Novofem film-coated tablets

Novofem

film-coated tablets

Estradiol hemihydrate and norethisterone acetate

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again


• If you have any further questions, ask your doctor or pharmacist


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours


• If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

1.What Novofem is and what it is used for

2. Before you take Novofem

3. How to take Novofem

4. Possible side effects

5. How to store Novofem

6. Further information

What Novofem is and what it is used for

Novofem belongs to a group of hormone replacement therapy (HRT) medicines, called sequential combined HRT, which are taken

every day without interruptions.

Novofem contains two hormones, an estrogen (estradiol) and a progestogen (norethisterone acetate).

The estradiol in Novofem is identical to the estradiol produced in the ovaries of women, and is classified as a natural

oestrogen. Norethisterone acetate is a synthetic progestagen, which acts in a similar manner as progesterone, another important female sex

hormone.

Novofem is prescribed:

• To relieve unpleasant symptoms of menopause like hot flushes, night sweats, vaginal dryness in postmenopausal women who still
  
  have their womb


• For the prevention of osteoporosis (thinning of the bones), in postmenopausal women if they are at high risk of future fractures
  
  and are unable to take other medicines for this purpose.

There is only limited experience of treating women older than 65 years with Novofem.

Before you take Novofem

Medical check-ups

Before you start taking HRT, your doctor should ask about your own and your family’s medical history. Your doctor may decide to examine your breasts and/or your abdomen, and may do an internal examination - but only if these examinations are necessary for you, or if you have any special concerns.

Once you’ve started on HRT, you should see your doctor for regular check-ups (at least once a year). At these check-ups, your doctor may
discuss with you the benefits and risks of continuing to take HRT.

For more information about the safety of HRT, see section 4 “Possible side effects”

Be sure to:

• 
  Go for regular breast screening and cervical smear tests
  


• 
  Regularly check your breasts for any changes such as dimpling of the skin, changes in the nipple, or any lumps you can see
  or feel.

Do not take Novofem

If any of the following applies to you, talk to your doctor. Do not start taking Novofem:

• If you have, have had or suspect having breast cancer


• If you have, have had or suspect having cancer of the womb lining (endometrial cancer), or any other oestrogen dependent
  cancer


• If you have abnormal vaginal bleeding of an unknown cause


• If you have endometrial hyperplasia (excessive growth of the womb lining) that is not being treated


• If you have or previously have had a blood clot in the blood vessels of the legs or the lungs (like deep vein thrombosis
  or pulmonary embolism)


• If you have recently had a heart attack, stroke, or have angina pectoris which causes discomfort, pressure or pain in
  the chest


• If you have or have had liver problems and your liver tests have not returned to normal


• If you are allergic (hypersensitive) to estradiol, norethisterone acetate or any other ingredients in Novofem
  tablets (listed in section 6, “Further information”)


• If you have porphyria (liver enzyme disease).

Take special care with Novofem

If you have (or have had) any of the following conditions, tell your doctor. Your doctor may want to follow you more closely.

Rarely, these conditions may come back or get worse during treatment with Novofem

• If you have or have had leiomyoma (benign tumours of the womb) or endometriosis, a condition in which the lining of
  the uterus (womb) grows outside the uterus, causing pain or bleeding


• If you have a history of blood clots (thrombosis) or have risk factors for blood clots (these risk factors and symptoms
  for a blood clot are listed in section 4,“Possible side effects”)


• If you have risk factors for development of oestrogen dependent tumours, such as immediate relatives (mother, sister,
  maternal or paternal grandmother) with breast and/or endometrial cancer


• If you have high blood pressure


• If you have a liver disorders such as liver adenoma (a benign tumour)


• If you have diabetes mellitus with or without vascular disorders


• If you have gallstones


• If you have migraine or severe headache


• If you have systemic lupus erythematosus (SLE) – an autoimmune disease


• If you previous have had endometrial hyperplasia


• If you have epilepsy


• I you have asthma


• If you have otosclerosis (progressive hearing loss).

If you need a blood test, tell your doctor that you are taking Novofem since oestrogen can affect the results of
certain laboratory results.

If you are going to have surgery, talk to your doctor. You may need to stop taking these tablets 4 to 6 weeks before the
operation, to reduce the risk of a blood clot. Your doctor will tell you when you can start treatment again.

Stop taking Novofem

If you are experiencing any of the following conditions below, stop taking Novofem, and contact your doctor immediately

• If you get a migraine-type headache for the first time


• If you develop yellow skin or eyes (jaundice) or other liver problems


• If you have a significant increase in blood pressure


• If you get blood clots called “deep vein thrombosis” (see also section 4, “Possible side effects”)


• If you become pregnant


• If you experience any of the conditions listed in section 2, “Before you take Novofem”.

Bleeding with Novofem

Novofem will cause a menstruation-like monthly bleeding, which usually occurs at the beginning of a new pack. If the periods
get heavier than normal you should tell your doctor However, some women may also experience breakthrough bleeding or spotting during the first few months of taking Novofem. This kind of bleeding is different from the menstruation-like bleeding. If you have any breakthrough bleeding or spotting that continues for longer than the first few months or starts after some time on HRT or continues even if you have stopped taking Novofem, you
should tell your doctor as soon as possible.

Using other medicines

Some medicines may reduce the effect of Novofem

• Medicines used for epilepsy (such as phenobarbital, phenytoin, and carbamazepine)


• Medicines used for tuberculosis (such as rifampicin and rifabutin)


• Medicines used for HIV infections (such as nevirapine, efavirenz, ritonavir and nelfinavir)


• Antiinfectives medicines (e.g. penicillins, tetracycline)


• Herbal products with St John’s Wort (Hypericum perforatum).

Novofem may enhance the effects and side effects of imipramine (antidepressant) and may have an impact on a concomitant

treatment with cyclosporine.

If you have diabetes your requirement for insulin or oral antidiabetics may be changed when taking Novofem.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those not
prescribed.

Pregnancy and breast-feeding

Do not take Novofem if you suspect being pregnant, are pregnant or breast-feeding.

Driving and using machines

Novofem does not affect the use of any machines or the ability to drive safely.

Important information about some of the ingredients of Novofem

Novofem contains lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

How to take Novofem

Always take Novofem exactly as your doctor has told you. You should check with your doctor or pharmacist if you are unsure.

If you are not switching from another hormone replacement therapy you can start treatment with Novofemon any convenient day. If you are switching from another hormone replacement therapy ask your doctor when you should start treatment with Novofem.

Take one tablet once a day, at about the same time each day

Each pack contains 28 tablets

Days 1 - 16 Take one red tablet everyday for 16 days


Days 16 - 28 Take one white tablet everyday for 12 days

Take the tablets with a glass of water. Once you have finished the pack, start a new pack continuing the treatment without interruption. A menstruation-like bleeding usually occurs at the beginning of a new pack.

For further information on the use of the calendar pack see “USER INSTRUCTIONS” in the beginning of the package leaflet.

Your doctor should aim to prescribe the lowest dose for the shortest time that gives you relief from your symptoms. Talk to your doctor if you do not experience symptom relief after 3 months of treatment. You should only continue treatment as long as the benefit outweighs the risk.

If you take more Novofem than you should

If you have taken more Novofem than you should, talk to a doctor or pharmacist. An overdose of Novofem could make you feel sick or vomit.

If you forget to take Novofem

Do not take a double dose to make up for forgotten individual doses. If you forget to take a tablet one day, discard the tablet and continue treatment as before. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.

If you stop taking Novofem

If you would like to stop your treatment with Novofem for any reason, please discuss your decision with your doctor, who will explain the effects of stopping treatment and discuss other possibilities with you.

If you have any further questions on the use of this product ask your doctor or pharmacist.

Possible side effects

Like all medicines, Novofem can have side effects, although not everybody gets them.

