Bradyarrhythmia Medications

Definition of Bradyarrhythmia: Any disturbance of the heart's rhythm resulting in rates less than 60 beats per minute.

Drugs associated with Bradyarrhythmia

The following drugs and medications are in some way related to, or used in the treatment of Bradyarrhythmia. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

Learn more about Bradyarrhythmia

Medical Encyclopedia:

• Arrhythmias

Harvard Health Guide:

• Symptoms and treatment for Bradycardia

Drug List:

Atreza

Atropen

Sal-Tropine

Glimepiride 2mg Tablet

1. Name Of The Medicinal Product

Glimepiride 2mg Tablet

2. Qualitative And Quantitative Composition

Each tablet contains 2mg glimepiride.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet

The tablets are green, oblong and scored on both sides.

4. Clinical Particulars

4.1 Therapeutic Indications

Glimepiride is indicated for the treatment of type II diabetes mellitus, when diet, physical exercise and weight reduction alone are not adequate.

4.2 Posology And Method Of Administration

For oral administration.

The basis for successful treatment of diabetes is a good diet, regular physical activity, as well as routine checks of blood and urine. Tablets or insulin cannot compensate if the patient does not keep to the recommended diet.

Dosage is determined by the results of blood and urinary glucose determinations.

The starting dose is 1 mg glimepiride per day. If good control is achieved this dosage should be used for maintenance therapy.

For the different dosage regimens appropriate strengths are available.

If control is unsatisfactory the dosage should be increased, based on the glycaemic control, in a stepwise manner with an interval of about 1 to 2 weeks between each step, to 2, 3 or 4 mg glimepiride per day.

A dosage of more than 4 mg glimepiride per day gives better results only in exceptional cases. The maximum recommended dose is 6 mg glimepiride per day.

In patients not adequately controlled with the maximum daily dose of metformin, concomitant glimepiride therapy can be initiated.

While maintaining the metformin dose, the glimepiride therapy is started with a low dose, and is then titrated up depending on the desired level of metabolic control up to the maximum daily dose. The combination therapy should be initiated under close medical supervision.

In patients not adequately controlled with the maximum daily dose of glimepiride, concomitant insulin therapy can be initiated if necessary. While maintaining the glimepiride dose, insulin treatment is started at low dose and titrated up depending on the desired level of metabolic control. The combination therapy should be initiated under close medical supervision.

Normally a single daily dose of glimepiride is sufficient. It is recommended that this dose be taken shortly before or during a substantial breakfast or

If a dose is forgotten, this should not be corrected by increasing the next dose. Tablets should be swallowed whole with some liquid.

If a patient has a hypoglycaemic reaction on 1 mg glimepiride daily, this indicates that they can be controlled by diet alone.

In the course of treatment, as an improvement in control of diabetes is associated with higher insulin sensitivity, glimepiride requirements may fall. To avoid hypoglycaemia timely dose reduction or cessation of therapy must therefore be considered. Change in dosage may also be necessary, if there are changes in weight or life style of the patient, or other factors that increase the risk of hypo-or hyperglycaemia.

Switch over from other oral hypoglycaemic agents to glimepiride

A switch over from other oral hypoglycaemic agents to glimepiride can generally be done. For the switch over to glimepiride the strength and the half-life of the previous medicinal product has to be taken into account. In some cases, especially in antidiabetics with a long half-life (e.g. chlorpropamide), a wash out period of a few days is advisable in order to minimise the risk of hypoglycaemic reactions due to the additive effect.

The recommended starting dose is 1 mg glimepiride per day. Based on the response the glimepiride dosage may be increased stepwise, as indicated earlier.

Switch over from Insulin to glimepiride

In exceptional cases, where type 2 diabetic patients are regulated on insulin, a changeover to glimepiride may be indicated. The changeover should be undertaken under close medical supervision.

Special Populations

Patients with renal or hepatic impairment:

See section 4.3.

Children and adolescents:

There are no data available on the use of glimepiride in patients under 8 years of age. For children aged 8 to 17 years, there are limited data on glimepiride as monotherapy (see sections 5.1 and 5.2).

The available data on safety and efficacy are insufficient in the paediatric population and therefore such use is not recommended.

4.3 Contraindications

Glimepiride is contraindicated in patients with the following conditions:

• hypersensitivity to glimepiride, other sulfonylureas or sulfonamides or to any of the excipients,

• insulin dependent diabetes,

• diabetic coma,

• ketoacidosis,

• severe renal or hepatic function disorders.In case of severe renal or hepatic function disorders, a change over to insulin is required.

4.4 Special Warnings And Precautions For Use

Glimepiride must be taken shortly before or during a meal.

When meals are taken at irregular hours or skipped altogether, treatment with glimepiride may lead to hypoglycaemia. Possible symptoms of hypoglycaemia include: headache, ravenous hunger, nausea, vomiting, lassitude, sleepiness, disordered sleep, restlessness, aggressiveness, impaired concentration, alertness and reaction time, depression, confusion, speech and visual disorders, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral convulsions, somnolence and loss of consciousness up to and including coma, shallow respiration and bradycardia. In addition, signs of adrenergic counter-regulation may be present such as sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias.

The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke.

Symptoms can almost always be promptly controlled by immediate intake carbohydrates (sugar). Artificial sweeteners have no effect.

It is known from other sulfonylureas that, despite initially successful countermeasures, hypoglycaemia may recur.

Severe hypoglycaemia or prolonged hypoglycaemia, only temporarily controlled by the usual amounts of sugar, require immediate medical treatment and occasionally hospitalisation.

Factors favouring hypoglycaemia include:

• unwillingness or (more commonly in older patients) incapacity of the patient to cooperate,

• undernutrition, irregular mealtimes or missed meals or periods of fasting,

• alterations in diet,

• imbalance between physical exertion and carbohydrate intake,

• consumption of alcohol, especially in combination with skipped meals,

• impaired renal function,

• serious liver dysfunction,

• overdosage with glimepiride,

• certain uncompensated disorders of the endocrine system affecting carbohydrate metabolism or counterregulation of hypoglycaemia (as for example in certain disorders of thyroid function and in anterior pituitary or adrenocortical insufficiency), concurrent administration of certain other medicinal products (see section 4.5).

Treatment with glimepiride requires regular monitoring of glucose levels in blood and urine. In addition determination of the proportion of glycosylated haemoglobin is recommended.

Regular hepatic and haematological monitoring (especially leucocytes and thrombocytes) are required during treatment with glimepiride.

In stress-situations (e.g. accidents, acute operations, infections with fever, etc.) a temporary switch to insulin may be indicated.

No experience has been gained concerning the use of glimepiride in patients with severe impairment of liver function or dialysis patients. In patients with severe impairment of renal or liver function change over to insulin is indicated.

Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to hemolytic anaemia. Since glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered.

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

If glimepiride is taken simultaneously with certain other medicinal products, both undesired increases and decreases in the hypoglycaemic action of glimepiride can occur. For this reason, other medicinal products should only be taken with the knowledge (or at the prescription) of the doctor.

Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). Its metabolism is known to be influenced by concomitant administration of CYP2C9 inducers (e.g rifampicin) or inhibitors (e.g fluconazole).

Results from an vivo interaction study reported in literature show that glimepiride AUC is increased approximately 2-fold by fluconazole, one of the most potent CYP2C9 inhibitors.

Based on the experience with glimepiride and with other sulfonylureas the following interactions have to be mentioned.

Potentiation of the blood-glucose-lowering effect and, thus, in some instances hypoglycaemia may occur when one of the following medicinal products is taken, for example:

- phenylbutazone, azapropazon and oxyfenbutazone,
- insulin and oral antidiabetic products, such as metformin
- salicylates and p
- anabolic steroids and male sex hormones,
- chloramphenicol, certain long acting sulfonamides, tetracyclines, quinolone antibiotics and clarithromycin
- coumarin anticoagulants,
- fenfluramine,
- fibrates,
- ACE inhibitors,	.
- fluoxetine, MAO-inhibitors,
- allopurinol, probenecid, sulfinpyrazone,
- sympatholytics,
- cyclophosphamide, trophosphamide and iphosphamides,
- miconazol, fluconazole,
- pentoxifylline (high dose parenteral),
- tritoqualine.

