Heparin Lock Flush Solution

Generic Name: heparin sodium

Dosage Form: injection, solution
Heparin Lock Flush Solution, USP

FOR MAINTENANCE OF PATENCY OF INTRAVENOUS INJECTION DEVICES ONLY.

NOT FOR ANTICOAGULANT THERAPY.

DERIVED FROM PORCINE INTESTINAL MUCOSA.

PRESERVATIVE FREE.

Heparin Lock Flush Solution Description

Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-α-D-glucose 6-sulfate, (3) ß-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose and (5) α-L-iduronic acid.  These sugars are present in decreasing amounts, usually in the order (2)> (1)> (4)> (3)> (5), and are joined by glycosidic linkages, forming polymers of varying sizes.  Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups.  In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions.

Heparin Lock Flush Solution, USP is a sterile preparation of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity, with sufficient sodium chloride to make it isotonic with blood.  The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. 

Structure of Heparin Sodium (representative subunits):

 

Each mL contains: 10 USP Units Heparin sodium (porcine); 9 mg sodium chloride; Water for Injection q.s.  Sodium hydroxide and/or hydrochloric acid for pH adjustment (5.0-7.5).

Each mL contains: 100 USP Units Heparin sodium (porcine); 9 mg sodium chloride; Water for Injection q.s.  Sodium hydroxide and/or hydrochloric acid for pH adjustment (5.0-7.5).

Heparin Lock Flush Solution - Clinical Pharmacology

Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo.  Heparin acts at multiple sites in the normal coagulation system.  Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin.  Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin.  Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor.

Bleeding time is usually unaffected by heparin.  Clotting time is prolonged by full therapeutic doses of heparin; in most cases it is not measurably affected by low doses of heparin.  Loglinear plots of heparin plasma concentrations with time, for a wide range of dose levels, are linear, which suggests the absence of zero order processes.  Liver and the reticulo-endothelial system are the sites of biotransformation.  The biphasic elimination curve, a rapidly declining alpha phase (t½= 10 minutes) and after the age of 40 a slower beta phase, indicates uptake in organs.  The absence of a relationship between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of heparin.

Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastine times (APTTs) compared with patients under 60 years of age.

Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

Indications and Usage for Heparin Lock Flush Solution

Heparin Lock Flush Solution, USP is intended to maintain patency of an indwelling venipuncture device designed for intermittent injection or infusion therapy or blood sampling.  Heparin Lock Flush Solution may be used following initial placement of the device in the vein, after each injection of a medication or after withdrawal of blood for laboratory tests (see DOSAGE AND ADMINISTRATION, Maintenance of Patency of IV Devices for directions for use).

Heparin Lock Flush Solution is not to be used for anticoagulant therapy.

Contraindications

Heparin sodium should NOT be used in patients with the following conditions: severe thrombocytopenia; an uncontrollable active bleeding state (see WARNINGS), except when this is due to disseminated intravascular coagulation.

Warnings

Heparin is not intended for intramuscular use.

Hypersensitivity

Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations (see Adverse Reactions, Hypersensitivity).

Hemorrhage

Hemorrhage can occur at virtually any site in patients receiving heparin.  An unexplained fall in hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious consideration of a hemorrhagic event.

Heparin sodium should be used with extreme caution in infants and in patients with disease states in which there is increased danger of hemorrhage.  Some of the conditions in which increased danger of hemorrhage exists are:

Cardiovascular–Subacute bacterial endocarditis, severe hypertension.

Surgical–During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord or eye.

Hematologic–Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras.

Gastrointestinal–Ulcerative lesions and continuous tube drainage of the stomach or small intestine.

Other–Menstruation, liver disease with impaired hemostasis.

Thrombocytopenia

Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of 0 to 30%.  Platelet counts should be obtained at baseline.  Mild thrombocytopenia (count greater than 100,000/mm3) may remain stable or reverse even if heparin is continued.  However, thrombocytopenia of any degree should be monitored closely.  If the count falls below 100,000/mm3 or if recurrent thrombosis develops (see Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis), the heparin product should be discontinued and, if necessary, an alternative anticoagulant administered.

Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT)

Heparin-induced Thrombocytopenia (HIT) is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets.  HIT may progress to the development of venous and arterial thromboses, a condition referred to as Heparin-induced Thrombocytopenia and Thrombosis (HITT).  Thrombotic events may also be the initial presentation for HITT.  These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death.  Thrombocytopenia of any degree should be monitored closely.  If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered if patients require continued anticoagulation.

Delayed Onset of HIT and HITT

Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis can occur up to several weeks after the discontinuation of heparin therapy.  Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT.

Use in Neonates

Preservative-Free Heparin Lock Flush Solution, USP should be used for maintaining the patency of intravenous injection devices in neonates.

Precautions

General

In infants, the cumulative amounts of heparin received from the frequent administration of Heparin Lock Flush Solution, USP during a 24- hour period should be considered.

Precautions must be exercised when drugs which are incompatible with heparin are administered through an indwelling intravenous catheter containing Heparin Lock Flush Solution, USP (see DOSAGE AND ADMINISTRATION, Maintenance of Patency of IV Devices).

Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT)

See WARNINGS.

Increased Risk to Older Patients, Especially Women–A higher incidence of bleeding has been reported in patients, particularly women over 60 years of age.

Laboratory Tests

Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin use (see DOSAGE AND ADMINISTRATION).

Drug Interactions

Platelet Inhibitors–Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium.

Other Interactions–Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of heparin.  Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility.

Pregnancy

Teratogenic Effects: Pregnancy Category C–

Animal reproduction studies have not been conducted with heparin sodium.  It is also not known whether heparin sodium can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.  Heparin sodium should be given to a pregnant woman only if clearly needed.

Nonteratogenic Effects–Heparin does not cross the placental barrier.

Nursing Mothers

Heparin is not excreted in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.  Not for use in neonates (see WARNINGS).

Geriatric Use

A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see PRECAUTIONS, General and CLINICAL PHARMACOLOGY).

Adverse Reactions

Hemorrhage

Hemorrhage is the chief complication that may result from heparin use (see WARNINGS).  An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug (see OVERDOSAGE).

Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT

See WARNINGS.

Local irritation and erythema have been reported with the use of Heparin Lock Flush Solution.

Hypersensitivity

Generalized hypersensitivity reactions have been reported, with chills, fever and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely.  Itching and burning, especially on the plantar side of the feet, may occur.