Allergic reactions (rare side effect - May affect up to 1 in 1000 women)

Though it is a rare event, allergic reactions may occur (which may include one or more of the following symptoms: flushing, skin rash, itching, hives, swelling, difficulty breathing, fever, palpitations and/or low blood pressure). If one of the mentioned symptoms appears stop taking Novofem and seek immediate medical help

Very common side effects:

May affect more than 1 in 10 women

• Headache


• Breast tenderness.

Common side effects:

May affect up to 1 in 10 women

• Increased blood pressure, aggravated hypertension


• Vaginal infection with a fungus (e.g. thrush)


• Dizziness, sleeplessness, depression


• Dyspepsia (indigestion), abdominal pain, flatulence


• Nausea (feeling sick)


• Rash, itching


• Vaginal bleeding (see section 2 subsection “Bleeding with Novofem”)


• Aggravation of uterine fibroids (benign tumour of the womb)


• Oedema (swelling of hands, ankles and feet)


• Weight increase.

Uncommon side effects:

May affect up to 1 in 100 women

• Migraine


• Changes in libido (changes in sexual desire)


• Peripheral embolism


• Vomiting (being sick)


• Gallbladder disease or gallstones


• Hair loss


• Muscle cramps.

Rare side effects

May affect up to 1 in 1,000 women

• Allergic reactions


• Nervousness


• Vertigo


• Diarrhoea


• Bloating


• Acne


• Uterine fibroid (benign tumour of the womb).

Very rare side effects:

May affect up to 1 in 10,000 women

• Hyperplasia of endometrium (excessive growth of the lining of the womb)


• Increased body and facial hair.

Effects on the skin

Brown patches on the face, skin rashes including red inflammation on the hands or the legs (erythema multiforme), formation of tender, red nodules on the front of the legs/knees (erythema nodosum) or a bruise-like rash.

Other side effects of HRT

As well as benefits, HRT has some risks which you need to consider when you’re deciding whether to take it, or whether to carry on taking it.

Effects on your risk of developing cancer

Breast cancer

Women who have breast cancer, or have had breast cancer in the past, should not take HRT.

Taking HRT slightly increases the risk of breast cancer; so does having a later menopause. The risk for a post-menopausal woman taking oestrogen-only HRT for 5 years is about the same as for a woman of the same age who’s still having periods over that time and not taking HRT. The risk for a woman who is taking oestrogen plus progestogen HRT is higher than for oestrogen-only HRT (but oestrogen plus progestogen HRT is beneficial for the endometrium, see ‘Endometrial cancer’ below).

For all kinds of HRT, the extra risk of breast cancer goes up the longer you take it, but returns to normal within about 5 years after stopping HRT.

Your risk of breast cancer is also higher:

• If you have a close relative (mother, sister or grandmother) who has had breast cancer


• If you are seriously overweight.

Compare

Looking at women aged 50 who are not taking HRT - on average, 32 in 1000 will be diagnosed with breast cancer by the time they reach the age of 65.

For women who start taking oestrogen-only HRT at age 50 and take it for 5 years, the figure will be between 33 and 34 in 1000 (i.e. an extra 1-2 cases).

If they take oestrogen-only HRT for 10 years, the figure will be 37 in 1000 (i.e. an extra 5 cases).

For women who start taking oestrogen plus progestogen HRT at age 50 and take it for 5 years, the figure will be 38 in 1000 (i.e. an extra 6 cases).

If they take oestrogen plus progestogen HRT for 10 years, the figure will be 51 in 1000 (i.e. an extra 19 cases)

If you notice any changes in your breast, such as:

• Dimpling of the skin


• Changes in the nipple


• Any lumps you can see or feel.

Make an appointment to see your doctor as soon as possible.

Endometrial cancer (cancer of the lining of the womb)

Taking oestrogen-only HRT for a long time can increase the risk of cancer of the lining of the womb (the endometrium). Taking a progestogen as well as the oestrogen helps to lower the extra risk.

If you still have your womb, your doctor may prescribe a progestogen as well as oestrogen. If so, these may be prescribed separately, or as a combined HRT product.

If you have had your womb removed (a hysterectomy), your doctor will discuss with you whether you can safely take oestrogen without a progestogen.

If you’ve had your womb removed because of endometriosis, any endometrium left in your body may be at risk. So your doctor may prescribe HRT that includes a progestogen as well as an oestrogen.

Your product, Novofem, contains a progestogen.

Compare

Looking at women who still have a uterus and who are not taking HRT – on average 5 in 1000 will be diagnosed with endometrial cancer between the ages of 50 and 65.

For women who take oestrogen-only HRT, the number will be 2 to 12 times higher, depending on the dose and how long you take it.

The addition of a progestogen to oestrogen-only HRT substantially reduces the risk of endometrial cancer.

If you get breakthrough bleeding or spotting, it’s usually nothing to worry about, especially during the first few months of taking HRT.

But if the bleeding or spotting:

• Carries on for more than the first few months


• Starts after you’ve been on HRT for a while


• Carries on even after you’ve stopped taking HRT.

Make an appointment to see your doctor. It could be a sign that your endometrium has become thicker.

Ovarian cancer

Ovarian cancer (cancer of the ovaries) is very rare, but it is serious. It can be difficult to diagnose, because there are often no obvious signs of the disease. Some studies have indicated that taking HRT for more than 5 years may increase the risk of ovarian cancer.

Effects on your heart or circulation

Blood clots

HRT may increase the risk of blood clots in the veins (also called deep vein thrombosis, or DVT), especially during the first year of taking it.

These blood clots are not always serious, but if one travels to the lungs, it can cause chest pain, breathlessness, collapse or even death. This condition is called pulmonary embolism, or PE.

DVT and PE are examples of a condition called venous thromboembolism, or VTE.

You are more likely to get a blood clot:

• If you are seriously overweight


• If you have had a blood clot before


• If any of your close family have had blood clots


• If you have had one or more miscarriages


• If you have any blood clotting problem that needs treatment with a medicine such as warfarin


• If you’re off your feet for a long time because of major surgery, injury or illness


• If you have a rare condition called SLE.

If any of these things apply to you, talk to your doctor to see if you should take HRT.

Compare

Looking at women in their 50s who are not taking HRT - on average, over a 5-year period, 3 in 1000 would be expected to get a blood clot.

For women in their 50s who are taking HRT, the figure would be 7 in 1000.

Looking at women in their 60s who are not taking HRT - on average, over a 5-year period, 8 in 1000 would be expected to get a blood clot.

For women in their 60s who are taking HRT, the figure would be 17 in 1000.

If you get:

• Painful swelling in your leg


• Sudden chest pain


• Difficulty breathing.

See a doctor as soon as possible and do not take any more HRT until your doctor says you can. These may be signs of a blood clot.

If you’re going to have surgery, make sure your doctor knows about it. You may need to stop taking HRT about 4 to 6 weeks before the operation, to reduce the risk of a blood clot. Your doctor will tell you when you can start taking HRT again.

Heart disease

HRT is not recommended for women who have heart disease, or have had heart disease recently. If you have ever had heart disease, talk to your doctor to see if you should be taking HRT.

HRT will not help to prevent heart disease.

Studies with one type of HRT (containing conjugated oestrogen plus the progestogen MPA) have shown that women may be slightly more likely to get heart disease during the first year of taking the medication. For other types of HRT, the risk is likely to be similar, although this is not yet certain.

If you get:

• A pain in your chest that spreads to your arm or neck.

See a doctor as soon as possible and do not take any more HRT until your doctor says you can. This pain could be a sign of heart disease.

Stroke

Recent research suggests that HRT slightly increases the risk of having a stroke. Other things that can increase the risk of stroke include:

• Getting older


• High blood pressure


• Smoking


• Drinking too much alcohol


• An irregular heartbeat

If you are worried about any of these things, or if you have had a stroke in the past, talk to your doctor to see if you should take HRT.

