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
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• 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.

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

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

Dostinex Tablets

1. Name Of The Medicinal Product

DOSTINEX

2. Qualitative And Quantitative Composition

One DOSTINEX tablet contains 0.5 mg cabergoline.

For excipients see Section 6.1 ('List of Excipients').

3. Pharmaceutical Form

Tablet.

Flat, capsule-shaped, 4 x 8 mm, scored, white tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Inhibition/suppression of physiological lactation

DOSTINEX is indicated for the inhibition of physiological lactation soon after delivery and for suppression of already established lactation:

1. After parturition, when the mother elects not to breast feed the infant or when breast feeding is contraindicated due to medical reasons related to the mother or the new-born.

2. After stillbirth or abortion.

DOSTINEX prevents/suppresses physiological lactation by inhibiting prolactin secretion.

In controlled clinical trials, DOSTINEX given as a single 1 mg administration during the first day post-partum, was effective in inhibiting milk secretion, as well as breast engorgement and pain in 70 - 90% of the women. Less than 5% of women experienced rebound breast symptomatology during the third post-partum week (which was usually mild in severity).

Suppression of milk secretion and relief of breast engorgement and pain are obtained in approximately 85% of nursing women treated with a total dose of 1 mg DOSTINEX given in four divided doses over two days. Rebound breast symptomatology after day 10 is uncommon (approximately 2% of cases).

Treatment of hyperprolactinaemic disorders

DOSTINEX is indicated for the treatment of dysfunctions associated with hyperprolactinaemia, including amenorrhoea, oligomenorrhoea, anovulation and galactorrhoea. DOSTINEX is indicated in patients with prolactin-secreting pituitary adenomas (micro- and macroprolactinomas), idiopathic hyperprolactinaemia, or empty sella syndrome with associated hyperprolactinaemia, which represent the basic underlying pathologies contributing to the above clinical manifestations.

On chronic therapy, DOSTINEX at doses ranging between 1 and 2 mg per week, was effective in normalising serum prolactin levels in approximately 84% of hyperprolactinaemic patients. Regular cycles were resumed in 83% of previously amennorhoeic women. Restoration of ovulation was documented in 89% of women with progesterone levels monitored during the luteal phase. Galactorrhoea disappeared in 90% of cases showing this symptom before therapy. Reduction in tumour size was obtained in 50 - 90% of female and male patients with micro- or macroprolactinoma.

4.2 Posology And Method Of Administration

DOSTINEX is to be administered by the oral route. Since in clinical studies DOSTINEX has been mainly administered with food and since the tolerability of this class of compounds is improved with food, it is recommended that DOSTINEX be preferably taken with meals for all the therapeutic indications.

Inhibition/suppression of physiological lactation

For inhibition of lactation DOSTINEX should be administered during the first day post-partum. The recommended therapeutic dose is 1 mg (two 0.5 mg tablets) given as a single dose.

For suppression of established lactation the recommended therapeutic dosage regimen is 0.25 mg (one-half 0.5 mg tablet) every 12 hours for two days (1 mg total dose). This dosage regimen has been demonstrated to be better tolerated than the single dose regimen in women electing to suppress lactation having a lower incidence of adverse events, in particular of hypotensive symptoms.

Treatment of hyperprolactinaemic disorders

The recommended initial dosage of DOSTINEX is 0.5 mg per week given in one or two (one-half of one 0.5 mg tablet) doses (e.g. on Monday and Thursday) per week. The weekly dose should be increased gradually, preferably by adding 0.5 mg per week at monthly intervals until an optimal therapeutic response is achieved. The therapeutic dosage is usually 1 mg per week and ranges from 0.25 mg to 2 mg per week. Doses of DOSTINEX up to 4.5 mg per week have been used in hyperprolactinaemic patients.

The maximum dose should not exceed 3mg per day.

The weekly dose may be given as a single administration or divided into two or more doses per week according to patient tolerability. Division of the weekly dose into multiple administrations is advised when doses higher than 1 mg per week are to be given since the tolerability of doses greater than 1 mg taken as a single weekly dose has been evaluated only in a few patients.