Thrombocytopenia has been reported to occur in patients receiving heparin, with a reported incidence of 0 to 30%.  While often mild and of no obvious clinical significance, such thrombocytopenia can be accompanied by severe thromboembolic complications such as skin necrosis, gangrene of the extremities that may lead to amputation, myocardial infarction, pulmonary embolism, stroke, and possibly death (see WARNINGS and PRECAUTIONS).

Certain episodes of painful, ischemic and cyanosed limbs have in the past been attributed to allergic vasospastic reactions.  Whether these are in fact identical to the thrombocytopenia-associated complications remains to be determined.

Overdosage

Symptoms

Bleeding is the chief sign of heparin overdosage.  Nosebleeds, blood in urine or tarry stools may be noted as the first sign of bleeding.  Easy bruising or petechial formations may precede frank bleeding.

Treatment - Neutralization of Heparin Effect

When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium.  No more than 50 mg should be administered, very slowly, in any 10 minute period.  Each mg of protamine sulfate neutralizes approximately 100 USP heparin units.  The amount of protamine required decreases over time as heparin is metabolized.  Although metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 1/2 hour after intravenous injection.

Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions.  Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available.

For additional information consult the labeling of Protamine Sulfate Injection, USP products.

DOSAGE AND ADMINISTRATION

Parental drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Slight discoloration does not alter potency.

Heparin Lock Flush Solution, USP is not recommended for use in the neonate (see WARNINGS).

Maintenance of Patency of IV Devices

To prevent clot formation in a heparin lock set or central venous catheter following its proper insertion, Heparin Lock Flush Solution, USP is injected via the injection hub in a quantity sufficient to fill the entire device.  This solution should be replaced each time the device is used.  Aspirate before administering any solution via the device in order to confirm patency and location of needle or catheter tip.  If the drug to be administered is incompatible with heparin, the entire device should be flushed with normal saline before and after the medication is administered; following the second saline flush, the Heparin Lock Flush Solution may be reinstilled into the device.  The device manufacturer’s instructions should be consulted for specifics concerning its use.  Usually this dilute heparin solution will maintain anticoagulation within the device for up to 4 hours.

NOTE:  Since repeated injections of small doses of heparin can alter tests for activated partial thromboplastin time (APTT), a baseline value for APTT should be obtained prior to insertion of a heparin lock set.

Withdrawal of Blood Samples

Heparin Lock Flush Solution may also be used after each withdrawal of blood for laboratory tests.  When heparin would interfere with or alter the results of blood tests, the heparin solution should be cleared from the device by aspirating and discarding it before withdrawing the blood sample.

HOW SUPPLIED

Product No.	NDC No.
504901	63323-549-01	Heparin Lock Flush Solution, USP, Preservative Free, 100 USP Units/mL, 1 mL fill, in a 3 mL flip-top, single dose plastic vial, in packages of 25.
505701	63323-557-01	Heparin Lock Flush Solution, USP, Preservative Free, 10 USP Units/mL, 1 mL fill, in a 3 mL flip-top, single dose plastic vial, in packages of 25.

Unused portion of the vial should be discarded.

Use only if solution is clear and seal intact.

STORAGE

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

REFERENCES

1. Tahata T, Shigehito M, Kusuhara K, Ueda Y, et al. Delayed-Onset of Heparin-Induced Thrombocytopenia – A Case Report – J Jpn Assn Torca Surg. 1992;40(3):110-111.


2. Warkentin T, Kelton J. Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis. Annals of Internal Medicine. 2001;135:502-506.


3. Rice L, Attisha W, Drexler A, Francis J. Delayed-Onset Heparin-Induced Thrombocytopenia.  Annals of Internal Medicine, 2002;136:210-215.


4. Dieck J., C. Rizo-Patron, et al. (1990). “A New Manifestation and Treatment Alternative for Heparin-Induced Thrombosis.” Chest 98(1524-26).


5. Smythe M, Stephens J, Mattson. Delayed-Onset Heparin-Induced Thrombocytopenia.  Annals of Emergency Medicine, 2005;45(4): 417-419.


6. Divgi A. (Reprint), Thumma S., Hari P., Friedman K. Delayed Onset Heparin-Induced Thrombocytopenia (HIT) Presenting After Undocumented Drug Exposure as Post-Angiography Pulmonary Embolism. Blood.  2003;102(11):127b.

For Product Inquiry: 1-800-551-7176

451198A

Issued: July 2010

PACKAGE LABEL - PRINCIPAL DISPLAY - Heparin Lock Flush Solution 1 mL Single Dose Vial Label

NDC 63323-549-01

504901

Heparin Lock Flush Solution, USP

100 USP Units/mL

(Derived from Porcine Intestinal Mucosa)

Preservative Free                 Rx only

1 mL Single Dose Vial

PACKAGE LABEL - PRINCIPAL DISPLAY - Heparin Lock Flush Solution 1 mL Single Dose Vial Tray Label

NDC 63323-549-01

504901

Heparin Lock Flush Solution, USP

100 USP Units/mL

(Derived from Porcine Intestinal Mucosa)

1 mL Single Dose Vial

Rx only

PACKAGE LABEL - PRINCIPAL DISPLAY - Heparin Lock Flush Solution 1 mL Single Dose Vial

NDC 63323-557-01

505701

Heparin Lock Flush Solution, USP

10 USP Units/mL

(Derived from Porcine Intestinal Mucosa)

Preservative Free                 Rx only

1 mL Single Dose Vial

PACKAGE LABEL - PRINCIPAL DISPLAY - Heparin Lock Flush Solution 1 mL Single Dose Vial Tray Label

NDC 63323-557-01

505701

Heparin Lock Flush Solution, USP

10 USP Units/mL

(Derived from Porcine Intestinal Mucosa)

1 mL Single Dose Vial

Rx only

HEPARIN LOCK FLUSH  heparin sodium  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 63323-557 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (HEPARIN) HEPARIN SODIUM 10 [USP'U]  in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE 9 mg  in 1 mL SODIUM HYDROXIDE   HYDROCHLORIC ACID

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 63323-557-01 25 VIAL In 1 BOX contains a VIAL 1 1 mL In 1 VIAL This package is contained within the BOX (63323-557-01)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Premarket Notification	K092938	08/29/2009

HEPARIN LOCK FLUSH  heparin sodium  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 63323-549 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (HEPARIN) HEPARIN SODIUM 100 [USP'U]  in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE 9 mg  in 1 mL HYDROCHLORIC ACID   SODIUM HYDROXIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 63323-549-01 25 VIAL In 1 TRAY contains a VIAL 1 1 mL In 1 VIAL This package is contained within the TRAY (63323-549-01)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Premarket Notification	K092938	08/12/2009

Labeler - APP Pharmaceuticals, LLC (608775388)

Establishment
Name	Address	ID/FEI	Operations
APP Pharmaceuticals, LLC		840771732	MANUFACTURE

Revised: 12/2010APP Pharmaceuticals, LLC

More Heparin Lock Flush Solution resources

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• Heparin Lock Flush Solution Use in Pregnancy & Breastfeeding
• Heparin Lock Flush Solution Drug Interactions
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Flixonase Allergy Nasal Spray

1. Name Of The Medicinal Product

Flixonase Allergy Nasal Spray

2. Qualitative And Quantitative Composition

Aqueous suspension of 0.05% micronised fluticasone propionate. Each actuation contains 50 micrograms of fluticasone propionate.

