitch KD. Effects of nedocromil sodium, cromolyn sodium, and a placebo in exercise-induced asthma. Ann Allergy. 1992; 68:143-8. [IDIS 292497] [PubMed 1310834]

8. Fisons. Tilade (nedocromil sodium) inhalation aerosol patient information. (undated)

9. Anon. Nedocromil for asthma. Med Lett Drugs Ther. 1993; 35:62-3. [PubMed 8390598]

10. Parish RC, Miller LJ. Nedocromil sodium. Ann Pharmacother. 1993; 27:599-606. [IDIS 314179] [PubMed 8394165]

11. Lal S, Dorow PD, Venho KK et al. Nedocromil sodium is more effective than cromolyn sodium for the treatment of chronic reversible obstructive airway disease. Chest. 1993; 104:438-47. [IDIS 319804] [PubMed 8393398]

12. Fisons Pharmaceuticals, Rochester, NY: Personal communication.

13. National Asthma Education and Prevention Program. Expert panel report II: guidelines for the diagnosis and management of asthma. 1997 Feb.

14. Kemp JP. Comprehensive asthma management: guidelines for clinicians. J Asthma. 1998; 35:601-20. [PubMed 9860081]

15. Kemp JP. Guidelines update: where do the new therapies fit in the management of asthma? Drugs. 2000; 59(Suppl 1):23-8.

a. King Pharmaceuticals. Tilade (nedocromil sodium) inhalation aerosol prescribing information. Bristol, TN; 2004 July.

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