Patients should be evaluated during dose escalation to determine the lowest dosage that produces the therapeutic response. Monitoring of serum prolactin levels at monthly intervals is advised since, once the effective therapeutic dosage regimen has been reached, serum prolactin normalisation is usually observed within two to four weeks.

After DOSTINEX withdrawal, recurrence of hyperprolactinaemia is usually observed. However, persistent suppression of prolactin levels has been observed for several months in some patients. Of the group of women followed up, 23/29 had ovulatory cycles which continued for greater than 6 months after DOSTINEX discontinuation.

Use in children

The safety and efficacy of DOSTINEX has not been established in subjects less than 16 years of age.

Use in the elderly

As a consequence of the indications for which DOSTINEX is presently proposed, the experience in elderly is very limited. Available data do not indicate a special risk.

4.3 Contraindications

Hypersensitivity to DOSTINEX, any excipient of the product or any ergot alkaloid.

History of pulmonary, pericardial and retroperitoneal fibrotic disorders.

DOSTINEX is contraindicated in patients with hepatic insufficiency and with toxaemia of pregnancy. DOSTINEX should not be co-administered with anti-psychotic medications or administered to women with a history of puerperal psychosis.

For long-term treatment: Evidence of cardiac valvulopathy as determined by pre-treatment echocardiography.

(See section 4.4 Special warnings and precautions for use – Fibrosis and cardiac valvulopathy and possibly related clinical phenomena)

4.4 Special Warnings And Precautions For Use

General:

The safety and efficacy of DOSTINEX have not yet been established in patients with renal and hepatic disease. As with other ergot derivatives, DOSTINEX should be given with caution to patients with severe cardiovascular disease, Raynaud's syndrome, renal insufficiency, peptic ulcer or gastrointestinal bleeding, or with a history of serious, particularly psychotic, mental disorders. Particular care should be taken when patients are taking concomitant psychoactive medication.

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

Symptomatic hypotension can occur with DOSTINEX administration for any indication. Care should be exercised when administering DOSTINEX concomitantly with other drugs known to lower blood pressure.

The effects of alcohol on overall tolerability of DOSTINEX are currently unknown.

Before DOSTINEX administration, pregnancy should be excluded and after treatment pregnancy should be prevented for at least one month.

Hepatic Insufficiency:

Lower doses should be considered in patients with severe hepatic insufficiency who receive prolonged treatment with DOSTINEX. Compared to normal volunteers and those with lesser degrees of hepatic insufficiency, an increase in AUC has been seen in patients with severe hepatic insufficiency (Child-Pugh Class C) who received a single 1 mg dose.

Postural Hypotension:

Postural hypotension can occur following administration of DOSTINEX. Care should be exercised when administering DOSTINEX concomitantly with other drugs known to lower blood pressure.

Somnolence/Sudden Sleep Onset:

DOSTINEX has been associated with somnolence. Dopamine agonists can be associated with sudden sleep onset episodes in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported uncommonly. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with cabergoline. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a reduction in dosage or termination of therapy may be considered. (See section 4.7 Effects on ability to drive and use machines)

Psychiatric:

Pathological gambling, increased libido, and hypersexuality have been reported in patients treated with dopamine agonists including DONSTINEX. This has been generally reversible upon reduction of the dose or treatment discontinuation.

Inhibition/suppression of physiological lactation:

As with other ergot derivatives, DOSTINEX should not be used in women with pregnancy-induced hypertension, for example, preeclampsia or post-partum hypertension, unless the potential benefit is judged to outweigh the possible risk.

In post-partum studies with DOSTINEX, blood pressure decreases were mostly asymptomatic and were frequently observed on a single occasion 2 to 4 days after treatment. Since decreases in blood pressure are frequently noted during the puerperium, independently of drug therapy, it is likely that many of the observed decreases in blood pressure after DOSTINEX administration were not drug-induced. However, periodic monitoring of blood pressure, particularly during the first few days after DOSTINEX administration, is advised.

A single dose of 0.25 mg of DOSTINEX should not be exceeded in nursing women treated for suppression of established lactation to avoid potential postural hypotension. A clinical study exploring the efficacy and tolerability of 0.5 mg of DOSTINEX given as a single dose for suppression of lactation has shown that the risk of side effects is approximately doubled in this indication if the drug is administered as a single dose of 0.5 mg.

