Isosorbide Dinitrate

Isosorbide Dinitrate Tablets, USP (Oral)

Isosorbide Dinitrate Description

Isosorbide Dinitrate (ISDN) is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate, an organic nitrate whose structural formula is:

The organic nitrates are vasodilators, active on both arteries and veins.

Isosorbide Dinitrate is a white, crystalline, odorless compound which is stable in air and in solution, has a melting point of 70°C and has an optical rotation of +134° (c=1, alcohol, 20°C). Isosorbide Dinitrate is freely soluble in organic solvents such as acetone, alcohol, and ether, but is only sparingly soluble in water.

Isosorbide Dinitrate is available as 5 mg, 10 mg, and 20 mg tablets for oral administration. Inactive ingredients: lactose (monohydrate), magnesium stearate, microcrystalline cellulose. The 5 mg also contains FD & C Red #40 Aluminum Lake. The 20 mg also contains D & C Yellow #10 Aluminum Lake, FD & C Blue #1 Aluminum Lake, and FD & C Yellow #6 Aluminum Lake.

Isosorbide Dinitrate - Clinical Pharmacology

The principal pharmacological action of Isosorbide Dinitrate is relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction, and coronary dilatation remains undefined.

Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the anti-anginal efficacy of continuously-delivered nitrates. In the large majority of these trials, active agents were no more effective than placebo after 24 hours (or less) of continuous therapy. Attempts to overcome nitrate tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has their anti-anginal efficacy been restored.

Pharmacokinetics

Absorption of Isosorbide Dinitrate after oral dosing is nearly complete, but bioavailability is highly variable (10% to 90%), with extensive first-pass metabolism in the liver. Serum levels reach their maxima about an hour after ingestion. The average bioavailability of ISDN is about 25%; most studies have observed progressive increases in bioavailability during chronic therapy.

Once absorbed, the volume of distribution of Isosorbide Dinitrate is 2 to 4 L/kg, and this volume is cleared at the rate of 2 to 4 L/min, so ISDN’s half-life in serum is about an hour. Since the clearance exceeds hepatic blood flow, considerable extrahepatic metabolism must also occur. Clearance is affected primarily by denitration to the 2-mononitrate (15 to 25%) and the 5-mononitrate (75 to 85%).

Both metabolites have biological activity, especially the 5-mononitrate. With an overall half-life of about 5 hours, the 5-mononitrate is cleared from the serum by denitration to isosorbide, glucuronidation to the 5-mononitrate glucuronide, and denitration/hydration to sorbitol. The 2-mononitrate has been less well studied, but it appears to participate in the same metabolic pathways, with a half-life of about 2 hours.

The daily dose-free interval sufficient to avoid tolerance to organic nitrates has not been well defined. Studies of nitroglycerin (an organic nitrate with a very short half-life) have shown that daily dose-free intervals of 10 to 12 hours are usually sufficient to minimize tolerance. Daily dose-free intervals that have succeeded in avoiding tolerance during trials of moderate doses (e.g., 30 mg) of immediate-release ISDN have generally been somewhat longer (at least 14 hours), but this is consistent with the longer half-lives of ISDN and its active metabolites.

Few well-controlled clinical trials of organic nitrates have been designed to detect rebound or withdrawal effects. In one such trial, however, subjects receiving nitroglycerin had less exercise tolerance at the end of the daily dose-free interval than the parallel group receiving placebo. The incidence, magnitude, and clinical significance of similar phenomena in patients receiving ISDN have not been studied.

Clinical Trials

In clinical trials, immediate-release oral Isosorbide Dinitrate has been administered in a variety of regimens, with total daily doses ranging from 30 mg to 480 mg. Controlled trials of single oral doses of Isosorbide Dinitrate have demonstrated effective reductions in exercise-related angina for up to 8 hours. Anti-anginal activity is present about 1 hour after dosing.

Most controlled trials of multiple-dose oral ISDN taken every 12 hours (or more frequently) for several weeks have shown statistically significant anti-anginal efficacy for only 2 hours after dosing. Once-daily regimens, and regimens with one daily dose-free interval of at least 14 hours (e.g., a regimen providing doses at 0800, 1400, and 1800 hours), have shown efficacy after the first dose of each day that was similar to that shown in the single-dose studies cited above. The effects of the second and later doses have been smaller and shorter-lasting than the effect of the first.

From large, well-controlled studies of other nitrates, it is reasonable to believe that the maximal achievable daily duration of anti-anginal effect from Isosorbide Dinitrate is about 12 hours. No dosing regimen for Isosorbide Dinitrate, however, has ever actually been shown to achieve this duration of effect. One study of 8 patients, who were administered a pretitrated dose (average 27.5 mg) of immediate-release ISDN at 0800, 1300, and 1800 hours for 2 weeks, revealed that significant anti-anginal effectiveness was discontinuous and totaled about 6 hours in a 24 hour period.

Indications and Usage for Isosorbide Dinitrate

Isosorbide Dinitrate tablets are indicated for the prevention of angina pectoris due to coronary artery disease. The onset of action of immediate-release oral Isosorbide Dinitrate is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.

Contraindications

Allergic reactions to organic nitrates are extremely rare, but they do occur. Isosorbide Dinitrate tablets are contraindicated in patients who are allergic to Isosorbide Dinitrate or any of its other ingredients.

Warnings

Amplification of the vasodilatory effects of Isosorbide Dinitrate by sildenafil can result in severe hypotension. The time course and dose dependence of this interaction have not been studied. Appropriate supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion.

The benefits of immediate release oral Isosorbide Dinitrate in patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use Isosorbide Dinitrate in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia. Because the effects of oral Isosorbide Dinitrate are so difficult to terminate rapidly, this formulation is not recommended in these settings.

Precautions

General

Severe hypotension, particularly with upright posture, may occur with even small doses of Isosorbide Dinitrate. This drug should therefore be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by Isosorbide Dinitrate may be accompanied by paradoxical bradycardia and increased angina pectoris.

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.

As tolerance to Isosorbide Dinitrate develops, the effect of sublingual nitroglycerin on exercise tolerance, although still observable, is somewhat blunted.

Some clinical trials in angina patients have provided nitroglycerin for about 12 continuous hours of every 24-hour day. During the daily dose-free interval in some of these trials, anginal attacks have been more easily provoked than before treatment, and patients have demonstrated hemodynamic rebound and decreased exercise tolerance. The importance of these observations to the routine, clinical use of immediate-release oral Isosorbide Dinitrate is not known.

In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence.