3. Pharmaceutical Form

Nasal spray, suspension.

4. Clinical Particulars

4.1 Therapeutic Indications

Flixonase Allergy Nasal Spray is indicated for the prophylaxis and treatment of allergic rhinitis including hay fever and that caused by other airborne allergens such as house dust mite and animal dander.

Flixonase Allergy Nasal Spray provides symptomatic relief of sneezing, itchy and runny nose, itchy and watery eyes, nasal congestion and associated sinus discomfort.

4.2 Posology And Method Of Administration

Flixonase Allergy Nasal Spray is for administration by the intranasal route only.

Adults aged 18 years and over: For the prophylaxis and treatment of allergic rhinitis: -

Two sprays into each nostril once a day, preferably in the morning. In some cases two sprays into each nostril twice daily may be required. Once symptoms are under control a maintenance dose of one spray per nostril once a day may be used. If symptoms recur the dosage may be increased accordingly. The minimum dose at which effective control of symptoms is maintained should be used.

The maximum daily dose should not exceed four sprays into each nostril.

Elderly:-

The normal adult dosage is applicable.

Children under 18 years of age: Should not be used by children and adolescents under 18 years of age.

Prophylaxis of allergic rhinitis requires treatment before contact with allergen. For full therapeutic benefit regular usage is recommended.

Maximum benefit may require 3-4 days of continuous treatment in some people (see section 5.1, Pharmacodynamic Properties).

Shake gently before use.

Before use the bottle needs to be primed by pumping until a fine spray is produced.

4.3 Contraindications

Hypersensitivity to fluticasone propionate or any other of the ingredients.

4.4 Special Warnings And Precautions For Use

Treatment should be stopped or the advice of a doctor sought if an improvement is not seen within 7 days. The advice of a doctor or pharmacist should also be sought if symptoms have improved but are not adequately controlled.

Flixonase Allergy Nasal Spray should not be used for more than 3 months continuously without consulting a doctor.

Medical advice should be sought before using Flixonase Allergy Nasal Spray in the case of;

• concomitant use of other corticosteroid products, such as tablets, creams, ointments, asthma medications, similar nasal sprays or eye/nose drops

• an infection in the nasal passages or sinuses.

• recent injury or surgery to the nose, or problems with ulceration in the nose.

Treatment with higher than recommended doses of nasal corticosteroids may result in clinically significant adrenal suppression. If there is evidence of higher than recommended doses being used then additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Significant interactions between fluticasone propionate and potent inhibitors of the cytochrome P450 3A4 system, e.g. ketoconazole and protease inhibitors, such as ritonavir, may occur. This may result in increased systemic exposure to fluticasone propionate.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of fluticasone propionate on other drugs

Drug interaction studies have shown no significant effect of fluticasone propionate on the pharmacokinetics of terfenadine and erythromycin.

Effects of other drugs on fluticasone propionate

Drug interaction studies have shown no significant effect of terfenadine and erythromycin on the pharmacokinetics of fluticasone propionate.

The use of fluticasone propionate in patients taking concurrent drugs which are potent inhibitors of the cytochrome P450 3A4 system, e.g. ketoconazole and protease inhibitors such as ritonavir may be associated with increased systemic exposure to fluticasone propionate. There have been reports of suppression of the hypothalamic-pituitary-adrenal axis in patients receiving fluticasone propionate with ritonavir. (See 4.4 Special Warnings and Precautions for Use).

4.6 Pregnancy And Lactation

There is inadequate evidence of the safety of fluticasone propionate in human pregnancy. Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development, including cleft palate and intra-uterine growth retardation. There may therefore be a very small risk of such effects in the human foetus. It should be noted however that the foetal changes in animals occur after relatively high systemic exposure; direct intranasal application ensures minimal systemic exposure. As with other drugs the use of Flixonase Allergy Nasal Spray during human pregnancy requires that the possible benefits of the drug be weighed against the possible hazards.

The secretion of fluticasone propionate in human breast milk has not been investigated. Subcutaneous administration of fluticasone propionate to lactating laboratory rats produced measurable plasma levels and evidence of fluticasone propionate in milk. However, following intranasal administration to primates, no drug was detected in the plasma, and it is therefore unlikely that the drug would be detectable in milk. When Flixonase Allergy Nasal Spray is used in breast feeding mothers the therapeutic benefits must be weighed against the potential hazards to mother and baby.

The label will include a warning that medical opinion should be sought, before using Flixonase Allergy Nasal Spray, in the case of pregnancy or breast feeding.

4.7 Effects On Ability To Drive And Use Machines

None reported.

4.8 Undesirable Effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/10,000 and <1/1000) and very rare (<1/10,000) including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. Rare and very rare events were generally determined from spontaneous data. In assigning adverse event frequencies, the background rates in placebo groups were not taken into account.

System Organ Class	Adverse Event	Frequency
Immune system disorders	Hypersensitivity reactions, anaphylaxis/anaphylactic reactions, bronchospasm, skin rash, oedema of the face or tongue	Very rare
Nervous system, disorders	Headache, unpleasant taste, unpleasant smell	Common
Eye disorders	Glaucoma, raised intraocular pressure, cataract	Very rare
Respiratory, thoracic and mediastinal disorders	Epistaxis	Very common
Nasal dryness, nasal irritation, throat dryness, throat irritation	Common
Nasal septal perforation	Very rare

As with other nasal sprays, dryness and irritation of the nose and throat, unpleasant taste and smell, headache and epistaxis have been reported.

Nasal ulceration and nasal septal perforation have been reported following the use of intranasal corticosteroids, usually when there has been previous nasal surgery.