Treatment of hyperprolactinaemic disorders:

Because hyperprolactinaemia accompanied with amenorrhoea/galactorrhoea and infertility may be associated with pituitary tumour, a complete evaluation of the pituitary is indicated before treatment with DOSTINEX is initiated.

DOSTINEX restores ovulation and fertility in women with hyperprolactinaemic hypogonadism

Because pregnancy might occur prior to reinitiation of menses, a pregnancy test is recommended at least every four weeks during the amenorrhoeic period and, once menses are reinitiated, every time a menstrual period is delayed by more than three days. Women who wish to avoid pregnancy should be advised to use mechanical contraception during treatment with DOSTINEX and after discontinuation of DOSTINEX until recurrence of anovulation. As a precautionary measure, women who become pregnant should be monitored to detect signs of pituitary enlargement since expansion of pre-existing pituitary tumours may occur during gestation

Before administration of DOSTINEX, pregnancy should be excluded. Because clinical experience is still limited and the product has a long half-life, as a precautionary measure it is recommended that once regular ovulatory cycles have been achieved women seeking pregnancy discontinue DOSTINEX one month before intended conception. Should pregnancy occur during treatment, DOSTINEX is to be discontinued. As a precautionary measure, women who become pregnant should be monitored to detect signs of pituitary enlargement since expansion of pre-existing pituitary tumours may occur during gestation.

Regular gynaecological assessment, including cervical and endometrial cytology, is recommended for patients taking DOSTINEX for extensive periods.

Fibrosis and cardiac valvulopathy and possibly related clinical phenomena:

Fibrotic and serosal inflammatory disorders such as pleuritis, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy involving one or more valves (aortic, mitral and tricuspid) or retroperitoneal fibrosis have occurred after prolonged usage of ergot derivatives with agonist activity at the serotonin 5HT_2B receptor, such as DOSTINEX. In some cases, symptoms or manifestations of cardiac valvulopathy improved after discontinuation of DOSTINEX.

Erythrocyte sedimentation rate (ESR) has been found to be abnormally increased in association with pleural effusion/fibrosis. Chest x-ray examination is recommended in cases of unexplained ESR increases to abnormal values.

Valvulopathy has been associated with cumulative doses, therefore, patients should be treated with the lowest effective dose. At each visit, the risk benefit profile of DOSTINEX treatment for the patient should be reassessed to determine the suitability of continued treatment with DOSTINEX.

Before initiating long-term treatment:

All patients must undergo a cardiovascular evaluation, including echocardiogram to assess the potential presence of asymptomatic valvular disease. It is also appropriate to perform baseline investigations of erythrocyte sedimentation rate or other inflammatory markers, lung function/chest X-ray and renal function prior to initiation of therapy. In patients with valvular regurgitation, it is not known whether cabergoline treatment might worsen the underlying disease. If fibrotic valvular disease is detected, the patient should not be treated with DOSTINEX (see section 4.3 Contraindications).

During long-term treatment:

Fibrotic disorders can have an insidious onset and patients should be regularly monitored for possible manifestations of progressive fibrosis. Therefore, during treatment, attention should be paid to the signs and symptoms of:

• Pleuro-pulmonary disease such as dyspnoea, shortness of breath, persistent cough or chest pain.

• Renal insufficiency or ureteral/abdominal vascular obstruction that may occur with pain in the loin/flank and lower limb oedema as well as any possible abdominal masses or tenderness that may indicate retroperitoneal fibrosis.

• Cardiac failure: cases of valvular and pericardial fibrosis have often manifested as cardiac failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be excluded if such symptoms occur.

Clinical diagnostic monitoring for development of fibrotic disorders, as appropriate, is essential. Following treatment initiation, the first echocardiogram must occur within 3-6 months, thereafter, the frequency of echocardiographic monitoring should be determined by appropriate individual clinical assessment with particular emphasis on the above-mentioned signs and symptoms, but must occur at least every 6 to 12 months.

DOSTINEX should be discontinued if an echocardiogram reveals new or worsened valvular regurgitation, valvular restriction or valve leaflet thickening (see section 4.3 Contraindications).