Weakening of the blood-glucose-lowering effect and, thus raised blood glucose levels may occur when one of the following medicinal products is taken, for example:

oestrogens and progestogens,

saluretics, thiazide diuretics,

thyroid stimulating agents, glucocorticoids,

phenothiazine derivatives, chlorpromazine,

adrenaline and sympathicomimetics,

nicotinic acid (high dosages) and nicotinic acid derivatives,

laxatives (long term use),

phenytoin, diazoxide,

glucagon, barbiturates and rifampicin,

acetazolamide.

H₂ antagonists, betablockers, clonidine and reserpine may lead to either potentiation or weakening of the blood glucose lowering effect.

Under the influence of sympatholytic medicinal products such as betablockers, clonidine, guanethidine and reserpine, the signs of adrenergic counterregulation to hypoglycaemia may be reduced or absent.

Alcohol intake may potentiate or weaken the hypoglycaemic action of glimepiride in an unpredictable fashion.

Glimepiride may either potentiate or weaken the effects of coumarin derivatives

4.6 Pregnancy And Lactation

Pregnancy

Risk related to the diabetes

Abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities and perinatal mortality. So the blood glucose level must be closely monitored during pregnancy in order to avoid the teratogenic risk. The use of insulin is required under such circumstances. Patients who consider pregnancy should inform their physician.

Risk related to glimepiride

There are no adequate data from the use of glimepiride in pregnant women. Animal studies have shown reproductive toxicity which likely was related to the pharmacologic action (hypoglycaemia) of glimepiride (see section 5.3).

Consequently, glimepiride should not be used during the whole pregnancy.

In case of treatment by glimepiride, if the patient plans to become pregnant or if a pregnancy is discovered, the treatment should be switched as soon as possible to insulin therapy.

Lactation

The excretion in human milk is unknown. Glimepiride is excreted in rat milk. As other sulfonylureas are excreted in human milk and because there is a risk of hypoglycaemia in nursing infants, breast-feeding is advised against during treatment with glimepiride.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it is advisable to drive or operate machinery in these circumstances.

4.8 Undesirable Effects

.

The following adverse reactions from clinical investigations are based on experience with glimepiride and other sulfonylureas, and are listed below by system organ class and in order of decreasing incidence (very common:

Blood and lymphatic system disorders

Rare: thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, erythropenia, haemolytic anaemia and pancytopenia, which are in general reversible upon discontinuation of medication.

Immune system disorders

Very rare: leukocytoclastic vasculitis, mild hypersensitivity reactions that may develop into serious reactions with dyspnoea, fall in blood pressure and sometimes shock.

Not known:cross-allergenicity with sulfonylureas, sulfonamides or related substances is possible.

Metabolism and nutrition disorders

Rare: hypoglycaemia.

These hypoglycaemic reactions mostly occur immediately, may be severe and are not always easy to correct. The occurrence of such reactions depends, as with other hypoglycaemic therapies, on individual factors such as dietary habits and dosage (see further under section 4.4).

Eye disorders

Not known:visual disturbances, transient, may occur especially on initiation of treatment, due to changes in blood glucose levels.

Gastrointestinal disorders

Very rare: nausea, vomiting, diarrhoea, abdominal distension, abdominal discomfort and abdominal pain, which seldom lead to discontinuation of therapy.

Hepato-biliary disorders

Not known:hepatic enzymes increased. Very rare: hepatic function abnormal (e.g. with cholestasis and jaundice) hepatitis and hepatic failure.

Skin and subcutaneous tissue disorders

Not known:hypersensitivity reactions of the skin may occur as pruritus, rash urticaria and photosensitivity.

Investigations

Very rare: blood sodium decrease.

4.9 Overdose

After ingestion of an overdosage hypoglycaemia may occur, lasting from 12 to 72 hours, and may recur after an initial recovery. Symptoms may not be present for up to 24 hours after ingestion. In general observation in hospital is recommended. Nausea, vomiting and epigastric pain may occur. The hypoglycaemia may in general be accompanied by neurological symptoms like restlessness, tremor, visual disturbances, co-ordination problems, sleepiness, coma and convulsions.

Treatment primarily consists of preventing absorption by inducing vomiting and then drinking water or lemonade with activated charcoal (adsorbent) and sodium-sulphate (laxative). If large quantities have been ingested, gastric lavage is indicated, followed by activated charcoal and sodium-sulphate. In case of (severe) overdosage hospitalisation in an intensive care department is indicated. Start the administration of glucose as soon as possible, if necessary by a bolus intravenous injection of 50 ml of a 50% solution, followed by an infusion of a 10% solution with strict monitoring of blood glucose. Further treatment should be symptomatic.

In particular when treating hypoglycaemia due to accidental intake of Glimepiride Winthrop in infants and young children, the dose of glucose given must be carefully controlled to avoid the possibility of producing dangerous hyperglycaemia. Blood glucose should be closely monitored.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Blood glucose lowering drugs, excl. insulins: Sulfonamides, urea derivatives. ATC Code: A10B B12.

Glimepiride is an orally active hypoglycaemic substance belonging to the sulfonylurea group. It may be used in non-insulin dependent diabetes mellitus.

Glimepiride acts mainly by stimulating insulin release from pancreatic beta cells.

As with other sulfonylureas this effect is based on an increase of responsiveness of the pancreatic beta cells to the physiological glucose stimulus. In addition, glimepiride seems to have pronounced extrapancreatic effects also postulated for other sulfonylureas.

Insulin release

Sulfonylureas regulate insulin secretion by closing the ATP-sensitive potassium channel in the beta cell membrane. Closing the potassium channel induces depolarisation of the beta cell and results

This leads to insulin release through exocytosis.

Glimepiride binds with a high exchange rate to a beta cell membrane protein which is associated with the ATP-sensitive potassium channel but which is different from the usual sulfnylurea binding site.

Extrapancreatic activity

The extrapancreatic effects are for example an improvement of the sensitivity of the peripheral tissue for insulin and a decrease of the insulin uptake by the liver.

The uptake of glucose from blood into peripheral muscle and fat tissues occurs via special transport proteins, located in the cells membrane. The transport of glucose in these tissues is the rate limiting step in the use of glucose. Glimepiride increases very rapidly the number of active glucose transport molecules in the plasma membranes of muscle and fat cells, resulting in stimulated glucose uptake.

Glimepiride increases the activity of the glycosyl-phosphatidylinositol-specific phospholipase C which may be correlated with the drug-induced lipogenesis and glycogenesis in isolated fat and muscle cells.

Glimepiride inhibits the glucose production in the liver by increasing the intracellular concentration of fructose-2,6

General

In healthy persons, the minimum effective oral dose is approximately 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to acute physical exercise, reduction of insulin secretion, is still present under glimepiride.

There was no significant difference in effect regardless of whether the medicinal product was given 30 minutes or immediately before a meal. In diabetic patients, good metabolic control over 24 hours can be achieved with a single daily dose.

Although the hydroxy metabolite of glimepiride caused a small but significant decrease in serum glucose in healthy persons, it accounts for only a minor part of the total drug effect.

Combination therapy with metformin

Improved metabolic control for concomitant glimepiride therapy compared to metformin alone in patients not adequately controlled with the maximum dosage of metformin has been shown in one study.

Combination therapy with insulin

Data for combination therapy with insulin are limited. In patients not adequately controlled with the maximum dosage of glimepiride, concomitant insulin therapy can be initiated. In two studies, the combination achieved the same improvement in metabolic control as insulin alone; however, a lower average dose of insulin was required in combination therapy.

Special populations

Children and adolescents

An active controlled clinical trial (glimepiride up to 8 mg daily or metformin up to 2,000 mg daily) of 24 weeks duration was performed in 285 children (8-17 years of age) with type 2 diabetes.

Both glimepiride and metformin exhibited a significant decrease from baseline in HbA_1c (glimepiride -0.95 (se 0.41); metformin -1.39 (se 0.40)). However, glimepiride did not achieve the criteria of non-inferiority to metformin in mean change from baseline of HbA_1c. The difference between treatments was 0.44% in favour of metformin. The upper limit (1.05) of the 95% confidence interval for the difference was not below the 0.3% non-inferiority margin.

Following glimepiride treatment, there were no new safety concerns noted in children compared to adult patients with type 2 diabetes mellitus. No long-term efficacy and safety data are available in paediatric patients.

