Herceptin 150mg Powder for concentrate for solution for infusion

1. Name Of The Medicinal Product

Herceptin

2. Qualitative And Quantitative Composition

One vial contains 150 mg of trastuzumab, a humanised IgG1 monoclonal antibody produced by mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity and ion exchange chromatography including specific viral inactivation and removal procedures.

The reconstituted Herceptin solution contains 21 mg/ml of trastuzumab.

For a full list of excipients, (see section 6.1).

3. Pharmaceutical Form

Powder for concentrate for solution for infusion.

Herceptin is a white to pale yellow lyophilised powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Breast Cancer

Metastatic Breast Cancer (MBC)

Herceptin is indicated for the treatment of patients with HER2 positive metastatic breast cancer:

- as monotherapy for the treatment of those patients who have received at least two chemotherapy regimens for their metastatic disease. Prior chemotherapy must have included at least an anthracycline and a taxane unless patients are unsuitable for these treatments. Hormone receptor positive patients must also have failed hormonal therapy, unless patients are unsuitable for these treatments.

- in combination with paclitaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease and for whom an anthracycline is not suitable.

- in combination with docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease.

- in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor positive metastatic breast cancer, not previously treated with trastuzumab.

Early Breast Cancer (EBC)

Herceptin is indicated for the treatment of patients with HER2 positive early breast cancer.

- following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (see section 5.1).

- following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel.

- in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.

Herceptin should only be used in patients with metastatic or early breast cancer whose tumours have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay (see sections 4.4 and 5.1).

Metastatic Gastric Cancer (MGC)

Herceptin in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2 positive metastatic adenocarcinoma of the stomach or gastro-esophageal junction who have not received prior anti-cancer treatment for their metastatic disease.

Herceptin should only be used in patients with metastatic gastric cancer whose tumours have HER2 overexpression as defined by IHC2+ and a confirmatory SISH or FISH result, or by an IHC 3+ result. Accurate and validated assay methods should be used (see Sections 4.4 and 5.1).

4.2 Posology And Method Of Administration

HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Herceptin treatment should only be initiated by a physician experienced in the administration of cytotoxic chemotherapy (see section 4.4).

MBC

Three-weekly schedule

The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.

Weekly schedule

The recommended initial loading dose of Herceptin is 4 mg/kg body weight. The recommended weekly maintenance dose of Herceptin is 2 mg/kg body weight, beginning one week after the loading dose.

Administration in combination with paclitaxel or docetaxel

In the pivotal trials (H0648g, M77001), paclitaxel or docetaxel was administered the day following the first dose of Herceptin (for dose, see the Summary of Product Characteristics for paclitaxel or docetaxel) and immediately after the subsequent doses of Herceptin if the preceding dose of Herceptin was well tolerated.

Administration in combination with an aromatase inhibitor

In the pivotal trial (BO16216) Herceptin and anastrozole were administered from day 1. There were no restrictions on the relative timing of Herceptin and anastrozole at administration (for dose, see the Summary of Product Characteristics for anastrozole or other aromatase inhibitors).

EBC

Three-weekly and weekly schedule

As a three-weekly regimen the recommended initial loading dose of Herceptin is 8 mg/kg body weight. The recommended maintenance dose of Herceptin at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.

As a weekly regimen (initial loading dose of 4 mg/kg followed by 2 mg/kg every week) concomitantly with paclitaxel following chemotherapy with doxorubicin and cyclophosphamide.

(See section 5.1 for chemotherapy combination dosing).

MGC

Three-weekly schedule

The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.

Breast Cancer (MBC and EBC) and Gastric Cancer (MGC)

Duration of treatment

Patients with MBC or MGC should be treated with Herceptin until progression of disease. Patients with EBC should be treated with Herceptin for 1 year (18 cycles three-weekly) or until disease recurrence, whatever occurs first.