Information for Patients

Patients should be told that the anti-anginal efficacy of Isosorbide Dinitrate is strongly related to its dosing regimen, so the prescribed schedule of dosing should be followed carefully. In particular, daily headaches sometimes accompany treatment with Isosorbide Dinitrate. In patients who get these headaches, the headaches are a marker of the activity of the drug. Patients should resist the temptation to avoid headaches by altering the schedule of their treatment with Isosorbide Dinitrate, since loss of headache may be associated with simultaneous loss of anti-anginal efficacy. Aspirin and/or acetaminophen, on the other hand, often successfully relieve Isosorbide Dinitrate-induced headaches with no deleterious effect on Isosorbide Dinitrate’s anti-anginal efficacy.

Treatment with Isosorbide Dinitrate may be associated with lightheadedness on standing, especially just after rising from a recumbent or seated position. This effect may be more frequent in patients who have also consumed alcohol.

Drug Interactions

The vasodilating effects of Isosorbide Dinitrate may be additive with those of other vasodilators. Alcohol, in particular, has been found to exhibit additive effects of this variety.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of Isosorbide Dinitrate. In a modified two-litter reproduction study there was no remarkable gross pathology and no altered fertility or gestation among rats fed Isosorbide Dinitrate at 25 or 100 mg/kg/day.

Pregnancy

Pregnancy Category C

At oral doses 35 and 150 times the maximum recommended human daily dose, Isosorbide Dinitrate has been shown to cause a dose-related increase in embryotoxicity (increase in mummified pups) in rabbits. There are no adequate, well-controlled studies in pregnant women. Isosorbide Dinitrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether Isosorbide Dinitrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Isosorbide Dinitrate is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Isosorbide Dinitrate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Adverse Reactions

Adverse reactions to Isosorbide Dinitrate are generally dose-related, and almost all of these reactions are the result of Isosorbide Dinitrate’s activity as a vasodilator. Headache, which may be severe, is the most commonly reported side effect. Headache may be recurrent with each daily dose, especially at higher doses. Transient episodes of lightheadedness, occasionally related to blood pressure changes, may also occur. Hypotension occurs infrequently, but in some patients it may be severe enough to warrant discontinuation of therapy. Syncope, crescendo angina, and rebound hypertension have been reported but are uncommon.

Extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia in normal-seeming patients. Methemoglobinemia is so infrequent at these doses that further discussion of its diagnosis and treatment is deferred (see OVERDOSAGE).

Data are not available to allow estimation of the frequency of adverse reactions during treatment with Isosorbide Dinitrate tablets.

Overdosage

Hemodynamic Effects

The ill effects of Isosorbide Dinitrate overdose are generally the results of Isosorbide Dinitrate’s capacity to induce vasodilatation, venous pooling, reduced cardiac output, and hypotension. These hemodynamic changes may have protean manifestations, including increased intracranial pressure, with any or all of persistent throbbing headache, confusion, and moderate fever; vertigo; palpitations; visual disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); air hunger and dyspnea, later followed by reduced ventilatory effort; diaphoresis, with the skin either flushed or cold and clammy; heart block and bradycardia; paralysis; coma; seizures; and death.

Laboratory determinations of serum levels of Isosorbide Dinitrate and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of Isosorbide Dinitrate overdose.

There are no data suggesting what dose of Isosorbide Dinitrate is likely to be life-threatening in humans. In rats, the median acute lethal dose (LD50) was found to be 1100 mg/kg.

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of Isosorbide Dinitrate and its active metabolites. Similarly, it is not known which, if any, of these substances can usefully be removed from the body by hemodialysis.

No specific antagonist to the vasodilator effects of Isosorbide Dinitrate is known, and no intervention has been subject to controlled studies as a therapy for Isosorbide Dinitrate overdose. Because the hypotension associated with Isosorbide Dinitrate overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient’s legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.

The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than good.

In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of Isosorbide Dinitrate overdose in these patients may be subtle and difficult, and invasive monitoring may be required.

Methemoglobinemia

Nitrate ions liberated during metabolism of Isosorbide Dinitrate can oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b5 reductase activity, however, and even assuming that the nitrate moieties of Isosorbide Dinitrate are quantitatively applied to oxidation of hemoglobin, about 1 mg/kg of Isosorbide Dinitrate should be required before any of these patients manifests clinically significant (≥10%) methemoglobinemia. In patients with normal reductase function, significant production of methemoglobin should require even larger doses of Isosorbide Dinitrate. In one study in which 36 patients received 2 to 4 weeks of continuous nitroglycerin therapy at 3.1 to 4.4 mg/hr (equivalent, in total administered dose of nitrate ions, to 4.8 to 6.9 mg of bioavailable Isosorbide Dinitrate per hour), the average methemoglobin level measured was 0.2%; this was comparable to that observed in parallel patients who received placebo.

Notwithstanding these observations, there are case reports of significant methemoglobinemia in association with moderate overdoses of organic nitrates. None of the affected patients had been thought to be unusually susceptible.

Methemoglobin levels are available from most clinical laboratories. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air.

When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1 to 2 mg/kg intravenously.

Isosorbide Dinitrate Dosage and Administration

As noted under CLINICAL PHARMACOLOGY, multiple-dose studies with ISDN and other nitrates have shown that maintenance of continuous 24-hour plasma levels results in refractory tolerance. Every dosing regimen for Isosorbide Dinitrate tablets must provide a daily dose-free interval to minimize the development of this tolerance. With immediate-release ISDN, it appears that one daily dose-free interval must be at least 14 hours long.

As also noted under CLINICAL PHARMACOLOGY, the effects of the second and later doses have been smaller and shorter-lasting than the effects of the first.

Large controlled studies with other nitrates suggest that no dosing regimen with Isosorbide Dinitrate tablets should be expected to provide more than about 12 hours of continuous anti-anginal efficacy per day.

As with all titratable drugs, it is important to administer the minimum dose which produces the desired clinical effect. The usual starting dose of Isosorbide Dinitrate is 5 mg to 20 mg, two or three times daily. For maintenance therapy, 10 mg to 40 mg, two or three times daily is recommended. Some patients may require higher doses. A daily dose-free interval of at least 14 hours is advisable to minimize tolerance. The optimal interval will vary with the individual patient, dose and regimen.

How is Isosorbide Dinitrate Supplied

Isosorbide Dinitrate tablets, USP are supplied as:

5 mg: Round, pink, scored tablets, debossed GG 259 on one side and plain on the reverse side, and supplied as:

NDC 0781-1635-01 bottles of 100

NDC 0781-1635-10 bottles of 1000

NDC 0781-1635-13 unit dose packages of 100

10 mg: Round, white, scored tablets, debossed GG 26 on one side and plain on the reverse side, and supplied as:

NDC 0781-1556-01 bottles of 100

NDC 0781-1556-05 bottles of 500

NDC 0781-1556-10 bottles of 1000

NDC 0781-1556-13 unit dose packages of 100

20 mg: Round, green, scored tablets, debossed GG 227 on one side and plain on the reverse side, and supplied as:

NDC 0781-1695-01 bottles of 100

NDC 0781-1695-10 bottles of 1000

NDC 0781-1695-13 unit dose packages of 100

Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). Protect from moisture. Dispense in a tight, light-resistant container.