The need for other clinical monitoring (e.g. physical examination including, cardiac auscultation, X-ray, CT scan) should be determined on an individual basis.

Additional appropriate investigations such as erythrocyte sedimentation rate, and serum creatinine measurements should be performed if necessary to support a diagnosis of a fibrotic disorder.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The concomitant use of other drugs during early puerperium, particularly of ergot alkaloids, was not associated with detectable interactions modifying the efficacy and safety of DOSTINEX.

No information is available about the interaction between DOSTINEX and other ergot alkaloids; therefore, the concomitant use of these medications during long-term treatment with DOSTINEX is not recommended.

Since DOSTINEX exerts its therapeutic effect by direct stimulation of dopamine receptors, it should not be concurrently administered with drugs which have dopamine-antagonist activity (such as phenothiazines, butyrophenones, thioxanthenes, metoclopramide) since these might reduce the prolactin-lowering effect of DOSTINEX.

As with other ergot derivatives, DOSTINEX should not be used with macrolide antibiotics (e.g. erythromycin) due to increased systemic bioavailability of DOSTINEX.

4.6 Pregnancy And Lactation

In a twelve year observational study on pregnancy outcomes following cabergoline therapy, information is available on 256 pregnancies. Seventeen of these 256 pregnancies (6.6%) eventuated in major congenital malformations or abortion. Information is available on 23/258 infants who had a total of 27 neonatal abnormalities, both major and minor. Musculoskeletal malformations were the most common neonatal abnormality (10), followed by cardio-pulmonary abnormalities (5). There is no information on perinatal disorders or long-term development of infants exposed to intra-uterine cabergoline. Based on recent published literature, the prevalence of major congenital malformations in the general population has been reported to be 6.9% or greater. Rates of congenital abnormality vary between different populations. It is not possible to accurately determine if there is an increased risk as no control group was included.

Before DOSTINEX administration, pregnancy should be excluded and after treatment pregnancy should be prevented for at least one month. As cabergoline has an elimination half-life of 79-115 hours in hyperprolactinaemic patients, once regular ovulatory cycles have been achieved women seeking pregnancy should discontinue DOSTINEX one month before intended conception. This will prevent possible foetal exposure to the drug and will not interfere with the possibility of conception since ovulatory cycles persist in some cases for six months after drug withdrawal. If conception occurs during therapy, treatment should be discontinued as soon as pregnancy is confirmed to limit foetal exposure to the drug.

(See section 4.4 Special warning and precautions for use – Treatment of Hyperprolactinemic Disorders)

In rats, DOSTINEX and/or its metabolites are excreted in milk. No information is available on the excretion in breast milk in humans; however, mothers should be advised not to breast-feed in case of failed lactation inhibition/suppression by DOSTINEX. Since it prevents lactation, DOSTINEX should not be administered to mothers with hyperprolactinemic disorders who wish to breast-feed their infants.

4.7 Effects On Ability To Drive And Use Machines

During the first days of DOSTINEX administration, patients should be cautioned about re-engaging in activities requiring rapid and precise responses such as driving an automobile or operating machinery.

Patients being treated with DOSTINEX and presenting with somnolence must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves and others at risk of serious injury or death (e.g. operating machines) unless patients have overcome such experiences of somnolence. See section 4.4 Special Warnings and special precautions for use.

4.8 Undesirable Effects

Adverse events are generally dose-related. In patients known to be intolerant to dopaminergic drugs, the likelihood of adverse events may be lessened by starting therapy with DOSTINEX at reduced doses, e.g. 0.25mg once a week, with subsequent gradual increase until the therapeutic dosage is reached. If persistent or severe adverse events occur, temporary reduction of dosage followed by a more gradual increase, e.g. increments of 0.25mg/week every two weeks, may increase tolerability.