Dose reduction

No reductions in the dose of Herceptin were made during clinical trials. Patients may continue therapy during periods of reversible, chemotherapy-induced myelosuppression but they should be monitored carefully for complications of neutropenia during this time. Refer to the Summary of Product Characteristics for paclitaxel, docetaxel or aromatase inhibitor for information on dose reduction or delays.

Missed doses

If the patient misses a dose of Herceptin by one week or less, then the usual maintenance dose (weekly regimen: 2 mg/kg; three-weekly regimen: 6 mg/kg) should be given as soon as possible. Do not wait until the next planned cycle. Subsequent maintenance doses (weekly regimen: 2 mg/ kg; three-weekly regimen: 6 mg/kg respectively) should then be given according to the previous schedule.

If the patient misses a dose of Herceptin by more than one week, a re-loading dose of Herceptin should be given over approximately 90 minutes (weekly regimen: 4 mg/kg; three-weekly regimen: 8 mg/kg). Subsequent Herceptin maintenance doses (weekly regimen: 2 mg/kg; three-weekly regimen 6 mg/kg respectively) should then be given (weekly regimen: every week; three-weekly regimen every 3 weeks) from that point.

Special patient populations

Clinical data show that the disposition of Herceptin is not altered based on age or serum creatinine (see section 5.2). In clinical trials, elderly patients did not receive reduced doses of Herceptin. Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not been carried out. However in a population pharmacokinetic analysis, age and renal impairment were not shown to affect trastuzumab disposition.

Paediatric population

Herceptin is not recommended for use in children below 18 years of age due to insufficient data on safety and efficacy.

Method of administration

Herceptin loading dose should be administered as a 90-minute intravenous infusion. Do not administer as an intravenous push or bolus. Herceptin intravenous infusion should be administered by a health-care provider prepared to manage anaphylaxis and an emergency kit should be available. Patients should be observed for at least six hours after the start of the first infusion and for two hours after the start of the subsequent infusions for symptoms like fever and chills or other infusion-related symptoms (see sections 4.4 and 4.8). Interruption or slowing the rate of the infusion may help control such symptoms. The infusion may be resumed when symptoms abate.

If the initial loading dose was well tolerated, the subsequent doses can be administered as a 30-minute infusion.

For instructions on use and handling of Herceptin refer to section 6.6.

4.3 Contraindications

Hypersensitivity to trastuzumab, murine proteins, or to any of the excipients.

Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.

4.4 Special Warnings And Precautions For Use

HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of the testing procedures (see section 5.1).

Currently no data from clinical trials are available on re-treatment of patients with previous exposure to Herceptin in the adjuvant setting.

Cardiotoxicity

Heart failure (New York Heart Association [NYHA] class II-IV) has been observed in patients receiving Herceptin therapy alone or in combination with paclitaxel or docetaxel, particularly following anthracycline (doxorubicin or epirubicin)–containing chemotherapy. This may be moderate to severe and has been associated with death (see section 4.8).

All candidates for treatment with Herceptin, but especially those with prior anthracycline and cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and physical examination, ECG, echocardiogram, or MUGA scan or magnetic resonance imaging. A careful risk-benefit assessment should be made before deciding to treat with Herceptin.

Herceptin and anthracyclines should not be used currently in combination except in a well-controlled clinical trial setting with cardiac monitoring. Patients who have previously received anthracyclines are also at risk of cardiotoxicity with Herceptin treatment, although the risk is lower than with concurrent use of Herceptin and anthracyclines. Because the half-life of Herceptin is approximately 4-5 weeks Herceptin may persist in the circulation for up to 20-25 weeks after stopping Herceptin treatment. Patients who receive anthracyclines after stopping Herceptin may possibly be at increased risk of cardiotoxicity. If possible, physicians should avoid anthracycline-based therapy for up to 25 weeks after stopping Herceptin. If anthracyclines are used, the patient's cardiac function should be monitored carefully.