5.2 Pharmacokinetic Properties

Absorption: The bioavailability of glimepiride after oral administration is complete. Food intake has no relevant influence on absorption, only absorption rate is slightly diminished. Maximum serum concentrations (C_max) are reached approx. 2.5 hours after oral intake (mean 0.3 µg/ml during multiple dosing of 4 mg daily) and there is a linear relationship between dose and both C_max and AUC (area under the time/concentration curve).

Distribution: Glimepiride has a very low distribution volume (approx. 8.8 litres) which is roughly equal to the albumin distribution space, high protein binding (>99%), and a low clearance (approx. 48 ml/min).

In animals, glimepiride is excreted in milk. Glimepiride is transferred to the placenta. Passage of the blood brain barrier is low.

Biotransformation and elimination: Mean dominant serum half-life, which is of relevance for the serum concentrations under multiple-dose conditions, is about 5 to 8 hours. After high doses, slightly longer half-lives were noted.

After a single dose of radiolabelled glimepiride, 58% of the radioactivity was recovered in the urine, and 35% in the faeces. No unchanged substance was detected in the urine. Two metabolites

Comparison of single and multiple once-daily dosing revealed no significant differences in pharmacokinetics, and the intraindividual variability was very low. There was no relevant accumulation.

Special populations

Pharmacokinetics were similar in males and females, as well as in young and elderly (above 65 years) patients. In patients with low creatinine clearance, there was a tendency for glimepiride clearance to increase and for average serum concentrations to decrease, most probably resulting from a more rapid elimination because of lower protein binding. Renal elimination of the two metabolites was impaired. Overall no additional risk of accumulation is to be assumed in such patients.

Pharmacokinetics in five non-diabetic patients after bile duct surgery were similar to those in healthy persons.

Children and adolescents

A fed study investigating the pharmacokinetics, safety, and tolerability of a 1 mg single dose of glimepiride in 30 paediatric patients (4 children aged 10-12 years and 26 children aged 12-17 years) with type 2 diabetes showed mean AUC_(0-last) , Cmax and t_1/2 similar to that previously observed in adults.

5.3 Preclinical Safety Data

Preclinical effects observed occurred at exposures sufficiently in excess of the maximum human exposure as to indicate little relevance to clinical use, or were due to the pharmacodynamic action (hypoglycaemia) of the compound. This finding is based on conventional safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and reproduction toxicity studies. In the latter (covering embryotoxicity, teratogenicity and developmental toxicity), adverse effects observed were considered to be secondary to the hypoglycaemic effects induced by the compound in dams and in offspring.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate

sodium starch glycollate (type A)

magnesium stearate

microcrystalline cellulose

povidone 25000

Colouring agents

Yellow iron oxide (E172)

Indigo-carmine aluminium lake (E132)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 30°C.

Store in the original package in order to protect from moisture.

6.5 Nature And Contents Of Container

White/opaque PVC/Aluminium blisters or clear/bluish PVC/Aluminium blisters.

15, 20, 30, 50, 60, 90 and 120 tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 17780/0002

9. Date Of First Authorisation/Renewal Of The Authorisation

26/01/10

10. Date Of Revision Of The Text

January 2010

Legal status

POM

Estradiol Spray

Pronunciation: ES-tra-DYE-ol
Generic Name: Estradiol
Brand Name: Evamist

Estradiol Spray should not be used to prevent heart disease, heart attacks, strokes, or dementia. Estrogens may increase the risk of heart disease (including heart attack), stroke, dementia, serious blood clots (eg, in the lungs or legs), cancer of the uterus, and breast cancer in some women. Tell your doctor right away if you have unusual vaginal bleeding while you use Estradiol Spray. Talk with your doctor if you have questions about the benefits and risks of using Estradiol Spray.

Estradiol Spray should be used for the shortest possible time at the lowest effective dose to minimize the risk of these side effects. Talk with your doctor regularly about your need to use Estradiol Spray.

Follow the directions for use very carefully. Do not allow others, especially CHILDREN, to come into contact with the area of your skin where Estradiol Spray has been applied. Young children who accidentally come into contact with Estradiol Spray may show unexpected signs of puberty (eg, breast budding in girls, breast enlargement in boys). If a child with whom you are in close contact unexpectedly starts to develop breasts or has other sexual changes, contact the child's doctor.

Estradiol Spray is used for:

Treating certain moderate to severe symptoms of menopause (eg, hot flashes).

Estradiol Spray is an estrogen hormone. It works by replacing estrogen in the body when it no longer produces enough on its own.

Do NOT use Estradiol Spray if:

• you are allergic to any ingredient in Estradiol Spray


• you are pregnant or suspect you may be pregnant


• you have undiagnosed abnormal vaginal bleeding


• you have blood clots (eg, in the lungs, legs, eyes) or a history of blood clots


• you have known or suspected breast cancer or another estrogen-dependent cancer, or you have a history of breast cancer


• you have a history of liver problems or liver disease


• you have had a heart attack or stroke within the past 12 months

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

Before using Estradiol Spray:

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

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


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


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


• if you have a history of endometriosis, growths in the uterus, abnormal mammogram, abnormal vaginal bleeding, a lump in the breast, or fibrocystic breast disease, or if a family member has had breast cancer


• if you have dementia or other memory problems


• if you have a history of asthma, cancer, high blood cholesterol or lipid levels, high or low blood calcium levels, diabetes, heart problems, high blood pressure, heart attack or stroke, kidney problems, liver tumor, mental or mood problems (eg, depression), underactive thyroid, migraine headaches, gallbladder or pancreas problems, seizures (eg, epilepsy), lupus, chorea, or the blood disease porphyria


• if you smoke, use tobacco, are very overweight, or will be having surgery


• if you have a history of yellowing of the eyes or skin during pregnancy or with past estrogen use


• if a member of your family has a history of blood clots (eg, in the legs, lungs, eyes), diabetes, lupus, or obesity


• if you have had your uterus removed (hysterectomy)

Some MEDICINES MAY INTERACT with Estradiol Spray. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Azole antifungals (eg, ketoconazole), HIV protease inhibitors (eg, ritonavir), or macrolide antibiotics (eg, erythromycin) because they may increase the risk of Estradiol Spray's side effects


• Barbiturates (eg, phenobarbital), carbamazepine, hydantoins (eg, phenytoin), rifampin, or St. John's wort because they may decrease Estradiol Spray's effectiveness


• Thyroid hormones (eg, levothyroxine) because their effectiveness may be decreased by Estradiol Spray

This may not be a complete list of all interactions that may occur. Ask your health care provider if Estradiol Spray may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Estradiol Spray:

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

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


• Estradiol Spray is applied to the inside of the forearm, between the elbow and the wrist. Do not apply Estradiol Spray to any other area of the body besides the forearm. If you get Estradiol Spray on another area of your skin, wash that area of your skin with soap and water right away.


• Apply Estradiol Spray to clean, intact skin only. Be sure the area is completely dry before applying Estradiol Spray.


• Do not apply Estradiol Spray to skin that is irritated or broken. Do not apply it to your face, in or around the vagina, or to your breasts.


• You will need to prime the pump before using it for the first time. To prime the pump, leave the cover on, hold the bottle in an upright position, and press the pump completely down 3 times. The pump is now ready for use.


• Hold the applicator upright and rest the plastic cone flat against the skin of your forearm. Be sure there are no gaps between the cone and your skin. Press the pump firmly and fully 1 time. Do NOT massage or rub the medicine in.


• If you are applying more than 1 spray, move the cone to an area of the skin next to but not touching the previous area. Then press the pump firmly and fully again.


• Replace the protective cover over the pump after use.


• Wash your hands with soap and water after using Estradiol Spray.


• Allow the medicine to dry for at least 2 minutes before dressing.


• Do not wash the application area for at least 1 hour after you apply Estradiol Spray.


• Do not allow others to apply Estradiol Spray for you. Do not allow other people or pets to come into contact with the site where you applied Estradiol Spray. If someone else comes into contact with Estradiol Spray, have them wash the area with soap and water right away.


• This pump contains enough medicine for 75 sprays (not counting the 3 sprays used to prime the pump). Throw away the pump after 75 sprays have been used, even if there is still medicine left in the pump. It may no longer give the correct amount of medicine with each dose.