Compare

Looking at women in their 50s who are not taking HRT - on average, over a 5-year period, 3 in 1000 would be expected to have a stroke.

For women in their 50s who are taking HRT, the figure would be 4 in 1000.

Looking at women in their 60s who are not taking HRT - on average, over a 5-year period, 11 in 1000 would be expected to have a stroke.

For women in their 60s who are taking HRT, the figure would be 15 in 1000.

If you get:

• Unexplained migraine-type headaches, with or without disturbed vision.

See a doctor as soon as possible and do not take any more HRT until your doctor says you can. These headaches may be an early warning sign of a stroke.

Dementia

There is no evidence that HRT improves processes of knowing, thinking, learning and judging (cognitive function). From a clinical study there is some evidence for an increased risk of dementia among women older than 65 years, who were using another oestrogen/progestogen combination than the one in Novofem. It is not known whether this applies to younger women and to women taking other HRT preparations.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store Novofem

Keep out of the reach and sight of children.

Do not use Novofem after the expiry date which is stated on the label and carton. The expiry date refers to the last day of that month.

Do not store above 25°C. Do not refrigerate. Keep the container in the outer carton in order to protect from light.

Medicines should not be disposed of via waste water or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

What Novofem contains

• The active substances are estradiol and norethisterone acetate.
  
  The red film-coated tablets contain: estradiol 1 mg (as estradiol hemihydrate).
  
  The white film-coated tablets contain: estradiol 1 mg (as estradiol hemihydrate) and norethisterone acetate 1 mg.


• The other ingredients are: lactose monohydrate, maize starch, gelatine, talc and magnesium stearate.
  
  
  Film-coating (red tablets) contain: hypromellose, talc, titanium dioxide (E171), propylene glycol and red iron oxide (E172).
  
  
  Film-coating (white tablets) contain: hypromellose, triacetin and talc.

What Novofem looks like and contents of the pack

The film-coated tablets are round with a diameter of 6 mm. The red tablets are engraved with NOVO 282.

The white tablets are engraved with NOVO 283.

Each pack of 28 tablets contains 16 red tablets and 12 white tablets

Pack sizes available:

1x28 film-coated tablets

3x28 film-coated tablets

Not all pack sizes may be marketed

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Novo Nordisk Limited

Broadfield Park

Brighton Road

Crawley

West Sussex

RH11 9RT

Manufacturer:

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

This leaflet was last approved in: 12/2008

Novofem is a trademark owned by Novo Nordisk FemCare AG, Switzerland

© 2002/2008

Novo Nordisk A/S

USER INSTRUCTIONS

How to use the calendar pack

1. Set the day reminder

Turn the inner disc to set the day of the week opposite the little plastic tab.

2. Take the first day’s tablet

Break the plastic tab and tip out the first tablet.

3. Move the dial every day

On the next day simply move the transparent dial clockwise one space as indicated by the arrow. Tip out the next tablet. Remember to take only one tablet once a day

You can only turn the transparent dial after the tablet in the opening has been removed.

8-2921-01-041-4

Non Drowsy Sudafed Linctus

1. Name Of The Medicinal Product

Non-Drowsy Sudafed Linctus

Benylin Dual Action Dry Cough & Congestion

Sudafed Dry Coughs with Decongestant Liquid

2. Qualitative And Quantitative Composition

Each 5 ml of Non-Drowsy Sudafed Linctus contains:
Pseudoephedrine hydrochloride	30.00 mg
Dextromethorphan hydrobromide	10.00 mg

3. Pharmaceutical Form

A clear red liquid for oral administration.

4. Clinical Particulars

4.1 Therapeutic Indications

For the symptomatic relief of upper respiratory tract disorders which may benefit from a combination of a nasal decongestant and an antitussive.

4.2 Posology And Method Of Administration

Adults and Children aged 12 years and over:

Oral. 10 ml every 4 - 6 hours up to 4 times a day.

Children under 12 years:

Non-Drowsy Sudafed Linctus is contraindicated in children under the age of 12 years (see section 4.3).

Use in the Elderly

There have been no specific studies of Sudafed in the elderly. Experience has indicated that normal adult dosage is appropriate.

Hepatic Dysfunction

Caution should be exercised when administering Non-Drowsy Sudafed Linctus to patients with severe hepatic impairment.

Renal Dysfunction

Caution should be exercised when administering Non-Drowsy Sudafed Linctus to patients with moderate to severe renal impairment.

Do not exceed the stated dose.

Keep of the reach and sight of children.

4.3 Contraindications

Non-Drowsy Sudafed Linctus is contraindicated in individuals with known hypersensitivity to the product or any of its components. Non-Drowsy Sudafed Linctus is contraindicated in individuals with severe hypertension or coronary artery disease.

Non-Drowsy Sudafed Linctus is contraindicated in individuals who are taking or have taken monoamine oxidase inhibitors within the preceding two weeks. The concomitant use of pseudoephedrine and this type of product may occasionally cause a rise in blood pressure.

Non-Drowsy Sudafed Linctus is not intended for use in chronic or persistent cough as occurs with asthma or where cough is accompanied by excessive secretions. Dextromethorphan, in common with other centrally acting antitussive agents should not be given to patients with or at risk of developing respiratory failure.

Not to be used in children under the age of 12 years.

4.4 Special Warnings And Precautions For Use

Although pseudoephedrine has virtually no pressor effects in normotensive patients, Non-Drowsy Sudafed Linctus should be used with caution in patients suffering mild to moderate hypertension. As with other sympathomimetic agents, Non-Drowsy Sudafed Linctus should be used with caution in patients with hypertension, heart disease, diabetes, hyperthyroidism, elevated intraocular pressure and prostatic enlargement.

Caution should be exercised when using the product in the presence of severe hepatic impairment or moderate to severe renal impairment (particularly if accompanied by cardiovascular disease).

There have been a few reports of abuse of dextromethorphan but there is no evidence of drug dependance at therapeutic doses.

Not more than 4 doses should be given in any 24 hours.

The pack carries the following statements:

Store below 25°C. Protect from light.

Keep out of the reach and sight of children.

'Warning: do not exceed stated dose.'

Avoid alcoholic drink.

As with all medicines if you are pregnant, or currently taking any other medicine, consult your doctor or pharmacist before taking this product.

If symptoms persist consult your doctor.

Causes no drowsiness.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of Non-Drowsy Sudafed Linctus with tricyclic antidepressants, sympathomimetic agents (such as decongestants, appetite suppressants and amfetamine-like psychostimulants) or with monoamine oxidase inhibitors, which interfere with the catabolism of sympathomimetic amines, may occasionally cause a rise in blood pressure.

Because of its pseudoephedrine content, Non-Drowsy Sudafed Linctus may partially reverse the hypotensive action of drugs which interfere with sympathetic activity including bretylium, betanidine, guanethedine, debrisoquine, methyldopa, alpha and beta-adrenergic blocking agents.

4.6 Pregnancy And Lactation

Although pseudoephedrine and dextromethorphan have been in widespread use for many years without apparent ill consequence, there are no specific data on their use during pregnancy. Caution should therefore be exercised by balancing the potential benefit of treatment to the mother against any possible hazards to the developing foetus.

Systemic administration of pseudoephedrine, up to 50 times the human daily dosage in rats and up to 35 times the human daily dosage in rabbits, did not produce teratogenic effects. There is insufficient information available to determine whether or not dextromethorphan has teratogenic potential.

Pseudoephedrine is excreted in breast milk in small amounts but the effect of this on breast fed infants is not known. It has been estimated that 0.5 - 0.7% of a single dose of pseudoephedrine ingested by a mother will be excreted in the breast milk over 24 hours. It is not known whether dextromethorphan or its metabolites are excreted in breast milk.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Serious adverse effects associated with the use of pseudoephedrine are rare. Symptoms of central nervous system excitation may occur including sleep disturbance and rarely, hallucinations. Skin rashes; with or without irritation have occasionally been reported.