In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac events was observed when Herceptin was administered after anthracycline-containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxel and carboplatin and was more marked when Herceptin was administered concurrently with taxanes than when administered sequentially to taxanes. Regardless of the regimen used, most symptomatic cardiac events occurred within the first 18 months. In one of the 3 pivotal studies conducted in which a median follow-up of 5.5 years was available (BCIRG006) a continuous increase in the cumulative rate of symptomatic cardiac or LVEF events was observed in patients who were administered Herceptin concurrently with a taxane following anthracycline therapy up to 2.37% compared to approximately 1% in the two comparator arms (anthracycline plus cyclophosphamide followed by taxane and taxane, carboplatin and Herceptin).

In EBC, the following patients were excluded from the HERA trial, there are no data about the benefit-risk balance, and therefore treatment can not be recommended in such patients:

• History of documented congestive heart failure

• High-risk uncontrolled arrhythmias

• Angina pectoris requiring a medicinal product

• Clinically significant valvular disease

• Evidence of transmural infarction on ECG

• Poorly controlled hypertension

Formal cardiological assessment should be considered in patients in whom there are cardiovascular concerns following baseline screening. Cardiac function should be further monitored during treatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac dysfunction. For early breast cancer patients, cardiac assessment, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration. In patients who receive anthracycline containing chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last administration, or longer if a continuous decrease of LVEF is observed. Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g. every 6-8 weeks). If patients have a continued decrease in left ventricular function, but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of Herceptin therapy has been seen. Caution should be exercised in treating patients with symptomatic heart failure, a history of hypertension or documented coronary artery disease, and in early breast cancer, in those patients with a left ventricular ejection fraction (LVEF) of 55 % or less.

If LVEF drops 10 ejection fraction (EF) points from baseline AND to below 50 %, treatment should be suspended and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or declined further, discontinuation of Herceptin should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up.

If symptomatic cardiac failure develops during Herceptin therapy, it should be treated with the standard medications for this purpose. Discontinuation of Herceptin therapy should be strongly considered in patients who develop clinically significant heart failure unless the benefits for an individual patient are deemed to outweigh the risks.

The safety of continuation or resumption of Herceptin in patients who experience cardiotoxicity has not been prospectively studied. However, most patients who developed heart failure in the pivotal (H0648g, H0649g, M77001, BO16216, BO16348, BO18255, NSABP B-31, NCCTG N9831, BCIRG 006) trials improved with standard medical treatment. This included diuretics, cardiac glycosides, beta-blockers and/or angiotensin-converting enzyme inhibitors. The majority of patients with cardiac symptoms and evidence of a clinical benefit of Herceptin treatment continued on therapy without additional clinical cardiac events.

Infusion reactions, allergic-like reactions and hypersensitivity

Serious adverse reactions to Herceptin infusion that have been reported infrequently include dyspnoea, hypotension, wheezing, hypertension, bronchospasm, supraventricular tachyarrythmia, reduced oxygen saturation, anaphylaxis, respiratory distress, urticaria and angioedema (see section 4.8). The majority of these events occur during or within 2.5 hours of the start of the first infusion. Should an infusion reaction occur the infusion should be discontinued or the rate of infusion slowed and the patient should be monitored until resolution of all observed symptoms (see section 4.2). The majority of patients experienced resolution of symptoms and subsequently received further infusions of Herceptin. Serious reactions have been treated successfully with supportive therapy such as oxygen, beta-agonists, and corticosteroids. In rare cases, these reactions are associated with a clinical course culminating in a fatal outcome. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a fatal infusion reaction. Therefore, these patients should not be treated with Herceptin (see section 4.3).

Initial improvement followed by clinical deterioration and delayed reactions with rapid clinical deterioration have also been reported. Fatalities have occurred within hours and up to one week following infusion. On very rare occasions, patients have experienced the onset of infusion symptoms and pulmonary symptoms more than six hours after the start of the Herceptin infusion. Patients should be warned of the possibility of such a late onset and should be instructed to contact their physician if these symptoms occur.