Systemic effects of nasal corticosteroids may occur, particularly when prescribed at high doses for prolonged periods.

4.9 Overdose

There are no data available on the effects of acute or chronic overdosage with Flixonase Allergy Nasal Spray. Intranasal administration of fluticasone propionate at 20 times the recommended starting dose in adults (2mg twice daily) for seven days to healthy human volunteers had no effect on hypothalamic-pituitary-adrenal axis function.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Fluticasone propionate is a glucocorticosteroid which has potent anti-inflammatory activity by acting via the glucocorticoid receptor. However, when used at up to four times the recommended daily dose on the nasal mucosa, has no detectable systemic activity and causes little or no hypothalamic pituitary adrenal (HPA) axis suppression. Following intranasal dosing of fluticasone propionate, (200 micrograms/day) no significant change in 24h serum cortisol AUC was found compared to placebo (ratio 1.01, 90%CI 0.9-1.14).

Fluticasone propionate has been shown to reduce inflammatory mediators in both the early and late phase reactions of allergic rhinitis.

Once daily dosing with 200μg fluticasone propionate is sufficient to help relieve symptoms (particularly nasal congestion) for up to 24 hours.

5.2 Pharmacokinetic Properties

Absorption: Following intranasal dosing of fluticasone propionate, (200 micrograms/day) steady-state maximum plasma concentrations were not quantifiable in most subjects (<0.01ng/mL). The highest Cmax observed was 0.017ng/mL. Direct absorption in the nose is negligible due to the low aqueous solubility with the majority of the dose being eventually swallowed. When administered orally the systemic exposure is <1% due to poor absorption and pre-systemic metabolism. The total systemic absorption arising from both nasal and oral absorption of the swallowed dose is therefore negligible.

Distribution: Fluticasone propionate has a large volume of distribution at steady-state (approximately 318L). Plasma protein binding is moderately high (91%).

Metabolism: Fluticasone propionate is cleared rapidly from the systemic circulation, principally by hepatic metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Swallowed fluticasone propionate is also subject to extensive first pass metabolism. Care should be taken when co-administering potent CYP3A4 inhibitors such as ketoconazole and ritonavir as there is potential for increased systemic exposure to fluticasone propionate.

Elimination: The elimination rate of intravenous administered fluticasone propionate is linear over the 250

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included in the other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Dextrose (anhydrous)

Microcrystalline cellulose

Carboxymethylcellulose sodium Phenylethyl alcohol

Benzalkonium chloride

Polysorbate 80

Purified water

Dilute hydrochloric acid

6.2 Incompatibilities

None reported

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Do not store above 30°C.

6.5 Nature And Contents Of Container

Flixonase Allergy Nasal Spray is supplied in an amber glass bottle fitted with a metering pump and a nasal applicator.

Each bottle provides approximately 60 metered sprays.

6.6 Special Precautions For Disposal And Other Handling

No special instructions.

7. Marketing Authorisation Holder

Beecham Group Plc

980 Great West Road

Brentford

Middlesex

TW8 9GS

Trading as

GlaxoSmithKline Consumer Healthcare, Brentford, TW8 9GS, U.K.

8. Marketing Authorisation Number(S)

PL 00079/0616

9. Date Of First Authorisation/Renewal Of The Authorisation

14/08/2007

10. Date Of Revision Of The Text

11/09/2008

Insuman Bazal

Insuman Bazal may be available in the countries listed below.

Ingredient matches for Insuman Bazal

Insulin, Isophane

Insulin, Isophane human (a derivative of Insulin, Isophane) is reported as an ingredient of Insuman Bazal in the following countries:

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International Drug Name Search

Terconazole Cream

Pronunciation: ter-KON-a-zole
Generic Name: Terconazole
Brand Name: Terazol

Terconazole Cream is used for:

Treating vaginal yeast infections in women. It may also be used for certain conditions as determined by your doctor.

Terconazole Cream is an antifungal agent. It works by weakening the fungal cell membrane, thereby killing sensitive fungi that cause yeast infections.

Do NOT use Terconazole Cream if:

• you are allergic to any ingredient in Terconazole Cream

Contact your doctor or health care provider right away if any of these apply to you.

Before using Terconazole Cream:

Some medical conditions may interact with Terconazole Cream. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a history of liver disease

Some MEDICINES MAY INTERACT with Terconazole Cream. However, no specific interactions with Terconazole Cream are known at this time.

Ask your health care provider if Terconazole Cream may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Terconazole Cream:

Use Terconazole Cream as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Terconazole Cream. Talk to your pharmacist if you have questions about this information.


• Remove cap from tube. Reverse cap and place puncture tip onto tube. Push cap firmly until tube end is punctured.


• Screw applicator onto tube. Squeeze tube forcing contents into barrel until it is full.


• Then remove applicator from tube. Hold tube with attached applicator up. Squeeze tube from bottom until medication fills applicator. Remove applicator from tube.


• Lie on your back with knees drawn up. Hold filled applicator by barrel and gently insert it into the vagina as far as it will go comfortably. Press plunger and deposit material. While keeping plunger depressed, remove the applicator from vagina.


• After each use, pull applicator apart and wash with soap and warm water. An unclean applicator may not function properly. Thoroughly clean the applicator after each use.


• To clear up your infection completely, use Terconazole Cream for the full course of treatment. Keep using it even if you feel better in a few days.


• If you miss a dose of Terconazole Cream, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Terconazole Cream.

Important safety information:

• If your sexual partner has any penile itching, redness, or discomfort, he should consult his health care provider and mention that you are being treated for a yeast infection.


• You can use the medication even if you are having your menstrual period. However, you should not use tampons because they may absorb the medication. Instead, use external pads or napkins until you have finished your medication. You may also wish to wear a sanitary napkin if the vaginal medicine leaks.


• Dry the genital area thoroughly after showering, bathing, or swimming. Change out of a wet bathing suit or damp exercise clothes as soon as possible. A dry environment is less likely to encourage the growth of yeast.


• Wipe from front to rear (away from the vagina) after a bowel movement.


• Do not douche unless your doctor specifically tells you to do so. Douching may disturb the vaginal balance.


• Do not scratch the affected area if you can avoid it. Scratching can cause more irritation and spread the infection.


• If you have sexual intercourse during treatment, you may increase the risk of reinfection.


• Terconazole Cream may decrease the effectiveness of condoms and diaphragms.


• Be sure to use Terconazole Cream for the full course of treatment. If you do not, the medicine may not clear up your infection completely. The fungus could also become less sensitive to this or other medicines. This could make the infection harder to treat in the future.