Urinary retention has been reported occasionally in men receiving pseudoephedrine; prostatic enlargement could have been an important predisposing factor.

Side effects attributed to dextromethorphan are uncommon; occasionally nausea, vomiting or gastro-intestinal disturbance may occur.

4.9 Overdose

The effects of acute toxicity from Non-Drowsy Sudafed Linctus may include nystagmus, hypertension, irritability, restlessness, tremor, convulsions, palpitations, difficulty with micturition, depression, nausea and vomiting.

Necessary measures should be taken to maintain and support respiration and control convulsions. Gastric lavage should be performed if indicated. Catherisation of the bladder may be necessary. If desired, the elimination of pseudoephedrine can be accelerated by acid diuresis or by dialysis.

Naloxone has been used successfully as a specific antagonist to dextromethorphan toxicity in a child.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pseudoephedrine has direct and indirect sympathomimetic activity and is an effective upper respiratory tract decongestant. Pseudoephedrine is substantially less potent than ephedrine in producing both tachycardia and elevation of systolic blood pressure and is considerably less potent in causing stimulation of the central nervous system.

Dextromethorphan provides antitussive activity by acting on the medullary cough centre.

5.2 Pharmacokinetic Properties

Pseudoephedrine is rapidly and completely absorbed after oral administration. After an oral dose of 180 mg to man, peak plasma concentrations of 500-900 ng/ml were obtained about 2 hours post dose. The plasma half-life was approximately 5.5 hours and was increased in subjects with alkaline urine and decreased in subjects with acid urine. The only metabolism was n-demethylation which occurred to a small extent. Excretion was mainly via the urine.

Dextromethorphan is well absorbed following oral administration with peak plasma levels (30 mg dose) being seen 2 hours post dose. It is metabolised in the liver by n- and o-demethylation followed by sulphate or glucuronic acid conjugation. It is excreted unchanged and as metabolites in the urine (up to 56 per cent of dose).

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sucrose

Sorbitol solution

Sodium benzoate

Methyl hydroxybenzoate

Ethanol (96 %)

Flavour, blackcurrant

L-menthol

Ponceau 4R (E124)

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months unopened.

6.4 Special Precautions For Storage

Store below 25ºC.

Protect from light.

6.5 Nature And Contents Of Container

100 ml amber glass bottles with a 2 piece or a 3 piece plastic child resistant, tamper evident closure fitted with a polyvinylidene chloride (PVDC) faced wad.

A spoon with a 5ml and a 2.5ml measure is supplied with this product.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0028

9. Date Of First Authorisation/Renewal Of The Authorisation

28^th March 1997

10. Date Of Revision Of The Text

04 March 2010

Novgos 3.6mg Implant

1. Name Of The Medicinal Product

Novgos 3.6 mg Implant

2. Qualitative And Quantitative Composition

One implant contains 3.6 mg goserelin (as goserelin acetate)

Excipients:

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Implant, pre-filled syringe.

The sterile, cylindrical, white to cream coloured implant is placed in a sterile injection needle.

4. Clinical Particulars

4.1 Therapeutic Indications

Novgos is a luteinization hormone releasing hormone (LHRH)- Agonist (analogue of the natural LHRH).

Novgos is used for treatment of patients with advanced prostate cancer where endocrine treatment is indicated.

4.2 Posology And Method Of Administration

1 implant every month.

Novgos is injected subcutaneously into the anterior abdominal wall.

Generally treatment of prostate cancer with Goserelin is a long-term treatment. Regular control examinations as performed usually in prostate cancer patients are recommended to assess the therapeutic effect.

Remarks for injection technique:

1. The implant consists of two bags, the sterile injection needle and the sterile applicator. Note that the implant is visibly fixed in the injection needle. Open both bags and connect the injection needle to the applicator via the Luer lock. Make sure that the connection is tight and that the plunger remains unchanged in its position.

2. Check that the implant is visible in the control window in the needle.

3. Remove the locking device from the plunger. Insert the cannula into the anterior abdominal wall and insert the implant by depressing the plunger completely.

Paediatric Patients

Novgos is contraindicated in children and adolescents (see section 4.3).

Special Patient Groups

No dosage or interval adjustment is necessary for patients with renal or hepatic impairment or in the elderly.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Novgos is not indicated for use in children and adolescents, as efficacy and tolerability for this group of patients has not been investigated.

4.4 Special Warnings And Precautions For Use

Special caution should be given to patients at particular risk of developing ureteric obstruction or spinal cord compression. Administration of Novgos should be carefully judged and closely monitored during the first months of therapy.

If spinal cord compression or renal impairment due to ureteric obstruction are present or develop, specific standard treatment of these complications should be instituted.

Consideration should be given to the initial use of an anti-androgen at the start of Novgos therapy since this has been reported to prevent the possible sequelae.

Continuous suppression of sexual hormone production leads to infertility in men.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

4.6 Pregnancy And Lactation

Not applicable as Novgos is intended for male patients only.

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.

4.8 Undesirable Effects

The adverse events are listed by system organ class and frequency using the following convention:

very common (

common (

uncommon (

rare (

very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

General

Cardiac disorders:

uncommon: changes in blood pressure (hypotension or hypertension)

Nervous system disorders:

very common: non-specific paraesthesias

very rare: pituitary apoplexy following initial administration

Skin and subcutaneous tissue disorders:

common: mild skin rash

Musculoskeletal and connective tissue disorders:

very rare: arthralgia/bone pain

General disorders and administration site conditions:

rare: local reactions at the injection site

Immune system disorders:

rare: hypersensitivity reactions, including symptoms of anaphylaxis

At the beginning of the therapy

Initially, there is a short-term increase in serum testosterone inducing a temporary increase of specific symptoms:

Nervous system disorders:

very rare: spinal cord compression

Renal and urinary disorders:

very rare: ureteric obstruction (due to obstruction of the urinary tract passage)

Musculoskeletal and connective tissue disorders:

common: bone pain

In these cases, the patients must be closely monitored and treated symptomatically during the first month of treatment.

During the therapy

Due to the decrease in serum testosterone during the treatment the use of LHRH-agonists causes loss in bone mineral density. For this reason, during long-term therapy with Novgos an increased fracture risk cannot be excluded, although no increased fracture rates have been observed so far.

Nervous system disorders :

very rare: pituitary adenomas

Endocrine disorders:

very common: hot flushes and sweating

Reproductive system and breast disorders:

very common: decrease in libido and potency, testicular atrophy

common: breast swelling

very rare: breast tenderness

Pituitary adenomas occur more often in prostate cancer patients. However, as no medical reports on the initial state of the pituitary gland were available for these few cases monitored under treatment, it cannot be excluded with certainty that their development was favoured by the use of Novgos.

4.9 Overdose

There is only limited experience of overdosage in humans. In cases where goserelin has unintentionally been re-administered early or given at a higher dose, no clinically relevant adverse reactions have been seen.

Animal tests suggest that no effect other than the intended therapeutic effects on sex hormone concentrations and on the reproductive tract will be evident with higher doses.

In case of toxication symptomatic treatment is required.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: LHRH-agonist

ATC code: L02A E03

The treatment with Novgos in men leads to fall of serum testosterone to the castration range.

Treatment with Novgos causes inhibition of growth or regression of hormone dependent cancer of the prostatic gland (oestradiol and/or progesterone receptor positive tumours).

Biosynthesis and secretion of the male and female sexual hormones (testosterone and oestradiol, respectively) are controlled by the hypothalamic LHRH and by luteinization hormone (LH) and follicle stimulating hormone (FSH) which are produced in the pituitary gland. The pulsating release of the natural LHRH from the hypothalamus triggers synthesis and excretion of LH and FSH from the anterior lobe of the pituitary gland.