Pulmonary events

Severe pulmonary events have been reported with the use of Herceptin in the post-marketing setting (see section 4.8). These events have occasionally been fatal. In addition, cases of interstitial lung disease including pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been reported. Risk factors associated with interstitial lung disease include prior or concomitant therapy with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy. These events may occur as part of an infusion-related reaction or with a delayed onset. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients should not be treated with Herceptin (see section 4.3). Caution should be exercised for pneumonitis, especially in patients being treated concomitantly with taxanes.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed. A risk for interactions with the concomitant use of other medicinal products cannot be excluded.

4.6 Pregnancy And Lactation

Pregnancy

Reproduction studies have been conducted in cynomolgus monkeys at doses up to 25 times that of the weekly human maintenance dose of 2 mg/kg Herceptin and have revealed no evidence of impaired fertility or harm to the foetus. Placental transfer of trastuzumab during the early (days 20–50 of gestation) and late (days 120–150 of gestation) foetal development period was observed. It is not known whether Herceptin can affect reproductive capacity. As animal reproduction studies are not always predictive of human response, Herceptin should be avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to the foetus.

In the post-marketing setting, cases of oligohydramnios, some associated with fatal pulmonary hypoplasia of the foetus, have been reported in pregnant women receiving Herceptin. Women of childbearing potential should be advised to use effective contraception during treatment with Herceptin and for at least 6 months after treatment has concluded. Women who become pregnant should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with Herceptin, close monitoring by a multidisciplinary team is desirable.

Lactation

A study conducted in lactating cynomolgus monkeys at doses 25 times that of the weekly human maintenance dose of 2 mg/kg Herceptin demonstrated that trastuzumab is secreted in the milk. The presence of trastuzumab in the serum of infant monkeys was not associated with any adverse effects on their growth or development from birth to 1 month of age. It is not known whether trastuzumab is secreted in human milk. As human IgG1 is secreted into human milk, and the potential for harm to the infant is unknown, women should not breast-feed during Herceptin therapy and for 6 months after the last dose.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and to use machines have been performed. Patients experiencing infusion-related symptoms should be advised not to drive and use machines until symptoms abate.

4.8 Undesirable Effects

Amongst the most serious and/or common adverse reactions reported in Herceptin usage to date are cardiotoxicity, infusion-related reactions, haematotoxicity (in particular neutropenia) and pulmonary adverse events.

In this section, the following categories of frequency have been used: very common (

List of adverse reactions

Presented in the following table are adverse reactions that have been reported in association with the use of Herceptin alone or in combination with chemotherapy in pivotal clinical trials and in the post-marketing setting. Pivotal trials included:

- H0648g and H0649g: Herceptin as a monotherapy or in combination with paclitaxel in metastatic -breast cancer.

- M77001: Docetaxel, with or without Herceptin in metastatic breast cancer.

- BO16216: Anastrozole with or without Herceptin in HER2 positive and hormone receptor positive metastatic breast cancer.

- BO16348: Herceptin as a monotherapy following adjuvant chemotherapy in HER2 positive breast cancer.

- BO18255: Herceptin in combination with a fluoropyrimidine and cisplatin versus chemotherapy alone as first-line therapy in HER2 positive advanced gastric cancer.

- B-31, N9831: Herceptin administered sequential to adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel.

- BCIRG 006: Herceptin administered sequential to adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with docetaxel or Herceptin administered in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.

All the terms included are based on the highest percentage seen in pivotal clinical trials.