• Use Terconazole Cream with caution in the ELDERLY; they may be more sensitive to its effects.


• Terconazole Cream should not be used in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Terconazole Cream while you are pregnant. It is not known if Terconazole Cream is found in breast milk. Do not breast-feed while taking Terconazole Cream.

Possible side effects of Terconazole Cream:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Body pain; burning or itching of the vagina; painful menstruation; stomach pain.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chills; flu-like symptoms (headache; tiredness; muscle aches; fever); vaginal sensitivity or irritation.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Terconazole side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Terconazole Cream:

Store Terconazole Cream at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Terconazole Cream out of the reach of children and away from pets.

General information:

• If you have any questions about Terconazole Cream, please talk with your doctor, pharmacist, or other health care provider.


• Terconazole Cream is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Terconazole Cream. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Terconazole resources

• Terconazole Side Effects (in more detail)
• Terconazole Use in Pregnancy & Breastfeeding
• Terconazole Support Group
• 6 Reviews for Terconazole - Add your own review/rating

Compare Terconazole with other medications

• Vaginal Yeast Infection

Mycophenolate Mofetil 250 mg Capsules

1. Name Of The Medicinal Product

Mycophenolate Mofetil 250 mg Capsules

2. Qualitative And Quantitative Composition

Each capsule contains 250 mg mycophenolate mofetil.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Capsule, hard

Light blue/peach size '1' hard gelatin capsule imprinting with 'MMF' on cap and '250' on body, containing white to off white powder

4. Clinical Particulars

4.1 Therapeutic Indications

Mycophenolate mofetil is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants.

4.2 Posology And Method Of Administration

Treatment with mycophenolate mofetil should be initiated and maintained by appropriately qualified transplant specialists.

Use in renal transplant:

Adults:

Oral mycophenolate mofetil should be initiated within 72 hours following transplantation. The recommended dose in renal transplant patients is 1.0 g administered twice daily (2 g daily dose).

Children and adolescents (aged 2 to 18 years):

The recommended dose of mycophenolate mofetil is 600 mg/m² administered orally twice daily (up to a maximum of 2 g daily). Mycophenolate Mofetil capsules should only be prescribed to patients with a body surface area of at least 1.25 m². Patients with a body surface area of 1.25 to 1.5 m² may be prescribed mycophenolate mofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area greater than 1.5 m² may be prescribed mycophenolate mofetil capsules at a dose of 1 g twice daily (2 g daily dose). As some adverse reactions occur with greater frequency in this age group (see section 4.8) compared with adults, temporary dose reduction or interruption may be required; these will need to take into account relevant clinical factors including severity of reaction.

Children (< 2 years):

There are limited safety and efficacy data in children below the age of 2 years. These are insufficient to make dose recommendations and therefore use in this age group is not recommended.

Use in cardiac transplant:

Adults:

Oral mycophenolate mofetil should be initiated within 5 days following transplantation. The recommended dose in cardiac transplant patients is 1.5 g administered twice daily (3 g daily dose).

Children and adolescents:

No data are available for paediatric cardiac transplant patients, therefore use in this patients group is not recommended until further data to support this is available.

Use in hepatic transplant:

Adults:

Intravenous mycophenolate mofetil should be administered for the first 4 days following hepatic transplant, with oral mycophenolate mofetil initiated as soon after this as it can be tolerated. The recommended oral dose in hepatic transplant patients is 1.5 g administered twice daily (3 g daily dose).

Children and adolescents: No data are available for paediatric hepatic transplant patients. , therefore use in this patients group is not recommended until further data to support this is available.

Use in elderly (:

The recommended dose of 1g administered twice a day for renal transplant patients and 1.5 g twice a day for cardiac or hepatic transplant patients is appropriate for the elderly.

Use in renal impairment:

In renal transplant patients with severe chronic renal impairment (glomerular filtration rate < 25 ml•min^-1•1.73 m^-2), outside the immediate post-transplant period, doses greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively (see section 5.2). No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.

Use in severe hepatic impairment:

No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease. No data are available for cardiac transplant patients with severe hepatic parenchymal disease.

Treatment during rejection episodes:

MPA (mycophenolic acid) is the active metabolite of mycophenolate mofetil. Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dose reduction or interruption of mycophenolate mofetil is not required. There is no basis for mycophenolate mofetil dose adjustment following cardiac transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.

4.3 Contraindications

Hypersensitivity reactions to mycophenolate mofetil have been observed (see section 4.8). Therefore, mycophenolate mofetil is contraindicated in patients with a hypersensitivity to mycophenolate mofetil or mycophenolic acid.

Mycophenolate Mofetil is contraindicated in women who are breast-feeding (see section 4.6).

For information on use in pregnancy and contraceptive requirements see section 4.6

4.4 Special Warnings And Precautions For Use

Patients receiving immunosuppressive regimens involving combinations of medicinal products, including mycophenolate mofetil, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.8). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As general advice to minimise the risk for skin cancer, exposure to sunlight and ultra violet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Patients receiving mycophenolate mofetil should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.

Patients treated with immunosuppressants, including mycophenolate mofetil, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8). Among the opportunistic infections are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.

Patients receiving mycophenolate mofetil should be monitored for neutropenia, which may be related to mycophenolate mofetil itself, concomitant medications, viral infections, or some combination of these causes. Patients taking mycophenolate mofetil should have complete blood counts weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year. If neutropenia develops (absolute neutrophil count < 1.3 x 10³/µl), it may be appropriate to interrupt or discontinue mycophenolate mofetil.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of mycophenolate mofetil therapy. Changes to mycophenolate mofetil therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection (see section 4.8).

Patients should be advised that during treatment with mycophenolate mofetil, vaccinations may be less effective and the use of live attenuated vaccines should be avoided (see section 4.5). Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.

Because mycophenolate mofetil has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation, mycophenolate mofetil should be administered with caution in patients with active serious digestive system disease.

Mycophenolate Mofetil is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. On theoretical grounds, therefore, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

It is recommended that mycophenolate mofetil should not be administered concomitantly with azathioprine because such concomitant administration has not been studied.

In view of the significant reduction in the AUC (area under the curve) of MPA by cholestyramine, caution should be used in the concomitant administration of mycophenolate mofetil with medicinal products that interfere with enterohepatic recirculation because of the potential to reduce the efficacy of mycophenolate mofetil.