Goserelin acetate, the active substance of Novgos, is a LHRH analogue with higher activity and longer half life as the natural hormone.

Long-term treatment with goserelin acetate leads to a receptor-down-regulation of the pituitary gland. The number of LHRH- receptors decreases. Thereby LH and FSH secretion and biosynthesis of oestradiol and testosterone in the gonads is suppressed.

After an initial increase during the first 3-5 days in men testosterone levels decrease. Castration range is normally achieved between the second and third week after the beginning of treatment with Novgos. Suppression of serum testosterone with Novgos is equal to the results of orchiectomy.

5.2 Pharmacokinetic Properties

The active substance is spread in a completely biodegradable matrix of Poly(D,L-lactide-co-glycolide). An average of 120 μg goserelin per day is released from Novgos. Seven to14 days after administration of Novgos, the maximum serum levels of goserelin are achieved. Subsequently they slowly fall during the third and fourth week of therapy. No accumulation occurs.

Goserelin slightly binds to serum protein (25 %). After subcutaneous administration of a single dose (aqueous solution of 250 μg) of goserelin in patients with normal renal function, elimination half time of 4.2 h in men was observed.

The influence of impaired renal function on goserelin serum levels and total body clearance has been investigated in male patients suffering from prostate cancer. With increasing renal impairment elimination of the substance was delayed. In this case, a close correlation between creatinine clearance and total body clearance could be shown.

However, goserelin was eliminated relatively fast (half-life 12.1h) in patients with severe renal impairment (creatinine-clearance <20ml/min), leading to the conclusion of an additional non-renal elimination pathway possibly located in the liver. Accumulation of goserelin associated with chronic application can therefore not be expected in patients with limited renal impairment.

There is no significant change in pharmacokinetics in patients with hepatic failure.

5.3 Preclinical Safety Data

Preclinical studies with LHRH agonists revealed in both sexes effects on the reproductive system, which were expected from the known pharmacological properties. These effects were shown to be reversible after discontinuation of the treatment and a due period of regeneration.

Goserelin acetate did not show teratogenicity in rats and rabbits. Based on the pharmacological effects of LHRH agonists on the reproductive system, embryotoxicity and -lethality was observed in rabbits.

Goserelin acetate was not mutagenic in a set of in vitro and in vivo assays.

Carcinogenicity studies were performed with other LHRH analogues in rats and mice over 24 months. In rats, a dose-related increase in pituitary adenomas was observed after subcutaneous administration at doses of 0.6 to 4 mg/kg/day. No such effect was observed in mice, allowing to regard the effect in rats as species-specific, having no relevance for humans.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Poly(D,L-lactide-co-glycolide) (1:1).

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

6.4 Special Precautions For Storage

Do not store above 25°C.

Store in the original package.

6.5 Nature And Contents Of Container

Each implant is placed in a sterile, siliconised stainless steel injection needle closed with a Luer-Lock screw cap and a needle cover. The needle unit is packaged together with a desiccant in a polyester/aluminium/polyethylene pouch. A sterilised applicator is provided packed in a separate pouch.

Novgos is available in packs of 1, 3 and 6 implants.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Genus Pharmaceuticals Limited

T/A Genus Pharmaceuticals

Park View House

65 London Road

Newbury

Berkshire, RG14 1JN, UK

8. Marketing Authorisation Number(S)

PL 06831/0233

9. Date Of First Authorisation/Renewal Of The Authorisation

02/04/09

10. Date Of Revision Of The Text

02/04/09

Non-Drowsy Sudafed Congestion, Cold & Flu Tablets (McNeil Products Ltd)

1. Name Of The Medicinal Product

Non-Drowsy Sudafed Congestion, Cold & Flu Tablets

2. Qualitative And Quantitative Composition

Non-Drowsy Sudafed Congestion, Cold & Flu Tablets contain 60 mg Pseudoephedrine hydrochloride and 500 mg Paracetamol.

3. Pharmaceutical Form

Tablets

4. Clinical Particulars

4.1 Therapeutic Indications

Non-Drowsy Sudafed Congestion, Cold & Flu Tablets is indicated for the symptomatic relief of conditions where congestion of the mucous membranes of the upper respiratory tract, is accompanied by pain or pyrexia, e.g. the common cold and influenza, sinusitis, nasopharyngitis.

4.2 Posology And Method Of Administration

Adults and children aged 12 years and over:

Oral. One tablet every 4-6 hours up to four times a day

Maximum daily dose: 4 tablets (240 mg pseudoephedrine and 2 g paracetamol).

Children under 12 years

Non-Drowsy Sudafed Congestion, Cold & Flu Tablets are contraindicated in children under the age of 12 years (see section 4.3).

The Elderly:

There have been no specific studies of Non-Drowsy Sudafed Congestion, Cold & Flu Tablets in the elderly. Experience has shown that normal adult dosage is appropriate.

In the elderly the rate and extent of paracetamol absorption is normal but plasma half-life is longer and paracetamol clearance is lower than in young adults.

Hepatic dysfunction

Caution should be exercised when administering Non-Drowsy Sudafed Congestion, Cold & Flu Tablets to patients with severe hepatic impairment (See Pharmacokinetics in Hepatic Impairment).

Renal dysfunction:

Caution should be exercised when administering Non-Drowsy Sudafed Congestion, Cold & Flu Tablets to patients with moderate to severe renal impairment, particularly if accompanied by cardiovascular disease (See Pharmacokinetics in Renal Impairment).

Do not exceed the stated dose.

Keep out of the reach and sight of children.

4.3 Contraindications

Non-Drowsy Sudafed Congestion, Cold & Flu Tablets is contraindicated in individuals with known hypersensitivity to paracetamol or any other constituents of the product.

Non-Drowsy Sudafed Congestion, Cold & Flu Tablets is contraindicated in patients with severe hypertension or coronary artery disease.

Non-Drowsy Sudafed Congestion, Cold & Flu Tablets is contraindicated in patients who are taking or have taken monoamine oxidase inhibitors within the preceding two weeks. The concomitant use of pseudoephedrine and this type of product may occasionally cause a rise in blood pressure.

Not to be used in children under the age of 12 years.

4.4 Special Warnings And Precautions For Use

Although pseudoephedrine has virtually no pressor effects in normotensive patients, Non-Drowsy Sudafed Congestion, Cold & Flu Tablets should be used with caution in patients suffering from mild to moderate hypertension.

As with other sympathomimetic agents Non-Drowsy Sudafed Congestion, Cold & Flu Tablets should be used with caution in patients with heart disease, diabetes, hyperthyroidism, elevated intraocular pressure or prostatic enlargement.

Caution should be exercised in the administration of Non-Drowsy Sudafed Congestion, Cold & Flu Tablets to patients with severe hepatic impairment or moderate to severe renal impairment, (particularly if accompanied by cardiovascular disease) (See Pharmacokinetics). The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.

Concomitant use of other products containing paracetamol or decongestants with Non-Drowsy Sudafed Congestion, Cold & Flu Tablets could lead to overdose and therefore should be avoided.

The following statements will appear on packs of this product:

Keep out of the reach and sight of children.

As with all medicines, if you are pregnant or currently taking any other medicine, consult your doctor or pharmacist before taking this product.

If symptoms persist consult your doctor.

Store below 25ºC. Keep dry. Protect from light.

Warning: Do not exceed the stated dose.

Causes no drowsiness.

Contains paracetamol.

The label contains the following additional statements:

Immediate medical advice should be sought in the event of an overdose, even if you feel well.

Do not take with any other paracetamol-containing products.

Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage (leaflet).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of Non-Drowsy Sudafed Congestion, Cold & Flu Tablets with tricyclic antidepressants, sympathomimetic agents (such as decongestants, appetite suppressants and amfetamine-like psychostimulants) or with monoamine oxidase inhibitors, which interfere with the catabolism of sympathomimetic amines, may occasionally cause a rise in blood pressure (See Contraindications).