12-2007M

7185

Sandoz Inc.

Princeton, NJ 08540

mg Label

NDC 0781-1635-01

Isosorbide

Dinitrate

Tablets, USP

5 mg ORAL

Rx only

100 Tablets

SANDOZ

mg Label

NDC 0781-1556-01

Isosorbide

Dinitrate

Tablets, USP

10 mg ORAL

Rx only

100 Tablets

SANDOZ

mg Label

NDC 0781-1695-01

Isosorbide

Dinitrate

Tablets, USP

20 mg ORAL

Rx only

100 Tablets

SANDOZ

Isosorbide Dinitrate  Isosorbide Dinitrate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0781-1635 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Isosorbide Dinitrate (ISOSORBIDE) Isosorbide Dinitrate 5 mg

Inactive Ingredients Ingredient Name Strength CELLULOSE, MICROCRYSTALLINE   FD&C RED NO. 40   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE

Product Characteristics Color PINK Score 2 pieces Shape ROUND Size 8mm Flavor Imprint Code GG259 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0781-1635-10 1000 TABLET In 1 BOTTLE None 2 0781-1635-01 100 TABLET In 1 BOTTLE None 3 0781-1635-13 10 BLISTER PACK In 1 CARTON contains a BLISTER PACK 3 10 TABLET In 1 BLISTER PACK This package is contained within the CARTON (0781-1635-13)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA086221	01/07/1988

Isosorbide Dinitrate  Isosorbide Dinitrate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0781-1556 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Isosorbide Dinitrate (ISOSORBIDE) Isosorbide Dinitrate 10 mg

Inactive Ingredients Ingredient Name Strength CELLULOSE, MICROCRYSTALLINE   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE

Product Characteristics Color WHITE Score 2 pieces Shape ROUND Size 8mm Flavor Imprint Code GG26 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0781-1556-13 10 BLISTER PACK In 1 CARTON contains a BLISTER PACK 1 10 TABLET In 1 BLISTER PACK This package is contained within the CARTON (0781-1556-13) 2 0781-1556-01 100 TABLET In 1 BOTTLE None 3 0781-1556-05 500 TABLET In 1 BOTTLE None 4 0781-1556-10 1000 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA086223	01/07/1988

Isosorbide Dinitrate  Isosorbide Dinitrate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0781-1695 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Isosorbide Dinitrate (ISOSORBIDE) Isosorbide Dinitrate 20 mg

Inactive Ingredients Ingredient Name Strength CELLULOSE, MICROCRYSTALLINE   D&C YELLOW NO. 10   FD&C BLUE NO. 1   FD&C YELLOW NO. 6   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE

Product Characteristics Color GREEN Score 2 pieces Shape ROUND Size 9mm Flavor Imprint Code GG227 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0781-1695-13 10 BLISTER PACK In 1 CARTON contains a BLISTER PACK 1 10 TABLET In 1 BLISTER PACK This package is contained within the CARTON (0781-1695-13) 2 0781-1695-10 1000 TABLET In 1 BOTTLE None 3 0781-1695-01 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA089367	04/07/1988

Labeler - Sandoz Inc (110342024)

Revised: 01/2012Sandoz Inc

Adcortyl Intra-Articular / Intradermal Injection 10mg / ml

1. Name Of The Medicinal Product

Adcortyl Intra-articular/Intradermal Injection 10mg/ml

2. Qualitative And Quantitative Composition

Adcortyl Intra-articular/Intradermal Injection contains triamcinolone acetonide 10mg per ml of sterile suspension.

3. Pharmaceutical Form

Sterile aqueous suspension for injection.

4. Clinical Particulars

4.1 Therapeutic Indications

Intra-articular use: for alleviating the joint pain, swelling and stiffness associated with rheumatoid arthritis and osteoarthrosis, with an inflammatory component; also for bursitis, epicondylitis, and tenosynovitis.

Intradermal use: for lichen simplex chronicus (neuro-dermatitis), granuloma annulare, lichen planus, keloids, alopecia areata and hypertrophic scars.

4.2 Posology And Method Of Administration

Adcortyl is for intra-articular or intra-dermal injection. The safety and efficacy of administration by other routes has yet to be established. Strict aseptic precautions should be observed. Since the duration of effect is variable, subsequent doses should be given when symptoms recur and not at set intervals.

Adults: The dose of Adcortyl injection for intra-articular administration, and injection into tendon sheaths and bursae, is dependent on the size of the joint to be treated and on the severity of the condition. Doses of 2.5-5mg (0.25-0.5ml) for smaller joints and 5-15mg (0.5-1.5ml) for larger joints usually alleviate the symptoms. Triamcinolone acetonide 40mg/ml (Kenalog) is available to facilitate administration of larger doses. (See Precautions re Achilles tendon).

Intradermal dosage is usually 2-3mg (0.2-0.3ml), depending on the size of the lesion. No more than 5mg (0.5ml) should be injected at any one site. If several sites are injected the total dosage administered should not exceed 30mg (3ml). The injection may be repeated if necessary, at one or two week intervals.

Elderly: Treatment of elderly patients, particularly if long term, should be planned bearing in mind the more serious consequences of the common side effects of corticosteroids in old age, especially osteoporosis, diabetes, hypertension, hypokalaemia, susceptibility to infection and thinning of the skin. Close supervision is required to avoid life-threatening reactions.

Children: Adcortyl is not recommended in children under 6 years. Adcortyl intra-articular/intradermal may be used in older children in suitably adjusted dosages. Growth and development of children on prolonged corticosteroid therapy should be carefully observed. Caution should be used in the event of exposure to chickenpox, measles or other communicable diseases. (See 4.4 Special Warnings and Special Precautions for Use.)

4.3 Contraindications

Hypersensitivity to any of the ingredients.

Systemic infections unless specific anti-infective therapy is employed.

Administration by intravenous, intrathecal or intraocular injection.

4.4 Special Warnings And Precautions For Use

Warnings (Intra-Articular Injection):

Corticosteroids should not be injected into unstable joints.

Patients should be specifically warned to avoid over-use of joints in which symptomatic benefit has been obtained. Severe joint destruction with necrosis of bone may occur if repeated intra-articular injections are given over a long period of time. Care should be taken if injections are given into tendon sheaths to avoid injection into the tendon itself. Repeated injection into inflamed tendons should be avoided as it has been shown to cause tendon rupture.

Due to the absence of a true tendon sheath, the Achilles tendon should not be injected with depot corticosteroids.

Adequate studies to demonstrate the safety of Adcortyl use by intra-turbinal, subconjunctival, sub-tenons, retrobulbar and intraocular (intravitreal) injections have not been performed. Endophthalmitis, eye inflammation, increased intraocular pressure and visual disturbances including vision loss have been reported with intravitreal administration. Several instances of blindness have been reported following injection of corticosteroid suspensions into the nasal turbinates and intralesional injection about the head.