The risk: benefit of mycophenolate mofetil in combination with tacrolimus or sirolimus has not been established (see section 4.5).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

Aciclovir: higher aciclovir plasma concentrations were observed when mycophenolate mofetil was administered with aciclovir in comparison to the administration of aciclovir alone. The changes in MPAG (the phenolic glucuronide of MPA) pharmacokinetics (MPAG increased by 8 %) were minimal and are not considered clinically significant. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are aciclovir concentrations, the potential exists for mycophenolate mofetil and aciclovir, or its prodrugs, e.g. valaciclovir, to compete for tubular secretion and further increases in concentrations of both substances may occur.

Antacids with magnesium and aluminium hydroxides: absorption of mycophenolate mofetil was decreased when administered with antacids.

Cholestyramine: following single dose administration of 1.5 g of mycophenolate mofetil to normal healthy subjects pre-treated with 4 g three times a day (TID) of cholestyramine for 4 days, there was a 40 % reduction in the AUC of MPA (see section 4.4 and section 5.2). Caution should be used during concomitant administration because of the potential to reduce efficacy of mycophenolate mofetil.

Medicinal products that interfere with enterohepatic circulation: caution should be used with medicinal products that interfere with enterohepatic circulation because of their potential to reduce the efficacy of mycophenolate mofetil.

Ciclosporin A: ciclosporin A (CsA) pharmacokinetics are unaffected by mycophenolate mofetil. In contrast, if concomitant ciclosporin treatment is stopped, an increase in MPA AUC of around 30% should be expected.

Ganciclovir: based on the results of a single dose administration study of recommended doses of oral mycophenolate and intravenous ganciclovir and the known effects of renal impairment on the pharmacokinetics of mycophenolate mofetil (see section 4.2) and ganciclovir, it is anticipated that co-administration of these agents (which compete for mechanisms of renal tubular secretion) will result in increases in MPAG and ganciclovir concentration. No substantial alteration of MPA pharmacokinetics is anticipated and mycophenolate mofetil dose adjustment is not required. In patients with renal impairment in which mycophenolate mofetil and ganciclovir or its prodrugs, e.g. valganciclovir, are co-administered, the dose recommendations for ganciclovir should be observed and patients should be monitored carefully.

Oral contraceptives: the pharmacokinetics and pharmacodynamics of oral contraceptives were unaffected by co-administration of mycophenolate mofetil (see also section 5.2).

Rifampicin: in patients not also taking ciclosporin, concomitant administration of mycophenolate mofetil and rifampicin resulted in a decrease in MPA exposure (AUC0-12h) of 18% to 70%. It is recommended to monitor MPA exposure levels and to adjust mycophenolate mofetil doses accordingly to maintain clinical efficacy when rifampicin is administered concomitantly.

Sirolimus: in renal transplant patients, concomitant administration of mycophenolate mofetil and CsA resulted in reduced MPA exposures by 30

Sevelamer: decrease in MPA Cmax and AUC0-12 by 30% and 25%, respectively, were observed when mycophenolate mofetil was concomitantly administered with sevelamer without any clinical consequences (i.e. graft rejection). It is recommended, however, to administer mycophenolate mofetil at least one hour before or three hours after sevelamer intake to minimise the impact on the absorption of MPA. There is no data on mycophenolate mofetil with phosphate binders other than sevelamer.

Trimethoprim/sulfamethoxazole: no effect on the bioavailability of MPA was observed.

Norfloxacin and metronidazole: in healthy volunteers, no significant interaction was observed when mycophenolate mofetil was concomitantly administered with norfloxacin and metronidazole separately. However, norfloxacin and metronidazole combined reduced the MPA exposure by approximately 30 % following a single dose of mycophenolate mofetil.

Ciprofloxacin and amoxicillin plus clavulanic acid: Reductions in pre-dose (trough) MPA concentrations of about 50% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. This effect tended to diminish with continued antibiotic use and to cease within a few days of their discontinuation. The change in predose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of mycophenolate mofetil. should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.

Tacrolimus: in hepatic transplant patients initiated on mycophenolate mofetil and tacrolimus, the AUC and Cmax of MPA, the active metabolite of mycophenolate mofetil, were not significantly affected by co-administration with tacrolimus. In contrast, there was an increase of approximately 20 % in tacrolimus AUC when multiple doses of mycophenolate mofetil (1.5 g BID) were administered to patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by mycophenolate mofetil (see also section 4.4).

Other interactions: co-administration of probenecid with mycophenolate mofetil in monkeys raises plasma AUC of MPAG by 3-fold. Thus, other substances known to undergo renal tubular secretion may compete with MPAG, and thereby raise plasma concentrations of MPAG or the other substance undergoing tubular secretion.

Live vaccines: live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished (see also section 4.4).

4.6 Pregnancy And Lactation

It is recommended that mycophenolate mofetil therapy should not be initiated until a negative pregnancy test has been obtained. Effective contraception must be used before beginning mycophenolate mofetil therapy, during therapy, and for six weeks following discontinuation of therapy (see section 4.5). Patients should be instructed to consult their physician immediately should pregnancy occur.

The use of mycophenolate mofetil is not recommended during pregnancy and should be reserved for cases where no more suitable alternative treatment is available. Mycophenolate Mofetil should be used in pregnant women only if the potential benefit outweighs the potential risk to the foetus. There is limited data from the use of mycophenolate mofetil in pregnant women. However, congenital malformations including ear malformations, i.e. abnormally formed or absent external/middle ear have been reported in children of patients exposed to mycophenolate mofetil in combination with other immunosuppressants during pregnancy. Cases of spontaneous abortions have been reported in patients exposed to Mycophenolate Mofetil. Studies in animals have shown reproductive toxicity (see section 5.3).

Mycophenolate mofetil has been shown to be excreted in the milk of lactating rats. It is not known whether this substance is excreted in human milk. Because of the potential for serious adverse reactions to mycophenolate mofetil in breast-fed infants, mycophenolate mofetil is contraindicated in breast-feeding mothers (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. The pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely.

4.8 Undesirable Effects

The following undesirable effects cover adverse reactions from clinical trials:

The principal adverse reactions associated with the administration of mycophenolate mofetil in combination with ciclosporin and corticosteroids include diarrhoea, leucopenia, sepsis and vomiting and there is evidence of a higher frequency of certain types of infections (see section 4.4).