Because of the pseudoephedrine content, Non-Drowsy Sudafed Congestion, Cold & Flu Tablets may partially reverse the hypotensive action of drugs which interfere with sympathetic activity including bretylium, betanidine, guanethidine, debrisoquine, methyldopa, alpha- and beta-adrenergic blocking agents (See Special warnings and precautions for use).

The use of drugs which induce hepatic microsomal enzymes, such as anticonvulsants and oral contraceptive steroids, may increase the extent of metabolism of paracetamol, resulting in reduced plasma concentrations of the drug and a faster elimination rate.

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine.

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

4.6 Pregnancy And Lactation

Non-Drowsy Sudafed Congestion, Cold & Flu Tablets, like most medicines, should not be used during pregnancy unless the potential benefit of treatment to the mother outweighs any possible risk to the developing foetus.

Pseudoephedrine and paracetamol have been in widespread use for many years without apparent ill consequence. Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. The safety of pseudoephedrine during pregnancy has not been directly established.

Pseudoephedrine is excreted in breast milk in small amounts but the effect of this on breast-fed infants is not known. It has been estimated that approximately 0.4 to 0.7% of a single 60 mg dose of pseudoephedrine ingested by a nursing mother will be excreted in the breast milk over 24 hours.

Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding. A pharmacokinetic study of paracetamol in 12 nursing mothers revealed that less than 1% of a 650 mg oral dose of paracetamol appeared in the breast milk. Similar findings have been reported in other studies, therefore maternal ingestion of therapeutic doses of paracetamol does not appear to present a risk to the neonate/infant.

4.7 Effects On Ability To Drive And Use Machines

No special comment - unlikely to produce an effect.

4.8 Undesirable Effects

Pseudoephedrine

Serious side effects associated with the use of pseudoephedrine are extremely rare. Symptoms of central nervous system excitation may occur, including sleep disturbance and, rarely, hallucinations.

Skin rashes, with or without irritation, have occasionally been reported with pseudoephedrine.

Urinary retention has been reported occasionally in men receiving pseudoephedrine: prostatic enlargement could have been an important predisposing factor.

Paracetamol

Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causality related to paracetamol.

4.9 Overdose

Pseudoephedrine

Symptoms

As with other sympathomimetic agents, symptoms and signs of pseudoephedrine overdose include irritability, restlessness, tremor, convulsions, palpitations, hypertension and difficulty with micturition.

Management

Necessary measures should be taken to maintain and support respiration and control convulsions. Gastric lavage should be performed if indicated. Catheterisation of the bladder may be necessary. Acid diuresis can accelerate the elimination of pseudoephedrine, although the potential therapeutic gain of this procedure is now in dispute. The value of dialysis in overdose is not known, although four hours of haemodialysis removed approximately 20 % of the total body load of pseudoephedrine in a combination product containing 60 mg pseudoephedrine and 8 mg acrivastine.

Paracetamol

Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk Factors:

If the patient

• Is on long term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.

Or

• Regularly consumes ethanol in excess of recommended amounts.

Or

• Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Paracetamol

Paracetamol is an analgesic and antipyretic. The therapeutic effects of paracetamol are thought to be related to inhibition of prostaglandin synthesis, as a result of inhibition of cyclo-oxygenase. There is some evidence that it is a more effective inhibitor of central as opposed to peripheral cyclo-oxygenase. Paracetamol has only weak anti-inflammatory properties. This may be explained by the concept that inflammatory tissues have higher levels of cellular peroxides than other tissues and that cellular peroxides prevent inhibition of cyclo-oxygenase by paracetamol.

Pseudoephedrine

Pseudoephedrine has direct and indirect sympathomimetic activity and is an effective upper respiratory decongestant. Pseudoephedrine is less potent than ephedrine in producing both tachycardia and elevation of systolic blood pressure and is also less potent in causing stimulation of the central nervous system. Pseudoephedrine produces its decongestant effect within 30 minutes persisting for at least 4 hours.

5.2 Pharmacokinetic Properties

Absorption

Paracetamol

Absorption of paracetamol occurs mainly by passive transfer from the small intestine. Gastric emptying is the rate-limiting step in the absorption of orally administered paracetamol. Any drug, disease or other condition, which alters the rate of gastric emptying, will therefore influence the rate of paracetamol absorption.

Peak plasma paracetamol concentration usually occurs between 30 and 90 minutes after oral ingestion, depending on the formulation. Mean maximum plasma concentrations of paracetamol of 12.84 ug/ml were determined following the administration of Calpol Six Plus suspension (containing 1g paracetamol) to adults.

Paracetamol is incompletely available to the systemic circulation after oral administration since a variable proportion is lost through first-pass metabolism. Oral bioavailability in adults appears to depend on the amount of paracetamol administered, increasing from 63% of the administered dose after 500mg to nearly 90% of the dose after 1 or 2 g (in tablet form).

Pseudoephedrine

Pseudoephedrine is well absorbed from the gut following oral administration. After the administration of one 60 mg pseudoephedrine tablet to healthy adult volunteers, the C_max for pseudoephedrine was approximately 180 ng/ml, with t_max occurring at approximately 1.5-2.0 hours.

Distribution

Paracetamol

Paracetamol is distributed uniformly throughout most body fluids, with an estimated volume of distribution of 0.95 l/kg. Following therapeutic doses, paracetamol is not appreciably bound to plasma proteins.

Pseudoephedrine

The apparent volume of distribution of pseudoephedrine (Vd/F) was approximately 2.8 l/kg.

Metabolism and elimination

Paracetamol

The plasma half-life of paracetamol after therapeutic doses is in the range 1.5-2.5 hours. Paracetamol is metabolised by the liver and several metabolites of paracetamol have been identified in man. The two major metabolites excreted in the urine are the glucuronide and sulphate conjugates. About 10 % of administered paracetamol is converted, via a minor pathway, by a cytochrome P-450 mixed function oxidase system to a reactive metabolite, acetamidoquinone. This metabolite is rapidly conjugated with reduced glutathione and excreted as cysteine and mercapturic acid conjugates. When large amounts of paracetamol are taken, hepatic glutathione may become depleted causing excessive accumulation within the hepatocyte of acetamidoquinone, which binds covalently to vital hepatocellular macromolecules. In overdose, this can lead to hepatic necrosis. Total body clearance of paracetamol following a single dose (1000 mg i.v) is approximately 5 ml/min/kg.

Renal excretion of paracetamol involves glomerular filtration and passive reabsorption, and the sulphate and glucuronide conjugates are subject to active renal tubular secretion. Renal clearance of paracetamol depends on urine flow rate, but not pH.

Less than 4 % of the administered drug is excreted as unchanged paracetamol. In healthy subjects, approximately 85-95% of a therapeutic dose is excreted in the urine within 24 hours.

Pseudoephedrine

The plasma t_½ was approximately 5.5 hours. Pseudoephedrine is partly metabolised in the liver by N. Pseudoephedrine and its metabolite are excreted in the urine; 55% to 90% of a dose is excreted unchanged. The apparent total body clearance of pseudoephedrine (Cl/F) was 6 - 6.5 ml/min/kg. The elimination rate constant (K_el) was approximately 0.13 hr^-1. The rate of urinary elimination is accelerated when the urine is acidified. Conversely, as the urine pH increases, the rate of urinary elimination is slowed.

Pharmacokinetics in Renal Impairment

Paracetamol

The mean plasma half-life of paracetamol is similar in normal and renally impaired subjects between 2-8hrs, but from 8-24hrs paracetamol is eliminated less rapidly. Marked accumulation of the glucuronide and sulphate conjugates occurs in chronic renal failure.