System organ class	Adverse reaction	Frequency
Infections and infestations	+Pneumonia	Common (<1 %)
Neutropenic sepsis	Common
Cystitis	Common
Herpes zoster	Common
Infection	Common
Influenza	Common
Nasopharyngitis	Common
Sinusitis	Common
Skin infection	Common
Rhinitis	Common
Upper respiratory tract infection	Common
Urinary tract infection	Common
Erysipelas	Common
Cellulitis	Common
Sepsis	Uncommon
Neoplasms benign, malignant and unspecified (incl. Cysts and polyps)	Malignant neoplasm progression	Not known
Neoplasm progression	Not known
Blood and lymphatic system disorders	Febrile Neutropenia	Very common
Anaemia	Common
Neutropenia	Common
Thrombocytopenia	Common
White blood cell count decreased/leukopenia	Common
Hypoprothrombinaemia	Not known
Immune system disorders	Hypersensitivity	Common
+Anaphylactic reaction	Not known
+Anaphylactic shock	Not known
Metabolism and nutrition disorders	Weight Decreased/Weight Loss	Common
Anorexia	Common
Hyperkalaemia	Not known
Psychiatric disorders	Anxiety	Common
Depression	Common
Insomnia	Common
Thinking abnormal	Common
Nervous system disorders	1Tremor	Very common
Dizziness	Very common
Headache	Very common
Peripheral neuropathy	Common
Paraesthesia	Common
Hypertonia	Common
Somnolence	Common
Dysgeusia	Common
Ataxia	Common
Paresis	Rare
Brain oedema	Not known
Eye disorders	Dry eye	Common
Lacrimation increased	Common
Papilloedema	Not known
Retinal haemorrhage	Not known
Ear and Labyrinth Disorders	Deafness	Uncommon
Cardiac disorders	1Blood pressure decreased	Very common
1Blood pressure increased	Very common
1Heart beat irregular	Very common
1Palpitation	Very common
1Cardiac flutter	Very common
+ Cardiac failure (congestive)	Common (2 %)
+1Supraventricular tachyarrhythmia	Common
Cardiomyopathy	Common
Ejection fraction decreased*	Very Common
Pericardial effusion	Uncommon
Cardiogenic shock	Not known
Pericarditis	Not known
Bradycardia	Not known
Gallop rhythm present	Not known
Vascular disorders	+1Hypotension	Common
Vasodilatation	Common
Respiratory, thoracic and mediastinal disorders	+1Wheezing	Very common
+Dyspnoea	Very common (14 %)
Asthma	Common
Cough	Common
Epistaxis	Common
Lung disorder	Common
Pharyngitis	Common
Rhinorrhoea	Common
+Pleural effusion	Uncommon
Pneumonitis	Rare
+Pulmonary fibrosis	Not known
+Respiratory distress	Not known
+ Respiratory failure	Not known
+Lung infiltration	Not known
+Acute pulmonary oedema	Not known
+Acute respiratory distress syndrome	Not known
+Bronchospasm	Not known
+Hypoxia	Not known
+Oxygen saturation decreased	Not known
Laryngeal oedema	Not known
Orthopnoea	Not known
Pulmonary oedema	Not known
Gastrointestinal disorders	Diarrhoea	Very common
Vomiting	Very common
Nausea	Very common
1Lip swelling	Very common
Abdominal pain	Very common
Pancreatitis	Common
Dyspepsia	Common
Haemorrhoids	Common
Constipation	Common
Dry mouth	Common
Hepatobiliary disorders	Hepatitis	Common
Liver Tenderness	Common
Jaundice	Rare
Hepatic Failure	Not known
Hepatocellular Injury	Common
Skin and subcutaneous disorders	Erythema	Very common
Rash

Disprin

1. Name Of The Medicinal Product

Disprin

2. Qualitative And Quantitative Composition

Active Ingredient	mg/Tablet	Specification
Aspirin	300.00	Ph Eur

3. Pharmaceutical Form

Dispersible tablet

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of mild to moderate pain in headaches, including migraine headaches, toothache, neuralgia, sciatica, period pains and sore throats.

Reduction of temperature in feverishness, influenza and colds.

Reduction of inflammation in rheumatism and lumbago.

4.2 Posology And Method Of Administration

Oral administration after dissolution in water.

Adults (including children 16 years and over): Two to three tablets every 4 hours. Do not exceed 13 tablets in 24 hours.