• Use Estradiol Spray at the same time each day.


• If you miss a dose of Estradiol Spray, use it as soon as possible. If your next dose is less than 12 hours away, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Estradiol Spray.

Important safety information:

• Estradiol Spray may cause dizziness. This effect may be worse if you take it with alcohol or certain medicines. Use Estradiol Spray with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Estradiol Spray is for external use only. Do not get it in your eyes, nose, vagina, or mouth. If you get it in any of these areas, rinse right away with warm clean water.


• Check with your doctor before you apply sunscreen to the application site while you are using Estradiol Spray.


• Estradiol Spray is flammable. Avoid fire, flame, or smoking until the medicine has dried on your skin.


• Eating grapefruit or drinking grapefruit juice may increase the risk of Estradiol Spray's side effects. Talk to your doctor before including grapefruit or grapefruit juice in your diet while you are taking Estradiol Spray.


• Tell your doctor or dentist that you take Estradiol Spray before you receive any medical or dental care, emergency care, or surgery. If possible, Estradiol Spray should be stopped at least 4 to 6 weeks before surgery or any time you might be confined to a bed or chair for a long period of time (such as a long plane flight, car ride, bedrest, or illness).


• Estradiol Spray may cause dark skin patches on your face. Exposure to the sun may make these patches darker. If patches develop, use a sunscreen or wear protective clothing when exposed to the sun, sunlamps, or tanning booths.


• If you wear contact lenses and you develop problems with them, contact your doctor.


• Diabetes patients - Estradiol Spray may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


• Estradiol Spray may interfere with certain lab tests. Be sure your doctor and lab personnel know you are using Estradiol Spray.


• Talk with your doctor regularly (eg, every 3 to 6 months) about whether you need to continue taking Estradiol Spray.


• Lab tests and medical exams, including physicals and blood pressure, may be performed while you use Estradiol Spray. You should have breast and pelvic exams, and a Pap test at least once a year. You should also have periodic mammograms as determined by your doctor. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Examine your breasts monthly as directed by your doctor. Report any lumps right away.


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


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


• PREGNANCY and BREAST-FEEDING: Do not use Estradiol Spray if you are pregnant. If you think you may be pregnant, contact your doctor right away. Estradiol Spray is found in breast milk. Do not breast-feed while you are taking Estradiol Spray.

Possible side effects of Estradiol Spray:

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

Breast pain or tenderness; headache; mild fluid retention; mild hair loss; mild nausea or vomiting; spotting or breakthrough bleeding; stomach cramps or bloating.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); blurred or double vision, vision loss, or other vision changes; breast lump or discharge; calf or leg pain or swelling; chest pain; confusion; coughing up blood; fainting; memory problems; mental or mood changes (eg, depression); migraine headache; numbness of an arm or leg; one-sided weakness; persistent or recurring abnormal vaginal bleeding; severe or persistent headache or dizziness; severe or persistent stomach pain, nausea, or vomiting; shortness of breath; slurred speech; swelling of the hands, legs, or feet; vaginal discharge, itching, or odor; yellowing of the skin or eyes.

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

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include abnormal vaginal bleeding; breast tenderness; dizziness; drowsiness or tiredness; severe or persistent nausea or vomiting; stomach pain.

Proper storage of Estradiol Spray:

Store Estradiol Spray at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Do not freeze. Store away from heat, moisture, and light. Do not store in the bathroom or near an open flame. Do not use Estradiol Spray after the expiration date. Keep Estradiol Spray out of the reach of children and away from pets.

General information:

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


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


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Estradiol resources

• Estradiol Use in Pregnancy & Breastfeeding
• Drug Images
• Estradiol Drug Interactions
• Estradiol Support Group
• 57 Reviews for Estradiol - Add your own review/rating

Compare Estradiol with other medications

• Atrophic Urethritis
• Atrophic Vaginitis
• Breast Cancer, Palliative
• Hypoestrogenism
• Oophorectomy
• Osteoporosis
• Postmenopausal Symptoms
• Primary Ovarian Failure
• Prostate Cancer

Nurofen for Children Orange / Nurofen for Children Orange Baby

1. Name Of The Medicinal Product

Nurofen for Children Orange

Nurofen for Children Orange Baby

Nurofen for Children 3 months to 9 years Orange

2. Qualitative And Quantitative Composition

Ibuprofen 100 mg/5ml (equivalent to 2.0% w/v).

For excipients, see 6.1.

3. Pharmaceutical Form

Oral suspension.

An off-white, orange-flavoured, syrupy suspension.

4. Clinical Particulars

4.1 Therapeutic Indications

Prescription and OTC: For the fast and effective reduction of fever, including post immunisation pyrexia and the fast and effective relief of the symptoms of colds and influenza and mild to moderate pain, such as a sore throat, teething pain, toothache, headache, minor aches and sprains.

4.2 Posology And Method Of Administration

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

For pain, fever and symptoms of cold and infuenza: The daily dosage of Nurofen For Children is 20-30 mg/kg bodyweight in divided doses. Using the spoon or syringe dosing device provided this can be achieved as follows:

Infants 3 - 6 months weighing more than 5kg: One 2.5ml dose may be taken 3 times in 24 hours.

Infants 6 - 12 months: One 2.5ml dose may be taken 3 to 4 times in 24 hours.

Children 1 - 3 years: One 5ml dose may be taken 3 times in 24 hours.

Children 4 - 6 years: 7.5ml (5ml +2.5ml spoonful) may be taken 3 times in 24 hours.

Children 7 - 9 years: Two 5ml doses may be taken 3 times in 24 hours.

Children 10 – 12 years: Three 5ml doses may be taken 3 times in 24 hours.

Doses should be given approximately every 6 to 8 hours, (or with a minimum of 4 hours between each dose if required).

Not suitable for children under 3 months of age unless advised by your doctor.

For Juvenile Rheumatoid Arthritis: The usual daily dosage is 30 to 40 mg/kg/day in three to four divided doses.

For post immunisation pyrexia: One 2.5 ml dose followed by one further 2.5 ml dose 6 hours later if necessary. No more than two 2.5ml doses in 24 hours. If the fever is not reduced, consult your doctor.

For oral administration.

For short term use only. If the child's (aged over 6months) symptoms persist for more than 3 days, consult your doctor.

For children under 6 months medical advice should be sought after 24 hours use (3 doses) if the symptoms persist.

4.3 Contraindications

Hypersensitivity to ibuprofen or any of the constituents in the product.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs.

Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

History of upper gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

Severe hepatic failure, renal failure or heart failure (See section 4.4, Special warnings and precautions for use)

Last trimester of pregnancy (See section 4.6 Pregnancy and lactation)

4.4 Special Warnings And Precautions For Use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and cardiovascular risks below).

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Respiratory:

Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease.

Other NSAIDs:

The use of Ibuprofen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

SLE and mixed connective tissue disease:

Systemic lupus erythematosus and mixed connective tissue disease - increased risk of aseptic meningitis (see section 4.8 Undesirable effects)

Renal:

Renal impairment as renal function may further deteriorate (See section 4.3 Contraindications and Section 4.8 Undesirable effects)

Hepatic:

Hepatic dysfunction (See section 4.3 Contraindications and Section 4.8 Undesirable effects)

Cardiovascular and cerebrovascular effects:

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g.

Impaired female fertility

There is limited evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment.

Gastrointestinal:

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available.

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Ibuprofen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Patients with a rare hereditary problems of fructose intolerance should not take this medicine.

The label will state:

Read the leaflet carefully before use.

Do not give this product if your baby or child:

• Is under 3 months old

• has (or has had two or more episodes of ) a stomach ulcer, perforation or bleeding

• is allergic to ibuprofen or any other ingredient of the product, aspirin or other related painkillers

• are taking other NSAID painkillers, or aspirin with a daily dose above 75mg

Speak to your doctor or pharmacist before giving this product if baby or child:

• has or had asthma, diabetes, high cholesterol, high blood pressure, a stroke, heart, liver, kidney or bowel problems

This product is intended for children aged between 3 months and 12 years.

If you are an adult taking this product:

Speak to a pharmacist or your doctor before taking if:

• You are a pregnant

• You are trying to get pregnant

• Are elderly

• Are a smoker

Do not exceed the stated dose.

Keep out of the reach and sight of children.

For short term use.