Precautions:

Intra-articular injection should not be carried out in the presence of active infection in or near joints. The preparation should not be used to alleviate joint pain arising from infectious states such as gonococcal or tubercular arthritis.

Undesirable effects may be minimised using the lowest effective dose for the minimum period, and by administering the daily requirement, whenever possible, as a single morning dose on alternate days. Frequent patient review is required to titrate the dose appropriately against disease activity (See dosage section).

Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment. Withdrawal of corticosteroids after prolonged therapy must, therefore, always be gradual to avoid acute adrenal insufficiency and should be tapered off over weeks or months according to the dose and duration of treatment. During prolonged therapy any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage. If corticosteroids have been stopped following prolonged therapy they may need to be reintroduced temporarily. Patients should carry steroid treatment cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may often be atypical and serious infections such as septicaemia and tuberculosis may be masked and may reach an advanced stage before being recognised.

Chickenpox and measles are of particular concern since these normally minor illnesses may be fatal in immunosuppressed patients.

Unless they have had chickenpox, patients receiving parenteral corticosteroids for purposes other than replacement should be regarded as being at risk of severe chickenpox. Manifestations of fulminant illness include pneumonia, hepatitis and disseminated intravascular coagulation; rash is not necessarily a prominent feature.

Passive immunisation with varicella-zoster immunoglobulin is needed for exposed non-immune patients receiving systemic corticosteroids or for those who have used them within the previous 3 months; varicella-zoster immunoglobulin should preferably be given within 3 days of exposure and not later than 10 days. Confirmed chickenpox warrants specialist care and urgent treatment. Corticosteroids should not be stopped and dosage may need to be increased.

Patients should be advised to avoid exposure to measles and to seek medical advice without delay if exposure occurs. Prophylaxis with normal immunoglobulin may be needed.

During corticosteroid therapy antibody response will be reduced and therefore affect the patient's response to vaccines. Live vaccines should not be administered.

Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5 pharmacokinetic interactions that can increase the risk of side effects), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should also be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.

Special Precautions:

Particular care is required when considering use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.

Recent intestinal anastomoses, diverticulitis, thrombophlebitis, existing or previous history of severe affective disorders (especially previous steroid psychosis), exanthematous disease, chronic nephritis, or renal insufficiency, metastatic carcinoma, osteoporosis (post-menopausal females are particularly at risk); in patients with an active peptic ulcer (or a history of peptic ulcer). Myasthenia gravis. Latent or healed tuberculosis; in the presence of local or systemic viral infection, systemic fungal infections or in active infections not controlled by antibiotics. In acute psychoses; in acute glomerulonephritis. Hypertension; congestive heart failure; glaucoma (or a family history of glaucoma), previous steroid myopathy or epilepsy. Liver failure.

Corticosteroid effects may be enhanced in patients with hypothyroidism or cirrhosis and decreased in hyperthyroid patients.

Diabetes may be aggravated, necessitating a higher insulin dosage. Latent diabetes mellitus may be precipitated.

Menstrual irregularities may occur, and this possibility should be mentioned to female patients.

Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroids, especially when a patient has a history of drug allergies.

All corticosteroids increase calcium excretion.

Aspirin should be used cautiously in conjunction with corticosteroids in patients with hypoprothrombinaemia.

This product contains 15mg/ml benzyl alcohol and must not be given to premature babies or neonates. Benzyl Alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Amphotericin B injection and potassium-depleting agents: Patients should be observed for hypokalaemia.

Anticholinesterases: Effects of anticholinesterase agent may be antagonised.

Anticoagulants, oral: Corticosteroids may potentiate or decrease anticoagulant action. Patients receiving oral anticoagulants and corticosteroids should therefore be closely monitored.

Antidiabetics: Corticosteroids may increase blood glucose; diabetic control should be monitored, especially when corticosteroids are initiated, discontinued, or changed in dosage.

Antihypertensives, including diuretics: corticosteroids antagonise the effects of antihypertensives and diuretics. The hypokalaemic effect of diuretics, including acetazolamide, is enhanced.

Anti-tubercular drugs: Isoniazid serum concentrations may be decreased.

Cyclosporin: Monitor for evidence of increased toxicity of cyclosporin when the two are used concurrently.

Digitalis glycosides: Co-administration may enhance the possibility of digitalis toxicity.

Oestrogens, including oral contraceptives: Corticosteroid half-life and concentration may be increased and clearance decreased.

Hepatic Enzyme Inducers (e.g. barbiturates, phenytoin, carbamazepine, rifampicin, primidone, aminoglutethimide): There may be increased metabolic clearance of Adcortyl. Patients should be carefully observed for possible diminished effect of steroid, and the dosage should be adjusted accordingly.

Human growth hormone: The growth-promoting effect may be inhibited.

Ketoconazole: Corticosteroid clearance may be decreased, resulting in increased effects.

Nondepolarising muscle relaxants: Corticosteroids may decrease or enhance the neuromuscular blocking action.

Nonsteroidal anti-inflammatory agents (NSAIDS): Corticosteroids may increase the incidence and/or severity of GI bleeding and ulceration associated with NSAIDS. Also, corticosteroids can reduce serum salicylate levels and therefore decrease their effectiveness. Conversely, discontinuing corticosteroids during high-dose salicylate therapy may result in salicylate toxicity. Aspirin should be used cautiously in conjunction with corticosteroids in patients with hypoprothrombinaemia.

Thyroid drugs: Metabolic clearance of adrenocorticoids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in adrenocorticoid dosage.

Vaccines: Neurological complications and lack of antibody response may occur when patients taking corticosteroids are vaccinated. (See 4.4 Special Warnings and Special Precautions for Use.)

4.6 Pregnancy And Lactation

The ability of corticosteroids to cross the placenta varies between individual drugs, however triamcinolone does cross the placenta.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development, including cleft palate, intra-uterine growth retardation and effects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate / lip in man. However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important.

As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential, however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

Lactation:

Corticosteroids may pass into breast milk, although no data are available for triamcinolone. Infants of mothers taking high doses of systemic corticosteroids for prolonged periods may have a degree of adrenal suppression.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Where adverse reactions occur they are usually reversible on cessation of therapy. The incidence of predictable side-effects, including hypothalamic-pituitary-adrenal suppression correlate with the relative potency of the drug, dosage, timing of administration and duration of treatment (See Warnings and Precautions).

Absorption of triamcinolone following Adcortyl injection, especially when given by the intra-articular route, is rare. However, patients should be watched closely for the following adverse reactions which may be associated with any corticosteroid therapy:

Anti-inflammatory and immunosuppressive effects: Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis (See Warnings and Precautions).