Do not give to children aged under 16 years unless specifically indicated (e.g. for Kawasaki's disease).

There is no indication that dosage need be modified in the elderly.

4.3 Contraindications

Should not be given to patients suffering from a previous history of peptic ulceration or active peptic ulceration or haemophilia.

4.4 Special Warnings And Precautions For Use

The product labelling will include:

Do not give to children under 16 years unless on the advice of a doctor.

Keep out of reach of children.

If you are receiving regular medical treatment, are asthmatic, allergic to aspirin or have or have had a stomach ulcer, seek your doctor's advice before taking this product.

There is a possible association between aspirin and Reye's Syndrome when given to children. Reye's Syndrome is a very rare disease which affects the brain and liver and can be fatal. For this reason aspirin should not be given to children aged under 16 years unless specifically indicated (e.g. for Kawasaki's disease).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Aspirin may enhance the effects of anticoagulants and inhibit the effects of uricosurics.

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).

4.6 Pregnancy And Lactation

There is clinical and epidemiological evidence of the safety of aspirin in human pregnancy, but it may prolong labour and contribute to maternal and neonatal bleeding and is best avoided at term and during breastfeeding.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

May precipitate bronchospasm and induce attacks of asthma or hypersensitivity in susceptible subjects. May also induce gastrointestinal haemorrhage, occasionally major.

4.9 Overdose

Salicylate poisoning is usually associated with plasma concentrations>350 mg/L (2.5 mmol/L). Most adult deaths occur in patients whose concentrations exceed 700 mg/L (5.1 mmol/L). Single doses less than 100 mg/kg are unlikely to cause serious poisoning.

Symptoms

Common features include vomiting, dehydration, tinnitus, vertigo, deafness, sweating, warm extremities with bounding pulses, increased respiratory rate and hyperventilation. Some degree of acid-base disturbance is present in most cases.

A mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH (normal or reduced hydrogen ion concentration) is usual in adults and children over the age of four years. In children aged four years or less, a dominant metabolic acidosis with low arterial pH (raised hydrogen ion concentration) is common. Acidosis may increase salicylate transfer across the blood brain barrier.

Uncommon features include haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopaenia, increased INR/PTR, intravascular coagulation, renal failure and non-cardiac pulmonary oedema.

Central nervous system features including confusion, disorientation, coma and convulsions are less common in adults than in children.

Management

Give activated charcoal if an adult presents within one hour of ingestion of more than 250 mg/kg. The plasma salicylate concentration should be measured, although the severity of poisoning cannot be determined from this alone and the clinical and biochemical features must be taken into account. Elimination is increased by urinary alkalinisation, which is achieved by the administration of 1.26% sodium bicarbonate. The urine pH should be monitored. Correct metabolic acidosis with intravenous 8.4% sodium bicarbonate (first check serum potassium). Forced diuresis should not be used since it does not enhance salicylate excretion and may cause pulmonary oedema.

Haemodialysis is the treatment of choice for severe poisoning and should be considered in patients with plasma salicylate concentrations>700 mg/L (5.1 mmol/L), or lower concentrations associated with severe clinical or metabolic features. Patients under ten years or over 70 have increased risk of salicylate toxicity and may require dialysis at an earlier stage.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Aspirin:

Aspirin inhibits the cyclo-oxygenase enzyme involved in conversion of phospholipids to prostaglandins and its effects on the body are believed to result primarily from prevention of prostaglandin production. These effects include peripheral analgesia, fever reduction, reduction in inflammation and inhibition of platelet aggregation.

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 within 8 hours before or within 30 minutes after immediate release aspirin dosing (81mg), a decreased effect of aspirin 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 clinically relevant effect is considered to be like for occasional ibuprofen use.

5.2 Pharmacokinetic Properties

Aspirin is rapidly absorbed from the stomach and upper gastrointestinal tract with peak levels after around 20-30 minutes following dissolution. It is subject to first-pass metabolism with an overall bioavailability of around 70%. Metabolism is by conversion to salicylic acid and then by further conversion to other metabolites. These are excreted by the kidneys in both free and conjugated form. The plasma half-life of aspirin is around 15-20 minutes and that of salicylic acid is 2-3 hours.