There may be some extra renal elimination of retained paracetamol conjugates in patients with chronic renal failure, with limited regeneration of the parent compound. An increase in the interval between doses of paracetamol has been recommended for adults with chronic renal failure. Haemodialysis may result in reduced plasma levels of paracetamol. Supplementary doses of paracetamol may be necessary in order to maintain therapeutic blood levels.

Pseudoephedrine

Following the administration of a single dose of Duact Capsules

(60 mg pseudoephedrine + 8 mg acrivastine) to patients with varying degrees of renal impairment, the C_max for pseudoephedrine increased approximately 1.5 fold in patients with moderate to severe renal impairment when compared to the C_max in healthy volunteers. The t_max was not affected by renal impairment. The t_½ increased 3 -12 fold in patients with mild to severe renal impairment respectively, when compared to the t_½ in healthy volunteers.

Pharmacokinetics in Hepatic Impairment

Paracetamol

The mean plasma paracetamol half-life is similar in normal subjects and those with mild liver disease, but is significantly prolonged (approximately 75%) in patients with severe liver disease. However, the clinical significance of the increase in half-life is unclear, since there is no evidence of drug accumulation or hepatotoxicity in patients with liver disease, and glutathione conjugation is not impaired. The administration of 4g paracetamol daily for 13 days to 20 subjects with chronic stable liver disease, resulted in no deterioration of liver function, and in mild liver disease, there is no evidence that paracetamol is harmful when taken at recommended doses. However, in severe liver disease, the plasma paracetamol half-life is significantly prolonged.

Pseudoephedrine

There have been no specific studies of pseudoephedrine in hepatic impairment.

Pharmacokinetics in the Elderly

Paracetamol

Differences in pharmacokinetic parameters observed between fit young and fit elderly subjects are not thought to be of clinical significance. However, there is some evidence to suggest that serum paracetamol half-life is markedly increased (by approximately 84%) and clearance of paracetamol is decreased (by approximately 47%) in frail, immobile, elderly subjects when compared to fit young subjects.

Pseudoephedrine

In elderly volunteers, following the administration of Duact Capsules (60 mg pseudoephedrine + 8 mg acrivastine) the t_½ for pseudoephedrine was 1.4 fold that seen in healthy volunteers. The apparent Cl/F was 0.8 fold that seen in healthy volunteers, and the Vd/F was essentially unchanged.

5.3 Preclinical Safety Data

Mutagenicity

Paracetamol

In vivo mutagencicity tests of paracetamol in mammals are limited and show conflicting results. Therefore, there is insufficient information to determine whether paracetamol poses a mutagenic risk to man.

Paracetamol has been found to be non-mutagenic in bacterial mutagenicity assays, although a clear clastogenic effect has been observed in mammalian cells in vitro following exposure to paracetamol (3 and 10 mM for 2 hr).

Pseudoephedrine

The results of a wide range of tests indicate that pseudoephedrine does not pose a mutagenic risk to man.

Carcinogenicity

Paracetamol

There is inadequate evidence to determine the carcinogenic potential of paracetamol in humans. A positive association between the use of paracetamol and cancer of the urethra (but not of other sites in the urinary tract) was observed in a case-control study in which approximate lifetime consumption of paracetamol (whether acute or chronic) was estimated. However, other similar studies have failed to demonstrate a statistically significant association between paracetamol and cancer of the urinary tract, or paracetamol and renal cell carcinoma.

There is limited evidence for the carcinogenicity of paracetamol in experimental animals. Liver cell tumours can be detected in mice and liver and bladder carcinomas can be detected in rats, following chronic feeding of 500mg/kg/day paracetamol.

Pseudoephedrine

There is insufficient information available to determine whether pseudoephedrine has carcinogenic potential.

Teratogenicity

Paracetamol

There is no information relating to the teratogenic potential of paracetamol. In humans, paracetamol crosses the placenta and attains concentrations in the foetal circulation similar to those in the maternal circulation. Intermittent maternal ingestion of therapeutic doses of paracetamol is not associated with teratogenic effects in humans.

Paracetamol has been found to be fetotoxic to cultured rat embryos.

Pseudoephedrine

Systemic administration of pseudoephedrine, up to 50 times the human daily dosage in rats and up to 35 times the human daily dosage in rabbits did not produce teratogenic effects.

Fertility

Paracetamol

There is no information relating to the effects of paracetamol on human fertility. A significant decrease in testicular weight was observed when male Sprague-Dawley rats were given daily high doses of paracetamol (500 mg/kg body weight/day) orally for 70 days.

Pseudoephedrine

Systemic administration of pseudoephedrine to rats, up to 7 times the human daily dosage in females and 35 times the human daily dosage in males, did not impair fertility or alter foetal morphological development and survival.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Pregelatinised maize starch

Povidone

Crospovidone

Stearic acid

Microcrystalline cellulose

Croscarmellose sodium

Magnesium stearate

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Store below 25°C. Keep dry and protect from light

6.5 Nature And Contents Of Container

Blister packs (12 tablets) consisting of a white, opaque PVC/PVdC film and either:

Aluminium foil blister lidding

Or

Paper/aluminium foil child resistant blister lidding

6.6 Special Precautions For Disposal And Other Handling

None applicable.

Administrative Data

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0025

9. Date Of First Authorisation/Renewal Of The Authorisation

28^th October 1997

10. Date Of Revision Of The Text

21 APRIL 2009

Norditropin Simplexx 15mg / 1.5ml

Norditropin

SimpleXx

15 mg/1.5 ml

solution for injection in cartridges

Somatropin

Read all of this leaflet carefully before you start using this medicine.

Keep this leaflet. You may need to read it again. If you have further questions, ask your doctor or pharmacist. This medicine has been prescribed for you personally. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 
  1. What Norditropin
  SimpleXx
  is and what it is used for
  


• 
  2. Before you use Norditropin
  SimpleXx
  


• 
  3. How to use Norditropin
  SimpleXx
  


• 
  4. Possible side effects
  


• 
  5. How to store Norditropin
  SimpleXx
  


• 
  6. Further information.
  

What Norditropin SimpleXx is and what it is used for

Norditropin SimpleXx contains a biosynthetic human growth hormone called somatropin which is identical to the growth hormone produced naturally in the body. Children need growth hormone to help them grow, but adults also need it for their general health.

Norditropin SimpleXx comes as a solution in a cartridge ready for you to inject after you have put it in the matching NordiPen injection pen.

Norditropin SimpleXx is used to treat growth failure in children:

• If they have no or very low production of growth hormone


• If they have Turner syndrome (a genetic problem which may affect growth)


• If they have reduced kidney function


• If they are short and were born small for gestational age (SGA).

Norditropin SimpleXx is used as a growth hormone replacement in adults:

In adults Norditropin SimpleXx is used to replace growth hormone if their growth hormone production has been decreased since childhood or has been lost in adulthood because of a tumour, treatment of a tumour or a disease that affects the gland which produces growth hormone.

Before you use Norditropin SimpleXx

Do not use Norditropin SimpleXx:

• If you are allergic (hypersensitive) to somatropin, to phenol or to any of the other ingredients of Norditropin SimpleXx (listed in section 6, Further information)


• If you have had a kidney transplant


• If you are pregnant or breast-feeding (See pregnancy and breast-feeding)


• If you have a cancer, a tumour or are still in anti-tumour therapy


• If you have an acute critical illness e.g. open heart surgery, abdominal surgery, multiple accidental trauma or acute respiratory failure.

Take special care with Norditropin SimpleXx

• If you have diabetes


• If you have ever had a cancer or another kind of tumour


• If you have recurrent headaches, eyesight problems, nausea or if vomiting occurs


• If you have abnormal thyroid function


• If you develop scoliosis


• If you are over 60 years of age, or have received somatropin treatment as an adult for more than 5 years, as experience is limited


• If you suffer from kidney disease your kidney function should be monitored by your physician.

Tell your doctor if any of these apply to you as Norditropin SimpleXx may not be suitable.