If symptoms persist or worsen, consult your doctor.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ibuprofen should not be used in combination with:

Aspirin: Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (see section 4.4).

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Other NSAIDs including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.4)

Ibuprofen should be used with caution in combination with:

Anticoagulants: NSAIDS may enhance the effects of anti-coagulants, such as warfarin (See section 4.4).

Antihypertensives and diuretics: NSAIDs may diminish the effect of these drugs. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Corticosteroids: as these may increase the risk of gastrointestinal ulceration or bleeding (see Section 4.4)

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: There is evidence for potential increases in plasma levels of lithium.

Methotrexate: There is a potential for an increase in plasma methotrexate.

Ciclosporin: Increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

4.6 Pregnancy And Lactation

Whilst no teratogenic effects have been demonstrated in animal studies, the use of this product should, if possible, be avoided during the first 6 months of pregnancy.

During the 3^rd trimester, ibuprofen is contraindicated as there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child. (See section 4.3 Contraindications).

In limited studies, ibuprofen appears in the breast milk in very low concentration and is unlikely to affect the breast-fed infant adversely.

See section 4.4 regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

None expected at recommended doses and duration of therapy.

4.8 Undesirable Effects

Hypersensitivity reactions have been reported and these may consist of:

(a) Non-specific allergic reactions and anaphylaxis

(b) Respiratory tract reactivity, eg asthma, aggravated asthma, bronchospasm, dyspnoea

(c) Various skin reactions, e.g. pruritus, urticaria, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme)

The following list of adverse effects relates to those experienced with ibuprofen at OTC doses, for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

Hypersensitivity reactions:

Uncommon: Hypersensitivity reactions with urticaria and pruritus.

Very rare: severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock).

Exacerbation of asthma and bronchospasm.

Gastrointestinal:

The most commonly observed adverse events are gastrointestinal in nature.

Uncommon: abdominal pain, nausea and dyspepsia.

Rare: diarrhoea, flatulence, constipation, and vomiting.

Very rare: peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis.

Exacerbation of ulcerative colitis and Crohn's disease (See section 4.4).

Nervous System:

Uncommon: Headache

Very rare: Aseptic meningitis – single cases have been reported very rarely.

Renal:

Very rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.

Hepatic:

Very rare: liver disorders.

Haematological:

Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.

Skin:

Uncommon: Various skin rashes

Very rare: Severe forms of skin reactions such as bullous reactions including Stevens-Johnson syndrome, erythema multiforme and toxic epidermal necrolysis can occur

Immune System:

In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (See section 4.4)

Cardiovascular and Cerebrovascular

Oedema, hypertension and cardiac failure, have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

4.9 Overdose

In children ingestion of more than 400 mg/kg may cause symptoms. In adults the dose response effect is less clear-cut. The half-life in overdose is 1.5-3 hours.

Symptoms

Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/ INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.

Management

Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ibuprofen is a proprionic acid derivative NSAID which has analgesic, antipyretic and anti-inflammatory properties. Ibuprofen inhibits prostaglandin synthesis, furthermore, ibuprofen reversibly inhibits platelet aggregation

Ibuprofen has been shown to an have onset of both analgesic and antipyretic action within 30 minutes.

ATC Code, M01A E01

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken with 8 h before or within 30 min after immediate release aspirin dosing (81mg), a decreased effect of ASA on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no relevant effect is considered to be likely for occasional use.

5.2 Pharmacokinetic Properties

Ibuprofen is rapidly absorbed following administration and is rapidly distributed throughout the whole body. The excretion is rapid and complete via the kidneys.

Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, peak levels are observed after 1 to 2 hours. These times may vary with different dosage forms.

The half-life of ibuprofen is about 2 hours.

In limited studies, ibuprofen appears in the breast milk in very low concentrations.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Citric acid

Sodium citrate

Sodium chloride

Sodium saccharin

Domiphen bromide

Purified water

Polysorbate 80

Maltitol liquid

Xanthan gum

Orange flavour

Glycerol.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

100 ml, 150ml - 3 years.

30 ml, 50 ml – 2 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Amber-coloured polyethylene terephthalate (PET) bottle with a child-resistant closure fitted with a low density polyethylene liner. The bottle contains 50 ml, 100 ml or 150 ml of product. A double-ended spoon with measures of 2.5 ml and 5 ml will be provided.

OR

Amber-coloured polyethylene terephthalate (PET) bottle with a child-resistant closure fitted with a low density polyethylene liner. The bottle contains 50 ml, 100 ml or 150 ml of product. A syringe composed of a polypropylene barrel and a PE piston with measures of 2.5 ml and 5 ml will be provided.

A 30ml amber glass bottle fitted with a polypropylene child resistant closure and tamper evident band. A double-ended spoon with measures of 2.5 ml and 5 ml will be provided.

Not all pack sizes will be marketed.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Ltd

Slough

SL1 4AQ

8. Marketing Authorisation Number(S)

PL 00063/0668

9. Date Of First Authorisation/Renewal Of The Authorisation

5 August 2004

10. Date Of Revision Of The Text

16/09/2011

Ayr Saline Solution

Pronunciation: SAY-leen
Generic Name: Saline
Brand Name: Ayr Saline

Ayr Saline Solution is used for:

Treating dry or irritated nasal passages caused by colds, allergies, low humidity, or overuse of decongestant nose spray.

Ayr Saline Solution is a salt solution. It works by rinsing and moisturizing the nostrils.

Do NOT use Ayr Saline Solution if:

• you are allergic to any ingredient in Ayr Saline Solution

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

Before using Ayr Saline Solution:

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

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


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


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

Some MEDICINES MAY INTERACT with Ayr Saline Solution. However, no specific interactions are known at this time.

This may not be a complete list of all interactions that may occur. Ask your health care provider if Ayr Saline Solution may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Ayr Saline Solution:

Use Ayr Saline Solution as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• To use nose drops, gently blow your nose. Lie down and tilt your head back. Breathe through your mouth. Insert the dropper tip in the nose no more than 1/3 inch. Try not to touch the dropper tip to the inside of your nose. Place the correct number of drops in your nose. Continue to lie down with your head tilted back for 2 minutes.


• If you miss a dose of Ayr Saline Solution, use the dose when you remember and continue to use Ayr Saline Solution as directed by your doctor or the package labeling.

Ask your health care provider any questions you may have about how to use Ayr Saline Solution.

Important safety information:

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


• PREGNANCY and BREAST-FEEDING: If you become pregnant while taking Ayr Saline Solution, discuss with your doctor the benefits and risks of using Ayr Saline Solution during pregnancy. If you are or will be breast-feeding while you are using Ayr Saline Solution, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Ayr Saline Solution:

All medicines may cause side effects, but many people have no, or minor, side effects. No COMMON side effects have been reported with the proper use of Ayr Saline Solution. Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

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

See also: Ayr Saline side effects (in more detail)

If OVERDOSE is suspected:

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

Proper storage of Ayr Saline Solution:

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

General information:

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


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


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Ayr Saline resources

• Ayr Saline Side Effects (in more detail)
• Ayr Saline Use in Pregnancy & Breastfeeding
• 0 Reviews for Ayr Saline - Add your own review/rating

Compare Ayr Saline with other medications

• Nasal Congestion

Arzerra (citrate formulation)

1. Name Of The Medicinal Product

Arzerra® 

2. Qualitative And Quantitative Composition

One ml of concentrate contains 20 mg of ofatumumab.

Each vial contains 100 mg of ofatumumab in 5 ml.

Ofatumumab is a human monoclonal antibody produced in a recombinant murine cell line (NS0).

Excipients:

This medicinal product contains 64.5 mg sodium per 300 mg dose and 430 mg sodium per 2,000 mg dose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Concentrate for solution for infusion (sterile concentrate).

Clear, colourless liquid. Visible particles may be present.

4. Clinical Particulars

4.1 Therapeutic Indications

Arzerra is indicated for the treatment of chronic lymphocytic leukaemia (CLL) in patients who are refractory to fludarabine and alemtuzumab.

4.2 Posology And Method Of Administration

Arzerra should be administered under the supervision of a physician experienced in the use of cancer therapy and in an environment where full resuscitation facilities are immediately available.