Fluid and electrolyte disturbances: sodium retention, fluid retention, congestive heart failure in susceptible patients, potassium loss, cardiac arrhythmias or ECG changes due to potassium deficiency, hypokalaemic alkalosis, increased calcium excretion and hypertension.

Musculoskeletal: muscle weakness, fatigue, steroid myopathy, loss of muscle mass, osteoporosis, avascular osteonecrosis, vertebral compression fractures, delayed healing of fractures, aseptic necrosis of femoral and humeral heads, pathological fractures of long bones and spontaneous fractures, tendon rupture.

Hypersensitivity: Anaphylatic reactions, angiodema, rash, pruritus and urticaria, particularly where there is a history of drug allergies.

Dermatological: impaired wound healing, thin fragile skin, petechiae and ecchymoses, facial erythema, increased sweating, purpura, striae, hirsutism, acneiform eruptions, lupus erythematous-like lesions and suppressed reactions to skin tests.

Gastrointestinal: dyspepsia, peptic ulcer with possible subsequent perforation and haemorrhage, pancreatitis, abdominal distension and ulcerative oesophagitis, candidiasis.

Neurological: euphoria, psychological dependence, depression, insomnia, convulsions, increased intracranial pressure with papilloedema (pseudo-tumour cerebri) usually after treatment, vertigo, headache, neuritis or paraesthesias and aggravation of pre-existing psychiatric conditions and epilepsy.

A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, depressed and labile mood, and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations, and aggravation of schizophrenia), behavioural disturbances, irritability, anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to be 5-6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown.

Endocrine: menstrual irregularities and amenorrhoea; development of the Cushingoid state; suppression of growth in childhood and adolescence; secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress (eg. trauma, surgery or illness); decreased carbohydrate tolerance; manifestations of latent diabetes mellitus and increased requirements for insulin or oral hypoglycaemic agents in diabetes, weight gain. Negative protein and calcium balance. Increased appetite.

Ophthalmic: posterior supcapsular cataracts, increased intraocular pressure, glaucoma, exophthalmos, papilloedema, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases.

Others: necrotising angiitis, thrombophlebitis, thromboembolism, leucocytosis, insomnia and syncopal episodes.

Withdrawal Symptoms and Signs:

On withdrawal, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and weight loss may occur. Too rapid a reduction in dose following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death (See Warnings and Precautions).

Intra-Articular Injection:

Reactions following intra-articular administration have been rare. In a few instances, transient flushing and dizziness have occurred. Local symptoms such as post-injection flare, transient pain, irritation, sterile abscesses, hyper- or hypo-pigmentation, Charcot-like arthropathy and occasional increase in joint discomfort may occur. Local fat atrophy may occur if the injection is not given into the joint space, but is temporary and disappears within a few weeks to months.

Intradermal Injection:

Local discomfort, sterile abscesses, hyper- and hypo-pigmentation and subcutaneous and cutaneous atrophy (which usually disappears unless the basic disease process is itself atrophic) have occurred. Very rare instances of blindness associated with intralesional therapy around the face and head have been reported.

4.9 Overdose

Not applicable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Triamcinolone acetonide is a synthetic glucocorticoid with marked anti-inflammatory and anti-allergic actions. Following local injection, relief of pain and swelling and greater freedom of movement are usually obtained within a few hours; such administration avoids the more severe systemic side-effects which may accompany parenteral or oral corticosteroid administration.

5.2 Pharmacokinetic Properties

Triamcinolone acetonide may be absorbed into the systemic circulation from synovial spaces. However clinically significant systemic levels after intra-articular injection are unlikely to occur except perhaps following treatment of large joints with high doses. Systemic effects do not ordinarily occur with intra-articular injections when the proper techniques of administration and the recommended dosage regimens are observed.

The systemic effects of intradermally administered triamcinolone acetonide have not been extensively studied. The risk of systemic absorption, though minimal, should be taken into consideration especially when repeated intralesional administrations may be necessary.

In common with other corticosteroids, triamcinolone is metabolised largely hepatically but also by the kidney and is excreted in urine. The main metabolic route is 6-beta-hydroxylation; no significant hydrolytic cleavage of the acetonide occurs. In view of the hepatic metabolism and renal excretion of triamcinolone acetonide, functional impairments of the liver or kidney may affect the pharmacokinetics of the drug. This may become clinically significant if large or frequent doses of intradermal or intra-articular triamcinolone acetonide are given.

5.3 Preclinical Safety Data

See 4.6 Pregnancy and Lactation.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Benzyl alcohol

Polysorbate 80

Sodium carboxymethylcellulose

Sodium chloride

Water.

6.2 Incompatibilities

The injection should not be physically mixed with other medicinal products.

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

In an upright position. Do not store above 25°C. Avoid freezing.

6.5 Nature And Contents Of Container

Carton containing glass ampoules 5 x 1ml or individually cartoned multidose vials of 5ml.

6.6 Special Precautions For Disposal And Other Handling

No special handling instructions.

7. Marketing Authorisation Holder

E.R. Squibb & Sons Ltd.

Uxbridge Business Park

Sanderson Road

Uxbridge

Middlesex

UB8 1DH

8. Marketing Authorisation Number(S)

PL 0034/5002R

9. Date Of First Authorisation/Renewal Of The Authorisation

25 July 1986 / 8 November 2002

10. Date Of Revision Of The Text

17 July 2008

TriTuss

Generic Name: dextromethorphan, guaifenesin, and phenylephrine (dex troe meth OR fan, gwye FEN e sin, fen il EFF rin)

Brand Names: Certuss-D, Duraphen Forte, Duraphen II DM, Sinutuss DM

What is TriTuss (dextromethorphan, guaifenesin, and phenylephrine)?

Dextromethorphan is a cough suppressant. It affects the signals in the brain that trigger cough reflex.

Guaifenesin is an expectorant. It helps loosen congestion in your chest and throat, making it easier to cough out through your mouth.

Phenylephrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of dextromethorphan, guaifenesin, and phenylephrine is used to treat stuffy nose, sinus congestion, cough, and chest congestion caused by the common cold or flu.

Dextromethorphan will not treat a cough that is caused by smoking, asthma, or emphysema.

Dextromethorphan, guaifenesin, and phenylephrine may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about TriTuss (dextromethorphan, guaifenesin, and phenylephrine)?

Do not give this medication to a child younger than 2 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Do not use a cough or cold medicine if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take cough or cold medicine before the MAO inhibitor has cleared from your body. Do not use any other over-the-counter cough, cold, allergy, or sleep medication without first asking your doctor or pharmacist. If you take certain products together you may accidentally take too much of one or more types of medicine. Read the label of any other medicine you are using to see if it contains a decongestant, expectorant, or cough suppressant. Dextromethorphan will not treat a cough that is caused by smoking, asthma, or emphysema.

What should I discuss with my healthcare provider before using TriTuss (dextromethorphan, guaifenesin, and phenylephrine)?