Using other medicines

Your doctor needs to know if you are already being treated with:

• 
  Glucocorticoids or sex steroids - your adult height may be affected if you use Norditropin SimpleXx and glucocorticoids or sex steroids at the same time


• 
  Insulin - as your dose may need to be adjusted


• 
  Thyroid hormone.

Tell your doctor or pharmacist if you are taking other medicines or have recently taken any. This includes medicines obtained without a prescription.

Pregnancy and breast-feeding

• 
  Pregnancy. Stop the treatment and tell your doctor if you become pregnant while you are using Norditropin SimpleXx


• 
  Breast-feeding. Do not use Norditropin SimpleXx while you are breast-feeding as somatropin might pass into your milk.

Driving and using machines

Norditropin SimpleXx does not affect the use of any machines or the ability to drive safely.

How to use Norditropin SimpleXx

Always use Norditropin SimpleXx exactly as your doctor has told you. Check with your doctor or pharmacist if you are unsure.

Usual dose

The dose for children depends on their body weight and body surface area. The adult dose depends on height, weight, gender and growth hormone sensitivity and will be adjusted until you are on the right dose.

• 
  Children with low production or lack of growth hormone: The usual dose is 25 to 35 microgram per kg body weight per day or 0.7 to 1.0 mg per m^² body surface area per day.


• 
  Children with Turner syndrome: The usual dose is 45 to 67 microgram per kg body weight per day or 1.3 to 2.0 mg per m^² body surface area per day.


• 
  Children with kidney disease: The usual dose is 50 microgram per kg body weight per day or 1.4 mg per m^² body surface area per day.


• 
  Children born small for gestational age (SGA): The usual dose is 35 microgram per kg body weight per day or 1.0 mg per m^² body surface area per day until final height is reached. (In clinical trials of short children born SGA doses of 33 and 67 microgram per kg body weight per day have typically been used.)


• 
  Adults with low production or lack of growth hormone: The usual starting dose is 0.1 to 0.3 mg per day. Your doctor will increase this dose each month until you are on the right dose. The usual maximum dose is 1.0 mg per day.

When to use Norditropin SimpleXx

• Inject your daily dose into the skin every evening just before bedtime.

Using the cartridges to inject yourself

• Norditropin SimpleXx solution comes in cartridges ready to be used in the matching NordiPen. The NordiPen instruction manual tells you how to use the cartridges in the injection pen


• Check each new Norditropin SimpleXx cartridge before you use it. Do not use any cartridge that is damaged or cracked


• Only use a Norditropin SimpleXx cartridge if the solution inside is clear and colourless


• Vary the area you inject so you do not harm your skin


• Do not share your Norditropin SimpleXx cartridge with anyone else.

How long you will need treatment for

• If you are using Norditropin SimpleXx for growth failure because of Turner syndrome, a kidney disease or if you were born small for gestational age (SGA), continue using Norditropin SimpleXx until you stop growing


• If you lack growth hormone, continue using Norditropin SimpleXx into adulthood


• Do not stop using Norditropin SimpleXx without discussing it with your doctor first.

If you use too much:

• 
  Tell your doctor if you inject too much Norditropin SimpleXx. Long-term overdosing can cause abnormal growth and coarsening of facial features.

If you forget a dose:

• Take the next dose as usual, at the normal time. Do not take a double dose to make up for a forgotten dose.

Possible side effects

Like all medicines, Norditropin SimpleXx can cause side effects, although not everybody gets them.

Very rare effects in children and adults

(may affect up to 1 in 10,000 people):

• 
  Rash; wheezing; swollen eyelids, face or lips; complete collapse. Any of these may be signs of allergic reactions


• 
  Headache, eyesight problems, feeling sick (nausea) and being sick (vomiting). These may be signs of raised pressure in the brain


• 
  Serum thyroxin levels may decrease

If you get any of these effects, see a doctor as soon as possible. Stop using Norditropin SimpleXx until your doctor says you can continue treatment.

Formation of antibodies directed against somatropin has been rarely observed during Norditropin therapy.

Cases of leukaemia and relapse of brain tumours have also been reported in patients treated with somatropin (the active ingredient in Norditropin SimpleXx), although there is no evidence that somatropin was responsible.

If you think you are suffering from any of these diseases, speak to your doctor.

Other side effects in children:

Uncommon effects

(may affect up to 1 in 100 children):

• 
  Headache
  


• 
  Redness, itching and pain in the area of injection.

Rare effects

(may affect up to 1 in 1000 children):

• 
  Rash
  


• 
  Muscle and joint pain


• 
  Swollen hands and feet due to fluid retention.

In rare cases, children using Norditropin SimpleXx have experienced hip and knee pain or have started limping. These symptoms may be caused by a disease affecting the top of the thigh bone (Legg-Calvé disease) or because the end of the bone has slipped from the cartilage (slipped capital femoral epiphysis) and may not be due to Norditropin SimpleXx.

In children with Turner syndrome, a few cases of increased growth of hands and feet compared to height have been observed in clinical trials.

A clinical trial in children with Turner syndrome has shown that high doses of Norditropin can possibly increase the risk of getting ear infections.

Other side effects in adults:

Very common effects

(may affect more than 1 in 10 adults):

• 
  Swollen hands and feet due to fluid retention.

Common effects

(may affect up to 1 in 10 adults):

• 
  Headache
  


• Feeling of skin crawling (formication) and numbness or pain mainly in fingers


• 
  Joint pain and stiffness; muscle pain.

Uncommon effects

(may affect up to 1 in 100 adults):

• 
  Type 2 diabetes
  


• 
  Carpal tunnel syndrome tingling and pain in fingers and hands


• 
  Itching (can be intense) and pain in the area of injection


• 
  Muscle stiffness.
  

If any of these side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist, as you may need to reduce your dose.

How to store Norditropin SimpleXx

Keep out of the reach and sight of children.

Do not use Norditropin SimpleXx after the expiry date which is stated on the package. The expiry date refers to the last day of that month.

Store unused Norditropin SimpleXx cartridges in a refrigerator (2°C to 8°C) in the outer carton, in order to protect from light. Do not freeze or expose to heat.

After starting to use a Norditropin SimpleXx 15 mg/1.5 ml cartridge in an injection pen you can keep it in the pen for up to 4 weeks in a refrigerator (2°C to 8°C).

Do not continue to use Norditropin SimpleXx cartridges which have been frozen or exposed to excessive temperatures.

Check each new Norditropin SimpleXx cartridge before you use it. Do not use any cartridge that is damaged or cracked.

Do not use any Norditropin SimpleXx cartridge if the solution inside is not clear and colourless.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

What Norditropin SimpleXx contains

• The active substance is somatropin


• The solution also contains mannitol; histidine; poloxamer 188; phenol; water for injections; hydrochloric acid and sodium hydroxide.

What Norditropin SimpleXx looks like and contents of the pack

Norditropin SimpleXx is a clear and colourless solution in a 1.5 ml glass cartridge ready for injection in the NordiPen injection pen.

1 ml of solution contains 10 mg somatropin.

1 mg of somatropin corresponds to 3 IU of somatropin.

Norditropin SimpleXx is available in three strengths:

5 mg/1.5 ml, 10 mg/1.5 ml and 15 mg/1.5 ml (equivalent to 3.3 mg/ml, 6.7 mg/ml and 10 mg/ml, respectively).

Manufacturer

Norditropin SimpleXx is made by:

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

Marketing authorisation holder

Novo Nordisk Limited

Broadfield Park

Brighton Road

Crawley

West Sussex

RH11 9RT

UK

This leaflet was last approved in 02/2010.

Norditropin
and SimpleXx
are Trademarks owned by Novo Nordisk Health Care AG Switzerland

NordiPen is a trademark owned by Novo Nordisk A/S, Denmark

© 1999 / 2008

8-2072-01-002-4