The following undesirable effects have been observed and reported during treatment with DOSTINEX with the following frequencies: Very common (

General
MedDRA System Organ Class	Frequency	Adverse Events
Vascular disorders	Common	Dostinex generally exerts a hypotensive effect in patients on long-term treatment; postural hypotension
Uncommon	Digital vasospasm, fainting
Musculoskeletal and connective tissue disorders	Uncommon	Leg cramps
Rare	Muscle weakness
Skin and subcutaneous tissue disorders	Uncommon	Dermal reactions, e.g. alopecia, pruritus, rash
Rare	Allergic skin reactions
Investigations	Uncommon	A decrease in haemoglobin values have been observed in amenhorrheic women during the first few months after menses
Hyperprolactinemic Disorders
MedDRA System Organ Class	Frequency	Adverse Events
Psychiatric disorders	Common	Depression, sleep disturbances
Not Known	Aggression, hypersexuality, pathological gambling, increased libido
Nervous system disorders	Very Common	Dizziness/vertigo, headache
Uncommon	Paraesthesia
Not Known	Sudden sleep onset, syncope
Vascular disorders	Common	Hot flushes
Gastrointestinal disorders	Very common	Abdominal pain, dyspepsia, gastritis, nausea
Common	Constipation, vomiting
Reproductive system and breast disorders	Common	Breast pain
General disorders and administration site conditions	Very Common	Asthenia, fatigue
Inhibition/Supression of Lactation
MedDRA System Organ Class	Frequency	Adverse Events
Nervous system disorders	Common	Dizziness/vertigo, headache, somnolence
Uncommon	Syncope
Cardiac disorders	Very common	Cardiac vulvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion)
Uncommon	Palpitations, epistaxis, decrease in haemoglobin in amenorrhoeic women after menses resumption. Asymptomatic decreases in blood pressure may occur usually once during the first 3-4 days post partum.
Respiratory, thoracic and mediastinal disorders	Uncommon	Pleural effusion, pulmonary fibrosis
Gastrointestinal disorders	Common	Abdominal pain, nausea
Uncommon	Vomiting
Rare	Epigastric pain
Investigations	Common	Asymptomatic decreases in blood pressure (
Vascular disorders	Uncommon	Hot flushes
General disorders and administration site conditions	Uncommon	Asthenia
Vision	Uncommon	Transient hemianopsia
Not known	Abnormal vision
Post-marketing Surveillance
MedDRA System Organ Class	Frequency	Undesirable Effects
Immune system disorders	Not Known	Hypersensitivity reaction
Psychiatric disorders	Uncommon	Increased libido
Not Known	Delusions,
Cardiac disorders	Very Common	Valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion)
Respiratory, thoracic and mediastinal disorders	Not Known	Dyspnoea, respiratory disorder, respiratory failure, pleural effusion, pulmonary fibrosis
Hepato-biliary disorders	Not Known	Hepatic function abnormal
Skin and subcutaneous tissue disorders	Uncommon	Alopecia, rash
General disorders and administration site conditions	Not known	Oedema
Investigations	Not Known	Blood creatinine phosphokinase increased,

4.9 Overdose

Symptoms of overdose would likely be those of over-stimulation of dopamine receptors e.g. nausea, vomiting, gastric complaints, postural hypotension, confusion/psychosis or hallucinations.

Supportive measures should be taken to remove any unabsorbed drug and maintain blood pressure, if necessary. In addition, the administration of dopamine antagonist drugs may be advisable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

DOSTINEX is a dopaminergic ergoline derivative endowed with a potent and long-lasting PRL-lowering activity. It acts by direct stimulation of the D₂-dopamine receptors on pituitary lactotrophs, thus inhibiting PRL secretion. In rats the compound decreases PRL secretion at oral doses of 3-25 mcg/kg, and in-vitro at a concentration of 45 pg/ml. In addition, DOSTINEX exerts a central dopaminergic effect via D₂ receptor stimulation at oral doses higher than those effective in lowering serum PRL levels. The long lasting PRL-lowering effect of DOSTINEX is probably due to its long persistence in the target organ as suggested by the slow elimination of total radioactivity from the pituitary after single oral dose in rats (t_½of approximately 60 hours).

The pharmacodynamic effects of DOSTINEX have been studied in healthy volunteers, puerperal women and hyperprolactinaemic patients. After a single oral administration of DOSTINEX (0.3 - 1.5 mg), a significant decrease in serum PRL levels was observed in each of the populations studied. The effect is prompt (within 3 hours from administration) and persistent (up to 7 - 28 days in healthy volunteers and hyperprolactinaemic patients, and up to 14 - 21 days in puerperal women). The PRL-lowering effect is dose-related both in terms of degree of effect and duration of action.