Do not use a cough or cold medicine if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take cough or cold medicine before the MAO inhibitor has cleared from your body. Do not use this medicine if you are allergic to dextromethorphan, guaifenesin, or phenylephrine.

Ask a doctor or pharmacist if it is safe for you to take this medication if you have emphysema or chronic bronchitis.

This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. This medication may pass into breast milk and could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Artificially-sweetened liquid forms of cold medicine may contain phenylalanine. This would be important to know if you have phenylketonuria (PKU). Check the ingredients and warnings on the medication label if you are concerned about phenylalanine.

How should I take TriTuss (dextromethorphan, guaifenesin, and phenylephrine)?

Use this medication exactly as directed on the label, or as it has been prescribed by your doctor. Do not use the medication in larger amounts, or use it for longer than recommended. Cold medicine is usually taken only for a short time until your symptoms clear up.

Do not give this medication to a child younger than 2 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children.

Measure the liquid form of this medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Take the medication with food if it upsets your stomach. Drink extra fluids to help loosen the congestion and lubricate your throat while you are taking this medication. Do not crush, chew, or break an extended-release tablet. Swallow the pill whole. It is specially made to release medicine slowly in the body. Breaking or opening the pill would cause too much of the drug to be released at one time. Talk with your doctor if your symptoms do not improve after 7 days of treatment, or if you have a fever with a headache, cough, or skin rash.

If you need to have any type of surgery, tell the surgeon ahead of time if you have taken a cold medicine within the past few days.

Store this medicine at room temperature, away from heat, light, and moisture.

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include feeling restless or nervous.

What should I avoid while taking TriTuss (dextromethorphan, guaifenesin, and phenylephrine)?

This medication can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Avoid drinking alcohol. It can increase some of the side effects of this medication.

Avoid taking diet pills, caffeine pills, or other stimulants (such as ADHD medications) without your doctor's advice. Taking a stimulant together with cough or cold medicine can increase your risk of unpleasant side effects.

Do not use any other over-the-counter cough, cold, allergy, or sleep medication without first asking your doctor or pharmacist. If you take certain products together you may accidentally take too much of one or more types of medicine. Read the label of any other medicine you are using to see if it contains a decongestant, expectorant, or cough suppressant.

TriTuss (dextromethorphan, guaifenesin, and phenylephrine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have any of these serious side effects:

• 
  

  severe dizziness, anxiety, restless feeling, or nervousness;

  
  


• 
  

  confusion, hallucinations; or

  
  


• 
  

  slow, shallow breathing.

  
  

Less serious side effects may include:

• 
  

  dizziness or headache,

  
  


• 
  

  a rash, or

  
  


• 
  

  nausea, vomiting, or stomach upset.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect TriTuss (dextromethorphan, guaifenesin, and phenylephrine)?

Before taking dextromethorphan, guaifenesin, and phenylephrine, tell your doctor if you are using any of the following drugs:

• 
  

  celecoxib (Celebrex);

  
  


• 
  

  cinacalcet (Sensipar);

  
  


• 
  

  darifenacin (Enablex);

  
  


• 
  

  imatinib (Gleevec);

  
  


• 
  

  quinidine (Quinaglute, Quinidex);

  
  


• 
  

  ranolazine (Ranexa)

  
  


• 
  

  ritonavir (Norvir);

  
  


• 
  

  sibutramine (Meridia);

  
  


• 
  

  terbinafine (Lamisil);

  
  


• 
  

  medicines to treat high blood pressure; or

  
  


• 
  

  antidepressant medications such as amitriptyline (Elavil, Etrafon), bupropion (Wellbutrin, Zyban), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), imipramine (Janimine, Tofranil), paroxetine (Paxil), sertraline (Zoloft), and others.

  
  

This list is not complete and there may be other drugs that can interact with dextromethorphan, guaifenesin, and phenylephrine. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More TriTuss resources

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

• Deconex DMX MedFacts Consumer Leaflet (Wolters Kluwer)


• Dextromethorphan/Guaifenesin/Phenylephrine Controlled-Release and Sustained-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Giltuss TR MedFacts Consumer Leaflet (Wolters Kluwer)


• Zotex Liquid MedFacts Consumer Leaflet (Wolters Kluwer)

Compare TriTuss with other medications

• Cough and Nasal Congestion

Where can I get more information?

• Your pharmacist can provide more information about dextromethorphan, guaifenesin, and phenylephrine.

See also: TriTuss side effects (in more detail)

Ethinylestradiol Tablets BP 10 mcg, 50 mcg, 1 mg

1. Name Of The Medicinal Product

Ethinylestradiol Tablets BP 10 mcg, 50mcg and 1mg

2. Qualitative And Quantitative Composition

Ethinylestradiol 10.5 mcg, 52.5mcg or 1.048mg

For excipients see 6.1.

3. Pharmaceutical Form

White uncoated tablets for oral administration.

4. Clinical Particulars

4.1 Therapeutic Indications

Post menopausal symptoms due to oestrogen deficiency.

Second line therapy for prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.

Palliative treatment of prostatic cancer.

Hormone replacement therapy for failure of ovarian development e.g. in patients with gonadal dysgenesis where initial oestrogen therapy is later followed by combined oestrogen/progestogen therapy.

Disorders of menstruation, given in conjunction with a progestogen.

4.2 Posology And Method Of Administration

Ethinylestradiol Tablets is an oestrogen-only preparation of hormone replacement therapy (HRT) for oral administration.

Post menopausal symptoms due to oestrogen deficiency including prevention of postmenopausal osteoporosis: the lowest dose that will control symptoms should be chosen. The usual dose range is 10 to 50 micrograms daily, usually on a cyclical basis (e.g., 3 weeks on and 1 week off).

For women without a uterus, who did not have endometriosis diagnosed, it is not recommended to add a progestogen.

In women with an intact uterus (or in endometriosis when endometrial foci may be present despite hysterectomy), where a progestogen is necessary, it should be added for at least 12-14 days every month/28 day cycle to reduce the risk to the endometrium.

The benefits of the lower risk of endometrial hyperplasia and endometrial cancer due to adding progestogen should be weighed against the increased risk of breast cancer (see sections 4.4 and 4.8).

Therapy with Ethinylestradiol Tablets may start at any time in women with established amenorrhoea or who are experiencing long intervals between spontaneous menses. In women who are menstruating, it is advised that therapy starts on the first day of bleeding. As Ethinylestradiol Tablets are usually taken on a cyclical basis direct switching from other oestrogen-only HRT preparations taken cyclically is possible.

HRT should only be continued as long as the benefit in alleviation of severe symptoms outweighs the risks of HRT.

Palliative treatment of prostatic cancer: 150 micrograms to 1.5 mg daily. Larger dose Ethinylestradiol Tablets are available.