Pre-medication

Patients should be pre-medicated 30 minutes to 2 hours prior to Arzerra infusion according to the following dosing schedule:

Infusion number (dose)	Intravenous corticosteroid dose	Analgesic dose	Antihistamine dose
1 (300 mg)	Equivalent to 100 mg prednisolone	Equivalent to 1,000 mg paracetamol	Equivalent to 10 mg cetirizine
2 (2,000 mg)	Equivalent to 100 mg prednisolone	Equivalent to 1,000 mg paracetamol	Equivalent to 10 mg cetirizine
3-8 (2,000 mg)	Equivalent to 0-100 mg prednisolone a)	Equivalent to 1,000 mg paracetamol	Equivalent to 10 mg cetirizine
9 (2,000 mg)	Equivalent to 100 mg prednisolone	Equivalent to 1,000 mg paracetamol	Equivalent to 10 mg cetirizine
10-12 (2,000 mg)	Equivalent to 50-100 mg prednisolone b)	Equivalent to 1,000 mg paracetamol	Equivalent to 10 mg cetirizine
a) If the second infusion is completed without a severe adverse drug reaction, the dose may be reduced at the discretion of the physician. b) If the ninth infusion is completed without a serious adverse drug reaction, the dose may be reduced at the discretion of the physician.

Posology

The recommended dose is 300 mg ofatumumab for the first infusion and 2,000 mg ofatumumab for all subsequent infusions. The infusion schedule is 8 consecutive weekly infusions, followed 4-5 weeks later by 4 consecutive monthly (i.e. every 4 weeks) infusions.

First and second infusions

The initial rate of the first and second infusion of Arzerra should be 12 ml/hour. During infusion, the rate should be doubled every 30 minutes to a maximum of 200 ml/hour (see section 6.6).

Subsequent infusions

If the second infusion has been completed without severe infusion related adverse drug reactions (ADRs), the remaining infusions can start at a rate of 25 ml/hour and should be doubled every 30 minutes up to a maximum of 400 ml/hour (see section 6.6).

Dose modification and reinitiation of therapy

Infusion related ADRs may lead to slower infusion rates.

• In case of a mild or moderate ADR, the infusion should be interrupted and restarted at half of the infusion rate at the time of interruption, when the patient's condition is stable. If the infusion rate had not been increased from the starting rate of 12 ml/hour prior to interrupting due to an ADR, the infusion should be restarted at 12 ml/hour, the standard starting infusion rate. The infusion rate can continue to be increased according to standard procedures, according to physician discretion and patient tolerance (not to exceed doubling the rate every 30 minutes).

• In case of a severe ADR, the infusion should be interrupted and restarted at 12 ml/hour, when the patient's condition is stable. The infusion rate can continue to be increased according to standard procedures, according to physician discretion and patient tolerance (not to exceed doubling the rate every 30 minutes).

Paediatric population

Arzerra is not recommended for use in children below 18 years due to insufficient data on safety and/or efficacy.

Elderly

No substantial differences were seen in safety and efficacy related to age. Based on available safety and efficacy data in the elderly, no dose adjustment is required (see section 5.2).

Renal impairment

No formal studies of Arzerra in patients with renal impairment have been performed. No dose adjustment is recommended for mild to moderate renal impairment (creatinine clearance >30 ml/min) (see section 5.2).

Hepatic impairment

No formal studies of Arzerra in patients with hepatic impairment have been performed. However, patients with hepatic impairment are unlikely to require dose modification (see section 5.2).

Method of administration

Arzerra is for intravenous infusion and must be diluted prior to administration (see section 6.6).

4.3 Contraindications

Hypersensitivity to ofatumumab or to any of the excipients (see section 6.1).

4.4 Special Warnings And Precautions For Use

Infusion reactions

Ofatumumab has been associated with infusion reactions leading to temporary interruption of treatment or withdrawal of treatment. Pre-medications attenuate infusion reactions but these may still occur, predominantly during the first infusion. Infusion reactions may include anaphylactoid events, cardiac events, chills/rigors, cough, cytokine release syndrome, diarrhoea, dyspnoea, fatigue, flushing, hypertension, hypotension, nausea, pain, pyrexia, rash, and urticaria. Even with pre-medication, severe reactions, including cytokine release syndrome, have been reported following use of ofatumumab. In cases of severe infusion reaction, the infusion of Arzerra must be interrupted immediately and symptomatic treatment instituted (see section 4.2).

Infusion reactions occur more frequently on the first day of infusion and tend to decrease with subsequent infusions. Patients with a history of decreased pulmonary function may be at a greater risk for pulmonary complications from severe reactions and should be monitored closely during infusion of ofatumumab.

Tumour lysis syndrome

In patients with CLL, tumour lysis syndrome (TLS) may occur with use of ofatumumab. Risk factors for TLS include a high tumour burden, high concentrations of circulating cells (³), hypovolaemia, renal insufficiency, elevated pre-treatment uric acid levels and elevated lactate dehydrogenase levels. Management of TLS includes correction of electrolyte abnormalities, monitoring of renal function, maintenance of fluid balance and supportive care.

Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) and death has been reported in CLL patients receiving cytotoxic pharmacotherapy, including ofatumumab. A diagnosis of PML should be considered in any Arzerra patient who reports the new onset of or changes in pre-existing neurologic signs and symptoms. If a diagnosis of PML is suspected Arzerra should be discontinued and referral to a neurologist should be considered.

Immunisations

The safety of, and ability to generate a primary or anamnestic response to, immunisation with live attenuated or inactivated vaccines during treatment with ofatumumab has not been studied. The response to vaccination could be impaired when B cells are depleted. Due to the risk of infection, administration of live attenuated vaccines should be avoided during and after treatment with ofatumumab, until B cell counts are normalised. The risks and benefits of vaccinating patients during therapy with ofatumumab should be considered.

Hepatitis B

Hepatitis B infection (HBV), including fatal infection, can occur in patients taking ofatumumab. Hepatitis B reactivation including fulminant hepatitis and death occurs with other monoclonal antibodies directed against CD20. Patients at high risk of HBV infection should be screened before initiation of Arzerra. Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection during treatment with ofatumumab and for 6-12 months following the last infusion of Arzerra. Arzerra should be discontinued in patients who develop viral hepatitis, and appropriate treatment should be instituted. Insufficient data exist regarding the safety of administration of ofatumumab in patients with active hepatitis.

Cardiovascular

Patients with a history of cardiac disease should be monitored closely. Arzerra should be discontinued in patients who experience serious or life-threatening cardiac arrhythmias.

Bowel obstruction

Bowel obstruction has been reported in patients receiving anti-CD20 monoclonal antibody therapy, including ofatumumab. Patients who present with abdominal pain, especially early in the course of ofatumumab therapy, should be evaluated and appropriate treatment instituted.

Laboratory monitoring

Since ofatumumab binds to all CD-20-positive lymphocytes (malignant and non-malignant), complete blood counts and platelet counts should be obtained at regular intervals during ofatumumab therapy and more frequently in patients who develop cytopenias.

Sodium content

This medicinal product contains 64.5 mg sodium per 300 mg dose and 430 mg sodium per 2,000 mg dose. This should be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Although no formal interaction studies have been performed with ofatumumab, there are no known clinically significant interactions with other medicinal products.

Live attenuated or inactivated vaccine efficacy may be impaired with ofatumumab. Therefore, the concomitant use of these agents with ofatumumab should be avoided. If the coadministration is judged unavoidable, the risks and benefits of vaccinating patients during therapy with ofatumumab should be considered (see section 4.4).

4.6 Pregnancy And Lactation

Pregnancy

There are no data from the use of ofatumumab in pregnant women. The effect on human pregnancy is unknown. Besides an expected pharmacological effect, i.e., depletion of B-cells, animal studies do not indicate direct or indirect harmful effects with respect to maternal toxicity, pregnancy or embryonal/foetal development (see section 5.3). Ofatumumab should not be administered to pregnant women unless the possible benefit to the mother outweighs the possible risk to the foetus.

Women of childbearing potential should use effective contraception during and for 12 months after the last ofatumumab treatment.

Lactation

The safe use of ofatumumab in humans during lactation has not been established. The excretion of ofatumumab in milk has not been studied in animals. It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Breastfeeding should be discontinued for the duration of treatment with ofatumumab and for 12 months following treatment.