Malignancies:

Patients receiving immunosuppressive regimens involving combinations of medicinal products, including mycophenolate mofetil, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.4). Lymphoproliferative disease or lymphoma developed in 0.6 % of patients receiving mycophenolate mofetil (2 g or 3 g daily) in combination with other immunosuppressants in controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year. Non-melanoma skin carcinomas occurred in 3.6 % of patients; other types of malignancy occurred in 1.1 % of patients. Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. Hepatic transplant patients were followed for at least 1 year, but less than 3 years.

Opportunistic infections:

All transplant patients are at increased risk of opportunistic infections; the risk increased with total immunosuppressive load (see section 4.4). The most common opportunistic infections in patients receiving mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year were candida mucocutaneous, cytomegalovirus (CMV) viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was 13.5 %.

Children and adolescents (aged 2 to 18 years):

The type and frequency of adverse reactions in a clinical study, which recruited 92 paediatric patients aged 2 to 18 years who were given 600 mg/m² mycophenolate mofetil orally twice daily, were generally similar to those observed in adult patients given 1 g mycophenolate mofetil twice daily. However, the following treatment-related adverse events were more frequent in the paediatric population, particularly in children under 6 years of age, when compared to adults: diarrhoea, sepsis, leucopenia, anaemia and infection.

Elderly patients (:

Elderly patients (

Other adverse reactions:

Adverse reactions, probably or possibly related to mycophenolate mofetil, reported in

Adverse reactions, probably or possibly related to Mycophenolate, reported in patients treated with Mycophenolate in renal, cardiac and hepatic clinical trials when used in combination with ciclosporin and corticosteroids.

Within the system organ classes, undesirable effects are listed under headings of frequency, using the following categories: very common (

System organ class	Adverse drug reactions
Investigations	Very common	----
Common	Hepatic enzyme increased, blood creatinine increased, blood lactate dehydrogenase increased, blood urea increased, blood alkaline phosphatase increased, weight decreased
Cardiac disorders	Very common	----
Common	Tachycardia
Blood and lymphatic system disorders	Very common	Leucopenia, thrombocytopenia, anaemia
Common	Pancytopenia, leucocytosis
Nervous system disorders	Very common	----
Common	Convulsion, hypertonia, tremor, somnolence, myasthenic syndrome, dizziness, headache, paraesthesia, dysgeusia
Respiratory, thoracic and mediastinal disorders	Very common	----
Common	Pleural effusion, dyspnoea, cough
Gastrointestinal disorders	Very common	Vomiting, abdominal pain, diarrhoea, nausea
Common	Gastrointestinal haemorrhage, peritonitis, ileus, colitis, gastric ulcer, duodenal ulcer, gastritis, oesophagitis, stomatitis, constipation, dyspepsia, flatulence, eructation
Renal and urinary disorders	Very common	----
Common	Renal impairment
Skin and subcutaneous tissue disorders	Very common	----
Common	Skin hypertrophy, rash, acne, alopecia,
Musculoskeletal and connective Tissue disorders	Very common	----
Common	Arthralgia
Metabolism and nutrition disorders	Very common	-----
Common	Acidosis, hyperkalaemia, hypokalaemia, hyperglycaemia, hypomagnesaemia, hypocalcaemia, hypercholesterolaemia, hyperlipidaemia, hypophosphataemia, hyperuricaemia, gout, anorexia
Infections and infestations	Very common	Sepsis, gastrointestinal candidiasis, urinary tract infection, herpes simplex, herpes zoster
Common	Pneumonia, influenza, respiratory tract infection, respiratory moniliasis, gastrointestinal infection, candidiasis, gastroenteritis, infection, bronchitis, pharyngitis, sinusitis, fungal skin infection, skin candida, vaginal candidiasis, rhinitis
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Very common	----
Common	Skin cancer, benign neoplasm of skin
Vascular disorders	Very common	-----
Common	Hypotension, hypertension, vasodilatation
General disorders and administration site conditions	Very common	----
Common	Oedema, pyrexia, chills, pain, malaise, asthenia,
Hepatobiliary disorders	Very common	----
Common	Hepatitis, jaundice, hyperbilirubinaemia
Psychiatric disorders	Very common	-----
Common	Agitation, confusional state, depression, anxiety, thinking abnormal, insomnia

Note: 501 (2 g mycophenolate mofetil daily), 289 (3 g mycophenolate mofetil daily) and 277 (2 g IV / 3 g oral mycophenolate mofetil daily) patients were treated in Phase III studies for the prevention of rejection in renal, cardiac and hepatic transplantation, respectively.

The following undesirable effects cover adverse reactions from post-marketing experience:

The types of adverse reactions reported during post-marketing with mycophenolate mofetil are similar to those seen in the controlled renal, cardiac and hepatic transplant studies. Additional adverse reactions reported during post-marketing are described below with the frequencies reported within brackets if known.

Gastrointestinal: gingival hyperplasia (

Disorders related to immunosuppression: serious life-threatening infections including meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leucoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including mycophenolate mofetil.

Agranulocytosis (

Blood and lymphatic system disorder:

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Mycophenolate Mofetil (see section 4.4).

Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with mycophenolate mofetil. These changes are not associated with impaired neutrophil function. These changes may suggest a 'left shift' in the maturity of neutrophils in haematological investigations, which may be mistakenly interpreted as a sign of infection in immunosuppressed patients such as those that receive mycophenolate mofetil.

Hypersensitivity: Hypersensitivity reactions, including angioneurotic oedema and anaphylactic reaction, have been reported.

Congenital disorders: see further details in section 4.6.

Respiratory, thoracic and mediastinal disorders:

There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with mycophenolate mofetil. in combination with other immunosuppressants, some of which have been fatal.

4.9 Overdose

Reports of overdoses with mycophenolate mofetil have been received from clinical trials and during post-marketing experience. In many of these cases, no adverse events were reported. In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the medicinal product.

It is expected that an overdose of mycophenolate mofetil could possibly result in oversuppression of the immune system and increase susceptibility to infections and bone marrow suppression (see section 4.4). If neutropenia develops, dosing with mycophenolate mofetil should be interrupted or the dose reduced (see section 4.4).

Haemodialysis would not be expected to remove clinically significant amounts of MPA or MPAG. Bile acid sequestrants, such as cholestyramine, can remove MPA by decreasing the enterohepatic re-circulation of the drug (see section 5.2).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Immunosuppressive agents

ATC code: L04A A06

Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid(MPA). MPA is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereas other cell types can utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.