Hormone replacement therapy for failure of ovarian development e.g. in patients with gonadal dysgenesis: 10 to 50 micrograms daily, usually on a cyclical basis. Initial oestrogen therapy should be followed by combined oestrogen/progestogen therapy.

Disorders of menstruation: 20 to 50 micrograms daily from day 5 to day 25 of each cycle. A progestogen is given daily in addition, either throughout the cycle or from days 15 to 25 of the cycle.

If a dose is forgotten it should be taken as soon as it is remembered. If it is nearly time for the next dose then the patient should wait until then. Two doses should not be taken together. Forgetting a dose may increase the likelihood of break-through bleeding and spotting.

4.3 Contraindications

• Active or recent arterial thromboembolic disease, e.g. angina, myocardial infarction

• Current or previous idiopathic venous thromboembolism (deep venous thrombosis, pulmonary embolism)

• Known, past or suspected breast cancer or other known or suspected oestrogen dependent tumours (e.g. endometrial cancer)

• Untreated endometrial hyperplasia

• Undiagnosed genital bleeding

• Acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal

• Porphyria

• Known hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Medical examination/follow-up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast cancer' below). Investigation, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual. A careful appraisal of the risks and benefits should be undertaken at least annually in women treated with hormone replacement therapy.

In women with an intact uterus, the benefits of the lower risk of endometrial hyperplasia and endometrial cancer due to adding a progestogen should be weighed against the increased risk of breast cancer (see below and Section 4.8).

Conditions which need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with ethinylestradiol tablets, in particular:

• Risk factors for oestrogen dependent tumours e.g. 1st degree heredity for breast cancer

• Leimyoma (uterine fibroids) or endometriosis

• A history of, or risk factors for, thromboembolic disorders (see below)

• Hypertension

• Liver disorders (e.g. liver adenoma)

• Diabetes Mellitus with or without vascular involvement

• Cholelithiasis

• Otosclerosis

• Asthma

• Migraine or (severe) headache and epilepsy

• Systemic Lupus erythematosis

• Hyperplasia of the endometrium (see below)

Reasons for immediate withdrawal of therapy

• Jaundice or deterioration in liver function

• Significant increase in blood pressure

• New onset of migraine-type headache

• Pregnancy

Endometrial hyperplasia

The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The addition of a progestogen for at least 12 days of the cycle in non-hysterectomised women reduces, but may not eliminate, this risk (see section 4.8).

The reduction in risk to the endometrium should be weighed against the increase in the risk of breast cancer of added progestogen (see 'Breast cancer' below and in Section 4.8)

Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Unopposed oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, especially if they are known to have residual endometriosis (but see above).

Breast cancer

Randomised controlled trials and epidemiological studies have reported an increased risk of breast cancer in women taking oestrogens or oestrogen-progestogen combinations for HRT for several years (see section 4.8). An observational study of almost 829,000 women has shown that, compared to never-users, use of oestrogen-progestogen combined HRT is associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of oestrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40). In this study the magnitude of the increase in breast cancer risk was similar for all oestrogen-only preparations, irrespective of the type, dose or route of administration of the oestrogen (oral, transdermal and implanted). Likewise the magnitude of the increased risk was similar for all oestrogen plus progestogen preparations, irrespective of the type of progestogen or the number of days of addition per cycle. For all HRT, an excess risk becomes apparent within 1-2 years of starting treatment and increases with duration of use of HRT but begins to decline when HRT is stopped and by 5 years reaches the same level as in women who have never taken HRT.

The increase in risk applies to all women studied, although the relative risk was significantly higher in those with a lean or normal body build (body mass index or BMI of < 25kg/m²) compared to those with a BMI of ².

At present the effect of HRT on the diagnosis of breast tumours remains unclear – all women should be encouraged to report any changes in their breasts to their doctor or nurse.

Ovarian Cancer

Long-term (at least 5 to 10 years) use of oestrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than oestrogen-only products.

Venous thromboembolism

HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two- to three fold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50 – 59 years and 8 per 1000 women aged between 60 – 69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50 – 59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60 – 69 years. The occurrence of such an event is more likely in the first year of HRT than later.

Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BMI > 30 kg/m2) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add further to this risk. Personal or strong family history of recurrent thromboembolism or recurrent spontaneous abortion, should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.

If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g., painful swelling of a leg, sudden pain in the chest, dyspnoea).

Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of stroke in healthy women during treatment with continuous combined conjugated oestrogens and medroxyprogesterone acetate (MPA). For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50 – 59 years and 11 per 1000 women aged 60 – 69 years. It is estimated that for women who use conjugated oestrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50 – 59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60 – 69 years. It is unknown whether the increased risk also extends to other HRT products.

Coronary Artery Disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated oestrogens and MPA. Large clinical trials showed a possible increased risk of cardiovascular morbidity in the first year of use and no benefit thereafter. For other HRT products there are as yet no randomised controlled trials to date examining benefit in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Other conditions

• Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Ethinylestradiol Tablets is increased.

• Women with pre-existing hypertriglyceridemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.

• Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

• Patients with rare hereditary problems of galactose intolerance, the Lapp-lactose deficiency, or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The metabolism of oestrogens may be increased by concomitant use of substances known to induce drug metabolising enzymes, specifically cytochrome P450 enzymes, such as anti-convulsants (e.g. phenobarbitol, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz) and modafinil.

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St Johns Wort (Hypericum Perforatum) may induce the metabolism of oestrogens.

Clinically, an increased metabolism of oestrogens may lead to decreased effect and changes in the uterine bleeding profile.

Ethinylestradiol doses greater than 50 micrograms per day may cause imipramine toxicity in patients on concomitant therapy.

Through its effects on the coagulation system, ethinylestradiol may reduce the effects of anticoagulants such as warfarin, phenindione or nicoumalone.

The doses of insulin or hypoglycaemic drugs may need to be adjusted due to the mild diabetogenic effect of ethinylestradiol.

Ethinylestradiol may inhibit the metabolism of theophylline and reduce its clearance.

Ethinylestradiol has been shown to decrease serum concentrations of lamotrigine when the two drugs are co-administered.

4.6 Pregnancy And Lactation

Ethinylestradiol Tablets are not indicated during pregnancy. If pregnancy occurs during medication with Ethinylestradiol Tablets treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent fetal exposure to oestrogens indicate no teratogenic or fetotoxic effects.

Ethinylestradiol Tablets are not indicated during lactation.

4.7 Effects On Ability To Drive And Use Machines

None stated

4.8 Undesirable Effects

Breast cancer

The risk of breast cancer increases with the number of years of HRT usage. According to data from a recent epidemiological study in about 829,000 postmenopausal women, the best estimate of the risk is that for women not using HRT, in total about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 65 years. Among those with current or recent use of oestrogen-only replacement therapy, it is estimated that the total number of additional cases during the corresponding period will be between 0 and 3 (best estimate = 1.5) per 1000 for 5 years' use and between 3 and 7 (best estimate = 5) per 1000 for 10 years' use (see table) Among those with current or recent use of oestrogen plus progestogen combined HRT, it is estimated that the total number of additional cases will be between 5 and 7 (best estimate = 6) per 1000 for 5 years' use and between 18 and 20 (best estimate = 19) per 1000 for 10 years' use (see section 4.4). The number of additional cases of breast cancer is broadly similar for women who start HRT irrespective of age at start of HRT use (between the ages of 45 and 65).