With regard to the endocrine effects of DOSTINEX not related to the antiprolactinaemic effect, available data from humans confirm the experimental findings in animals indicating that the test compound is endowed with a very selective action with no effect on basal secretion of other pituitary hormones or cortisol. The pharmacodynamic actions of DOSTINEX not correlated with the therapeutic effect only relate to blood pressure decrease. The maximal hypotensive effect of DOSTINEX as single dose usually occurs during the first 6 hours after drug intake and is dose-dependent both in terms of maximal decrease and frequency.

5.2 Pharmacokinetic Properties

The pharmacokinetic and metabolic profiles of DOSTINEX have been studied in healthy volunteers of both sexes and in female hyperprolactinaemic patients.

After oral administration of the labelled compound, radioactivity was rapidly absorbed from the gastrointestinal tract as the peak of radioactivity in plasma was between 0.5 and 4 hours.

Ten days after administration about 18% and 72% of the radioactive dose was recovered in urine and faeces, respectively. Unchanged drug in urine accounted for 2-3% of the dose.

In urine, the main metabolite identified was 6-allyl-8β-carboxy-ergoline, which accounted for 4-6% of the dose. Three additional metabolites were identified in urine, which accounted overall for less than 3% of the dose. The metabolites have been found to be much less potent than DOSTINEX in inhibiting prolactin secretion in vitro. DOSTINEX biotransformation was also studied in plasma of healthy male volunteers treated with [¹⁴C]-cabergoline: a rapid and extensive biotransformation of cabergoline was shown.

The low urinary excretion of unchanged DOSTINEX has been confirmed also in studies with non-radioactive product. The elimination half-life of DOSTINEX, estimated from urinary excretion rates, is long (63-68 hours in healthy volunteers (using a radio-immuno assay), 79-115 hours in hyperprolactinaemic patients (using a HPLC method).

On the basis of the elimination half-life, steady state conditions should be achieved after 4 weeks, as confirmed by the mean peak plasma levels of DOSTINEX obtained after a single dose (37 ± 8 pg/ml) and after a 4 week multiple regimen (101 ± 43 pg/ml).

In vitro experiments showed that the drug at concentrations of 0.1-10 ng/ml is 41-42% bound to plasma proteins. Food does not appear to affect absorption and disposition of DOSTINEX.

5.3 Preclinical Safety Data

There were maternotoxic effects but no teratogenic effects in mice given cabergoline at doses up to 8 mg/kg/day (approximately 55 times the maximum recommended human dose) during the period of organogenesis.

A dose of 0.012 mg/kg/day (approximately 1/7 the maximum recommended human dose) during the period of organogenesis in rats caused an increase in post-implantation embryofetal losses. These losses could be due to the prolactin inhibitory properties of cabergoline in rats. At daily doses of 0.5 mg/kg/day (approximately 19 times the maximum recommended human dose) during the period of organogenesis in the rabbit, cabergoline caused maternotoxicity characterized by a loss of body weight and decreased food consumption. Doses of 4 mg/kg/day (approximately 150 times the maximum recommended human dose) during the period of organogenesis in the rabbit caused an increased occurrence of various malformations. However, in another study in rabbits, no treatment-related malformations or embryofetotoxicity were observed at doses up to 8 mg/kg/day (approximately 300 times the maximum recommended human dose).

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Leucine

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

The tablets are contained in type I amber glass bottles with tamper resistant screw caps and containing silica gel desiccant.

Each bottle contains 2, 4 or 8 tablets and is enclosed in an outer cardboard carton.

6.6 Special Precautions For Disposal And Other Handling

Bottles of DOSTINEX are supplied with desiccant in caps. This desiccant must not be removed.

7. Marketing Authorisation Holder

Pharmacia Limited

Ramsgate Road

Sandwich

Kent

CT13 9JN

8. Marketing Authorisation Number(S)

PL 00032/0372

9. Date Of First Authorisation/Renewal Of The Authorisation

24 June 2002

10. Date Of Revision Of The Text

November 2010

Ref Code: DX 8_1 UK