5.2 Pharmacokinetic Properties

Following oral administration, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, MPA. As evidenced by suppression of acute rejection following renal transplantation, the immunosuppressant activity of mycophenolate mofetil is correlated with MPA concentration. The mean bioavailability of oral mycophenolate mofetil, based on MPA AUC, is 94 % relative to intravenous mycophenolate mofetil. Food had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g BID to renal transplant patients. However, MPA C_max was decreased by 40 % in the presence of food. Mycophenolate mofetil is not measurable systemically in plasma following oral administration. MPA at clinically relevant concentrations is 97 % bound to plasma albumin.

As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed at approximately 6 – 12 hours post-dose. A reduction in the AUC of MPA of approximately 40 % is associated with the co-administration of cholestyramine (4 g TID), indicating that there is a significant amount of enterohepatic recirculation.

MPA is metabolised principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG), which is not pharmacologically active.

A negligible amount of substance is excreted as MPA (< 1 % of dose) in the urine. Orally administered radiolabelled mycophenolate mofetil results in complete recovery of the administered dose with 93 % of the administered dose recovered in the urine and 6 % recovered in the faeces. Most (about 87 %) of the administered dose is excreted in the urine as MPAG.

At clinically encountered concentrations, MPA and MPAG are not removed by haemodialysis. However, at high MPAG plasma concentrations (> 100µg/ml), small amounts of MPAG are removed.

In the early post-transplant period (< 40 days post-transplant), renal, cardiac and hepatic transplant patients had mean MPA AUCs approximately 30 % lower and C_max approximately 40 % lower compared to the late post-transplant period (3 – 6 months post-transplant).

Renal impairment:

In a single dose study (6 subjects/group), mean plasma MPA AUC observed in subjects with severe chronic renal impairment (glomerular filtration rate < 25 ml•min^-1•1.73 m^-2) were 28 – 75 % higher relative to the means observed in normal healthy subjects or subjects with lesser degrees of renal impairment. However, the mean single dose MPAG AUC was 3 – 6-fold higher in subjects with severe renal impairment than in subjects with mild renal impairment or normal healthy subjects, consistent with the known renal elimination of MPAG. Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.

Delayed renal graft function:

In patients with delayed renal graft function post-transplant, mean MPA AUC (0–12h) was comparable to that seen in post-transplant patients without delayed graft function. Mean plasma MPAG AUC (0-12h) was 2 - 3-fold higher than in post-transplant patients without delayed graft function. There may be a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. Dose adjustment of mycophenolate mofetil does not appear to be necessary.

Hepatic impairment:

In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on this process probably depend on the particular disease. However, hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.

Children and adolescents (aged 2 to 18 years):

Pharmacokinetic parameters were evaluated in 49 paediatric renal transplant patients given 600 mg/m² mycophenolate mofetil orally twice daily. This dose achieved MPA AUC values similar to those seen in adult renal transplant patients receiving mycophenolate mofetil at a dose of 1 g BID in the early and late post-transplant period. MPA AUC values across age groups were similar in the early and late post-transplant period.

Elderly patients (:

Pharmacokinetic behaviour of mycophenolate mofetil in the elderly has not been formally evaluated.

Oral contraceptives:

The pharmacokinetics of oral contraceptives were unaffected by co-administration of mycophenolate mofetil (see section 4.5). A study of the co-administration of mycophenolate mofetil (1 g BID) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.15 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) conducted in 18 non-transplant women (not taking other immunosuppressants) over 3 consecutive menstrual cycles showed no clinically relevant influence of mycophenolate mofetil on the ovulation suppressing action of the oral contraceptives. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and progesterone were not significantly affected.

5.3 Preclinical Safety Data

In experimental models, mycophenolate mofetil was not tumourigenic. The highest dose tested in the animal carcinogenicity studies resulted in approximately 2 – 3 times the systemic exposure (AUC or C_max) observed in renal transplant patients at the recommended clinical dose of 2 g/day and 1.3 – 2 times the systemic exposure (AUC or C_max) observed in cardiac transplant patients at the recommended clinical dose of 3 g/day.

Two genotoxicity assays (in vitro mouse lymphoma assay and in vivo mouse bone marrow micronucleus test) showed a potential of mycophenolate mofetil to cause chromosomal aberrations. These effects can be related to the pharmacodynamic mode of action, i.e. inhibition of nucleotide synthesis in sensitive cells. Other in vitro tests for detection of gene mutation did not demonstrate genotoxic activity.

Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg•kg^-1•day^-1. The systemic exposure at this dose represents 2 – 3 times the clinical exposure at the recommended clinical dose of 2 g/day in renal transplant patients and 1.3 – 2 times the clinical exposure at the recommended clinical dose of 3 g/day in cardiac transplant patients. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg•kg^-1•day^-1 caused malformations (including anophthalmia, agnathia, and hydrocephaly) in the first generation offspring in the absence of maternal toxicity. The systemic exposure at this dose was approximately 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.

In teratology studies in rats and rabbits, foetal resorptions and malformations occurred in rats at 6 mg•kg^-1•day^-1 (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg•kg¹•day^-1 (including cardiovascular and renal anomalies, such as ectopia cordis and ectopic kidneys, and diaphragmatic and umbilical hernia), in the absence of maternal toxicity. The systemic exposure at these levels is approximately equivalent to or less than 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients.

Refer to section 4.6.

The haematopoietic and lymphoid systems were the primary organs affected in toxicology studies conducted with mycophenolate mofetil in the rat, mouse, dog and monkey. These effects occurred at systemic exposure levels that are equivalent to or less than the clinical exposure at the recommended dose of 2 g/day for renal transplant recipients. Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended doses. Gastrointestinal and renal effects consistent with dehydration were also observed in the monkey at the highest dose (systemic exposure levels equivalent to or greater than clinical exposure). The nonclinical toxicity profile of mycophenolate mofetil appears to be consistent with adverse events observed in human clinical trials which now provide safety data of more relevance to the patient population (see section 4.8).

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule contents:

Cellulose microcrystalline

Hydroxy propyl cellulose

Povidone K 90

Croscarmellose sodium

Talc

Magnesium stearate

Capsule shell:

Gelatin

Sodium lauryl sulfate

FD & C Blue 2 (E132)

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Black Ink composition:

Shellac

Black iron oxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Store below 30°C.

6.5 Nature And Contents Of Container

Mycophenolate Mofetil 250 mg capsules are packed in PVC/PVDC/Aluminium blister.

1 carton contains 100 capsules (in blister packs of 10).

1 carton contains 300 capsules (in blister packs of 10).

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, Mycophenolate Mofetil capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in Mycophenolate Mofetil capsules. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.

Any unused product or waste