Fertility

There are no data on the effects of ofatumumab on human fertility. Effects on male and female fertility have not been evaluated in animal studies.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects of Arzerra on the ability to drive and use machines have been performed.

No detrimental effects on such activities are predicted from the pharmacology of ofatumumab. The clinical status of the subject and the ADR profile of ofatumumab should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills (see section 4.8).

4.8 Undesirable Effects

The safety of ofatumumab in patients with relapsed or refractory CLL has been evaluated in two open-label studies. In study Hx-CD20-406, 154 patients were enrolled to receive an initial dose of 300 mg followed by 7 consecutive weekly infusions of 2,000 mg, followed five weeks later with 4 consecutive monthly infusions of 2,000 mg. The second study (Hx-CD20-402) was a dose-finding study and patients in three cohorts (3 patients, 3 patients, 27 patients) received a starting dose of 100 mg, 300 mg or 500 mg, followed a week later with 3 consecutive weekly infusions of 500 mg, 1,000 mg or 2,000 mg of ofatumumab, respectively. The adverse reactions reported are from final data from the initial dose-range finding and a planned interim analysis of study Hx-CD20-406.

Adverse reactions are listed below by MedDRA body system organ class and by frequency. Very common (

MedDRA System Organ Class	Very common	Common	Uncommon
Infections and Infestations	Lower respiratory tract infection, including pneumonia, upper respiratory tract infection	Sepsis, including neutropenic sepsis and septic shock, herpes virus infection, urinary tract infection
Blood and lymphatic system disorders	Neutropenia, anaemia	Febrile neutropenia, thrombocytopenia, leukopenia	Agranulocytosis, coagulopathy, red cell aplasia, lymphopenia
Immune system disorders		Anaphylactoid reactions, hypersensitivity
Metabolism and nutrition disorders			Tumour lysis syndrome
Cardiac disorders		Tachycardia
Vascular disorders		Hypotension, hypertension
Respiratory, thoracic and mediastinal disorders		Bronchospasm, hypoxia, dyspnoea, chest discomfort, pharyngolaryngeal pain, cough, nasal congestion
Gastrointestinal disorders		Small bowel obstruction, diarrhoea, nausea
Skin and subcutaneous tissue disorders	Rash	Urticaria, pruritus, flushing
Musculoskeletal and connective tissue disorders		Back pain
General disorders and administration site conditions		Cytokine release syndrome, pyrexia, rigors, chills, hyperhidrosis, fatigue

Infusion reactions: In the pivotal study (Hx-CD20-406), infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions (see section 4.4).

Infections: In the pivotal study, a total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced

Neutropenia: Of 108 patients with normal neutrophil counts at baseline who were part of the pivotal study, 45 (42%) developed

4.9 Overdose

No case of overdose has been reported.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: monoclonal antibodies, ATC code: L01XC10

This medicinal product has been authorised under a so-called 'conditional approval' scheme.

This means that further evidence on this medicinal product is awaited. The European Medicines Agency (EMA) will review new information on the product every year and this SmPC will be updated as necessary.

Mechanism of action

Ofatumumab is a human monoclonal antibody (IgG1) that binds specifically to a distinct epitope encompassing both the small and large extracellular loops of the CD20 molecule. The CD20 molecule is a transmembrane phosphoprotein expressed on B lymphocytes from the pre-B to mature B lymphocyte stage and on B cell tumours. The B cell tumours include CLL (generally associated with lower levels of CD20 expression) and non-Hodgkin's lymphomas (where > 90% tumours have high levels of CD20 expression). The CD20 molecule is not shed from the cell surface and is not internalised following antibody binding.

The binding of ofatumumab to the membrane-proximal epitope of the CD20 molecule induces recruitment and activation of the complement pathway at the cell surface, leading to complement-dependent cytotoxicity and resultant lysis of tumour cells. Ofatumumab has been shown to induce appreciable lysis of cells with high expression levels of complement defence molecules. Ofatumumab has also been shown to induce cell lysis in both high and low CD20 expressing cells and in rituximab-resistant cells. In addition, the binding of ofatumumab allows the recruitment of natural killer cells allowing the induction of cell death through antibody-dependent cell-mediated cytotoxicity.

Pharmacodynamic effects

Peripheral B cells counts decreased after the first ofatumumab infusion in patients with haematologic malignancies. In patients with refractory CLL, the median decrease in B cell counts was 23% after the first infusion and 92% after the eighth infusion. Peripheral B cell counts remained low throughout the remainder of therapy in most patients, then gradually recovered (median decrease in B cell counts was 68% below baseline 3 months after the end of ofatumumab therapy).

Immunogenicity

There is a potential for immunogenicity with therapeutic proteins such as ofatumumab; however the formation of anti-ofatumumab antibodies may be decreased because ofatumumab is a human antibody that depletes B cells in patients already immunocompromised by CLL.

In the pivotal clinical study (Hx-CD20-406), serum samples from 154 CLL patients treated with ofatumumab were tested for anti-ofatumumab antibodies. In the 46 patients who received at least 8 infusions and had serum ofatumumab concentrations that had decreased sufficiently to allow detection of anti-ofatumumab antibodies (33 of whom received all 12 infusions), all samples tested negative for anti-ofatumumab antibodies.

Clinical studies

The clinical efficacy of ofatumumab has been demonstrated in a planned interim analysis of an ongoing study Hx-CD20-406 (single-arm, open-label, multicentre), and one completed supportive study, Hx-CD20-402 (open-label, dose ranging, multicentre).

Hx-CD20-406

Arzerra was administered as a monotherapy to 154 patients with CLL. Patient median age was 63 years (range: 41 to 86 years), and the majority were male (72%) and white (97%). Patients received a median of 5 prior therapies, including rituximab (57%). Of these 154 patients, 59 patients were refractory to fludarabine and alemtuzumab therapy (defined as failure to achieve at least a partial response with fludarabine or alemtuzumab treatment or disease progression within 6 months of the last dose of fludarabine or alemtuzumab). Baseline cytogenetic (FISH) data were available for 151 patients. Chromosomal aberrations were detected in 118 patients; there were 33 patients with 17p deletion, 50 patients with 11q deletion, 16 patients with trisomy 12q, 30 patients with a normal karyotype and 19 patients with 13q deletion as the sole aberration.

The overall response rate was 58% in patients refractory to fludarabine and alemtuzumab (see Table 1 for a summary of the efficacy data from the study). Patients who had prior rituximab therapy, either as monotherapy or in combination with other medicinal products, responded to treatment with ofatumumab at a similar rate as those who had not had prior rituximab therapy.

Table 1. Summary of response to Arzerra in patients with CLL

(Primary) endpoint 1	Patients refractory to fludarabine and alemtuzumab n = 59
Overall response rate
Responders, n (%)	34 (58)
99% CI (%)	40, 74
Response rate in patients with prior rituximab therapy
Responders, n (%)	19/35 (54)
95% CI (%)	37, 71
Response rate in patients with chromosomal abnormality
17p deletion
Responders, n (%)	7/17 (41)
95% CI (%)	18, 67
11q deletion
Responders, n (%)	15/24 (63)
95% CI (%)	41, 81
Median overall survival
Months	13.7
95% CI	9.4, non-estimable
Progression-free survival
Months	5.7
95% CI	4.5, 8.0
Median duration of response
Months	7.1
95% CI	3.7, 7.6
Median time to next CLL therapy
Months	9.0
95% CI	7.3, 10.7
1 The overall response was assessed by an Independent Response Committee using the 1996 National Cancer Institute Working Group (NCIWG) guidelines for CLL.

Improvements also were demonstrated in components of the NCIWG response criteria. These included improvements associated with constitutional symptoms, lymphadenopathy, organomegaly, or cytopenias (see Table 2).