	No of additional cases of breast cancer diagnosed per 1000 users (95% confidence intervals)
Type of HRT	5 years of use	10 years of use
Oestrogen-only	1.5 (0 – 3)	5 (3 – 7)
Combined	6 (5 – 7)	19 (18 – 20)

Endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed oestrogens and is substantially reduced by the addition of a progestogen (see section 4.4). According to the data from epidemiological studies, the best estimate of the risk of endometrial cancer is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. It is estimated that, among those who use oestrogen-only replacement therapy, there will be 4 additional cases per 1000 after 5 years' use and 10 additional cases per 1000 after 10 years' use. Adding a progestogen to oestrogen-only therapy substantially reduces, but may not eliminate, this increased risk.

Other adverse reactions have been reported in association with oestrogen treatment;

Genito-urinary tract: endometrial neoplasia, endometrial cancer, intermenstrual bleeding, increase in the size of uterine fibromyomata, endometrial proliferation or aggravation of endometriosis, excessive production of cervical mucus.

Breast: tenderness, pain, enlargement, secretion.

Gastro-intestinal tract: nausea, vomiting, cholelithiasis, cholestatic jaundice.

Cardiovascular system: hypertension, thrombosis, thrombophlebitis, thromboembolism, myocardial infarction, stroke.

Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use.

Skin: erythema nodosum, erythema multiforme, vascular purpura, rash, chloasma.

Eyes: corneal discomfort if contact lenses are used.

CNS: headache, migraine, mood changes (elation or depression).

Metabolic: sodium and water retention, reduced glucose tolerance and change in body weight, hypercalcaemia.

In men: feminisation, gynaecomastia, testicular atrophy and impotence.

4.9 Overdose

Acute overdose of ethinylestradiol may cause nausea and vomiting and may result in withdrawal bleeding in females.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. Therefore, if possible, treatment for prevention of osteoporosis should start as soon as possible after the onset of menopause in women with increased risk for future osteoporotic fractures. The effect of oestrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued.

The active ingredient, ethinylestradiol, is chemically and biologically identical to endogenous human oestradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone loss following menopause or ovariectomy.

The main therapeutic use of exogenous oestrogens is replacement in deficiency states.

5.2 Pharmacokinetic Properties

Ethinylestradiol is rapidly and completely absorbed from the gut but it undergoes some first pass metabolism in the gut wall.

Ethinylestradiol is rapidly distributed throughout most body tissues with the largest concentration found in adipose tissue. It distributes into breast milk in low concentrations. More than 80% of ethinylestradiol in serum is conjugated as the sulphate and almost all the conjugated form is bound to albumin.

Ethinylestradiol is metabolised in the liver. Hydroxylation appears to be the main metabolic pathway. 60% of a dose is excreted in the urine and 40% in the faeces. About 30% is excreted in the urine and bile as the glucuronide or sulphate conjugate.

The rate of metabolism of ethinylestradiol is affected by several factors, including enzyme-inducing agents, antibiotics and cigarette smoking.

After oral administration, an initial peak occurs in plasma at 2 to 3 hours, with a secondary peak at about 12 hours after dosing; the second peak is interpreted as evidence for extensive enterohepatic circulation of ethinylestradiol.

The elimination half-life of ethinylestradiol ranges from 5 to 16 hours.

5.3 Preclinical Safety Data

None stated

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Starch Maize

Magnesium Stearate

IMS 99%

Purified water

6.2 Incompatibilities

None stated.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Store below 25° C

6.5 Nature And Contents Of Container

Pigmented polypropylene container fitted with a tamper evident closure containing 21, 28, 100, or 500 tablets. All pack sizes may not be marketed.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

UCB Pharma Ltd

208 Bath Road

Slough

Berkshire

SL1 3WE

8. Marketing Authorisation Number(S)

10mcg: PL 00039/0548

50mcg: PL 00039/0549

1mg: PL 00039/0550

9. Date Of First Authorisation/Renewal Of The Authorisation

4 July 2005

10. Date Of Revision Of The Text

15 March 2011

Tearisol

Generic Name: hypromellose (Ophthalmic route)

hye-PROE-me-lose

Commonly used brand name(s)

In the U.S.

• Genteal


• Genteal Mild


• Gonak


• Goniosoft


• Goniovisc


• Isopto Tears


• Nature's Tears


• Tearisol


• Tears Again Mc

Available Dosage Forms:

• Solution


• Gel/Jelly

Therapeutic Class: Surgical Aid, Ocular

Uses For Tearisol

Hydroxypropyl methylcellulose belongs to the group of medicines known as artificial tears. It is used to relieve dryness and irritation caused by reduced tear flow. It helps prevent damage to the eye in certain eye diseases. Hydroxypropyl methylcellulose may also be used to moisten hard contact lenses and artificial eyes. In addition, it may be used in certain eye examinations.

Some of these preparations are available only with your doctor's prescription.

Before Using Tearisol

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

Although there is no specific information comparing use of hydroxypropyl methylcellulose in children with use in other age groups, this medicine is not expected to cause different side effects or problems in children than it does in adults.

Geriatric

Many medicine have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults. Although there is no specific information comparing use of hydroxypropyl methylcellulose in the elderly with use in other age groups, this medicine is not expected to cause different side effects or problems in older people than it does in younger adults.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

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.

Proper Use of hypromellose

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

To use:

• First, wash your hands. Then tilt the head back and pull the lower eyelid away from the eye to form a pouch. Drop the medicine into the pouch and gently close the eyes. Do not blink. Keep the eyes closed for 1 or 2 minutes to allow the medicine to be absorbed.


• To keep the medicine as germ-free as possible, do not touch the applicator tip to any surface (including the eye). Also, keep the container tightly closed.

For patients wearing hard contact lenses:

• Take care not to float the lens from your eye when applying this medicine. If you have any questions about this, check with your health care professional.

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 dry eyes:
  
  • For ophthalmic solution (eye drops) dosage form:
    
    • Adults and children—Use 1 drop three or four times a day.
    
    
  
  

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.

Precautions While Using Tearisol

If you experience eye pain, changes in vision, continued redness or irritation of the eye, or if your symptoms continue for more than 3 days or become worse, check with your doctor.

Tearisol 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:

• Eye irritation not present before use of this medicine

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:

Less common - more common with 1% solution

• Blurred vision


• matting or stickiness of eyelashes

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.

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