Table 2. Summary of clinical improvement with a minimum duration of 2 months in subjects with abnormalities at baseline

Efficacy endpoint or haematological parametera	Subjects with benefit/subjects with abnormality at baseline (%)
Patients refractory to fludarabine and alemtuzumab
Lymphocyte count
	31/42 (74)
Normalisation (9/l)	20/42 (48)
Complete resolution of constitutional symptomsb	15/31 (48)
Lymphadenopathyc
	34/55 (62)
Complete resolution	9/55 (16)
Splenomegaly
	16/30 (53)
Complete resolution	14/30 (47)
Hepatomegaly
	11/18 (61)
Complete resolution	9/18 (50)
Haemoglobin <11 g/dl at baseline to >11 g/dl post baseline	8/26 (31)
Platelet counts <100x109/l at baseline to >50% increase or >100x109/l post baseline	12/29 (41)
Neutrophils <1x109/l at baseline to 9/l	1/19 (5)
a Excludes subject visits from date of first transfusion, treatment with erythropoietin, or treatment with growth factors. For subjects with missing baseline data, latest screening/unscheduled data was carried forward to baseline. b Complete resolution of constitutional symptoms (fever, night sweats, fatigue, weight loss) defined as the presence of any symptoms at baseline, followed by no symptoms present. c Lymphadenopathy measured by sum of the products of greatest diameters (SPD) as assessed by physical examination.

Arzerra was also given to a group of patients (n=79) with bulky lymphadenopathy (defined as at least one lymph node > 5cm) who were also refractory to fludarabine. The overall response rate in this group was 47% (99% CI: 32%, 62%). The median progression-free survival was 5.9 months (95% CI: 4.9, 6.4) and the median overall survival was 15.4 months (95% CI: 10.2, 20.2). The response rate in patients with prior rituximab therapy was 44% (95% CI: 29, 60). These patients also experienced comparable clinical improvement, in terms of the efficacy endpoints and haematological parameters detailed above, to patients refractory to both fludarabine and alemtuzumab,

Additionally a group of patients (n=16) who were intolerant/ineligible for fludarabine treatment and/or intolerant to alemtuzumab treatment were treated with Arzerra. The overall response rate in this group was 56% (99% CI: 24%, 85%).

Hx-CD20-402

A dose-ranging study was conducted in 33 patients with relapsed or refractory CLL. Patient median age was 61 years (range: 27 to 82 years), the majority were male (58%), and all were white. Treatment with ofatumumab (when given as 4 once weekly infusions), led to a 50% objective response rate in the highest dose group (1st dose: 500 mg; 2nd, 3rd and 4th dose: 2,000 mg) and included 12 partial remissions and one nodular partial remission. For the highest dose group, the median time to progression was 15.6 weeks (95% CI: 15-22.6 weeks) in the full analysis population, and 23 weeks (CI: 20-31.4 weeks) in responders. The duration of response was 16 weeks (CI: 13.3 – 19.0 weeks) and the time to next CLL therapy was 52.4 weeks (CI: 36.9 – non-estimable).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Arzerra in all subsets of the paediatric population in Chronic Lymphocytic Leukaemia (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic Properties

Absorption

Ofatumumab is administered by intravenous infusion; therefore, absorption is not applicable. Maximum ofatumumab serum concentrations were generally observed at or shortly after the end of the infusion. Pharmacokinetic data were available from 146 patients with refractory CLL. The geometric mean C_max value was 63 μg/ml after the first infusion (300 mg); after the eighth weekly infusion (seventh infusion of 2,000 mg), the geometric mean C_max value was 1,482 μg/ml and geometric mean AUC_(0- value was 674,463 μg.h/ml; after the twelfth infusion (fourth monthly infusion; 2,000 mg), the geometric mean C_max value was 881 μg/ml and geometric mean AUC_(0- was 265,707 μg.h/ml.

Distribution

Ofatumumab has a small volume of distribution, with mean Vss values ranging from 1.7 to 5.1 l across studies, dose levels, and infusion number.

Biotransformation

Ofatumumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzymes. Classical biotransformation studies have not been performed.

Elimination

Ofatumumab is eliminated in two ways: a target-independent route like other IgG molecules and a target-mediated route which is related to binding to B cells. There was a rapid and sustained depletion of CD20⁺ B cells after the first ofatumumab infusion, leaving a reduced number of CD20⁺ cells available for the antibody to bind at subsequent infusions. As a result, ofatumumab clearance values were lower and t_½ values were significantly larger after later infusions than after the initial infusion; during repeated weekly infusions, ofatumumab AUC and C_max values increased more than the expected accumulation based on first infusion data.

Across the studies in patients with CLL, the mean values for CL and t_½ were 64 ml/h (range 4.3-1,122 ml/h) and 1.3 days (range 0.2-6.0 days) after the first infusion, 8.5 ml/h (range 1.3-41.5 ml/h) and 11.5 days (range 2.3-30.6 days) after the fourth infusion, 9.5 ml/h (range 2.2-23.7 ml/h) and 15.8 days (range 8.8-61.5 days) after the eighth infusion, and 10.1 ml/h (range 3.3-23.6 ml/h) and 13.9 days (range 9.0-29.2 days) after the twelfth infusion.

Elderly (greater than or equal to 65 years of age)

Age was not found to be a significant factor on ofatumumab pharmacokinetics in a cross-study population pharmacokinetic analysis of patients ranging in age from 21 to 86 years of age.

Children and adolescents

No pharmacokinetic data are available in paediatric patients.

Gender

Gender had a modest effect (14-25%) on ofatumumab pharmacokinetics in a cross-study analysis, with higher C_max and AUC values observed in female patients (41% of the patients in this analysis were male and 59% were female); these effects are not considered clinically relevant, and no dose adjustment is recommended.

Renal impairment

Baseline calculated creatinine clearance was not found to be a clinically significant factor on ofatumumab pharmacokinetics in a cross-study population analysis in patients with calculated creatinine clearance values ranging from 33 to 287 ml/min. No dose adjustment is recommended for mild to moderate renal impairment (creatinine clearance >30 ml/min). There are no pharmacokinetic data in patients with severe renal impairment (creatinine clearance <30 ml/min).

Hepatic impairment

No pharmacokinetic data are available in patients with hepatic impairment. IgG1 molecules such as ofatumumab are catabolised by ubiquitous proteolytic enzymes, which are not restricted to hepatic tissue; therefore, changes in hepatic function are unlikely to have any effect on the elimination of ofatumumab.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazards for humans.

Intravenous and subcutaneous administration to monkeys resulted in the expected depletion of peripheral and lymphoid tissue B cell counts with no associated toxicological findings. As anticipated, a reduction in the IgG humoral immune response to keyhole limpet haemocyanin was noted, but there were no effects on delayed-type hypersensitivity responses. In a few animals, increased red cell destruction occurred presumably as a result of monkey anti-drug antibodies coating the red cells. A corresponding increase in reticulocyte counts seen in these monkeys was indicative of a regenerative response in the bone marrow.

Intravenous administration of ofatumumab to pregnant cynomolgus monkeys at 100 mg/kg once weekly from days 20 to 50 of gestation did not elicit maternal or foetal toxicity or teratogenicity. At day 100 of gestation, depletion of B-cells relating to the pharmacological activity of ofatumumab were observed in foetal cord blood and foetal splenic tissues. Pre- and post-natal development studies have not been performed. Post-natal recovery has therefore not been demonstrated.

As ofatumumab is a monoclonal antibody, genotoxicity and carcinogenicity studies have not been conducted with ofatumumab.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride

Sodium citrate (E331)

Citric acid monohydrate (E330)

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

Vial

2 years.

Diluted infusion

Chemical and physical in-use stability has been demonstrated for 48 hours at ambient conditions (less than 25 °C).

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8 ºC, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Store and transport refrigerated (2°C – 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions of the diluted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

Clear Type I glass vial with a latex-free bromobutyl rubber stopper and aluminium over-seal, containing 5 ml of concentrate for solution for infusion.

Arzerra is available in packs of 3 or 10 vials and it is supplied with two extension sets.

6.6 Special Precautions For Disposal And Other Handling

Arzerra concentrate for solution for infusion does not contain a preservative; therefore dilution should be carried out under aseptic conditions. The diluted solution for infusion must be used within 24 hours of preparation. Any unused solution remaining after this time should be discarded.

• Before diluting Arzerra

Check the Arzerra concentrate for particulate matter and discoloration prior to dilution. Ofatumumab should be a colourless solution. Do not use the Arzerra concentrate if there is discolouration.

Do not shake the ofatumumab vial for this inspection.

The concentrate may contain a small amount of visible translucent-to-white, amorphous, ofatumumab particles. The filters provided as part of the extension set will remove these particles.

• How to dilute the solution for infusion

The Arzerra concentrate must be diluted in sodium chloride 9 mg/ml (0.9%) solution for in