5.3 Preclinical Safety Data

No preclinical findings of relevance have been reported.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Calcium carbonate, maize starch, citric acid, talc, sodium lauryl sulphate, saccharin, crospovidone and lime flavour.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Store below 25°C in a dry place.

6.5 Nature And Contents Of Container

Cardboard carton containing tablets in strips of aluminium foil with vinyl heat seal. Pack sizes: 6, 8, 12, 16, 24, 32, 48, 96 and 500 tablets. (Those pack sizes printed in bold are currently sold).

6.6 Special Precautions For Disposal And Other Handling

Oral administration after dissolution in water.

7. Marketing Authorisation Holder

Reckitt Benekiser Healthcare (UK) Limited

Dansom Lane

Hull

HU8 7DS

United Kingdom.

8. Marketing Authorisation Number(S)

PL 00063/0017.

9. Date Of First Authorisation/Renewal Of The Authorisation

24/04/1995 / 23/02/2004

10. Date Of Revision Of The Text

26/01/2009

Endocet

Pronunciation: OX-i-KOE-done/a-SEET-a-MIN-oh-fen
Generic Name: Oxycodone/Acetaminophen
Brand Name: Examples include Endocet and Percocet

Endocet contains acetaminophen. Severe and sometimes fatal liver problems, including the need for liver transplant, have been reported with the use of acetaminophen. Most cases of these liver problems occurred in patients taking excessive doses of acetaminophen (more than 4,000 mg per day). Also, patients who developed these liver problems were often using more than 1 medicine that contained acetaminophen. Discuss any questions or concerns with your doctor.

Endocet is used for:

Relieving moderate to moderately severe pain. Endocet may also be used to treat other conditions as determined by your doctor.

Endocet is a combination of a narcotic and an analgesic/antipyretic. It works in the brain and nervous system to decrease pain.

Do NOT use Endocet if:

• you are allergic to any ingredient in Endocet


• you have high blood carbon dioxide levels (hypercarbia) or a certain severe bowel problem (paralytic ileus)


• you have severely slow or difficult breathing or severe asthma, or you are having an asthma attack


• you are taking sodium oxybate (GHB)

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

Before using Endocet:

Some medical conditions may interact with Endocet. 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 had an allergic reaction to any codeine- or morphine-related medicine (eg, hydrocodone, dihydrocodeine, hydromorphone)


• if you have a history of asthma, chronic obstructive pulmonary disease (COPD), or other lung or breathing problems


• if you have or recently have had any head injury, increased pressure in the brain, growths in the brain (eg, tumors), or infection of the brain or nervous system


• if you have a history of heart problems (eg, cor pulmonale), low blood pressure, the blood disease porphyria, stomach or bowel problems (eg, blockage, paralysis), inflammation of the pancreas (pancreatitis), gallbladder problems, liver problems (eg, hepatitis), kidney problems, seizures, thyroid problems, adrenal gland problems (eg, Addison disease), curvature of the spine (scoliosis), prostate problems (eg, an enlarged prostate), or trouble urinating


• if you are in very poor health; are dehydrated or have low blood volume; or have drowsiness, stomach pain, or severe diarrhea caused by antibiotic use (pseudomembranous colitis)


• if you drink alcohol; have a history of drug or alcohol abuse, mood or mental problems, or suicidal thoughts or actions; or are going through withdrawal from alcohol or other substances

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

• Anticholinergics (eg, scopolamine, oxybutynin) because the risk of a certain severe bowel problem (paralytic ileus) may be increased


• Cimetidine, muscle relaxants (eg, cyclobenzaprine), phenothiazines (eg, chlorpromazine), or sulfinpyrazone because the risk of side effects, such as severe drowsiness, slow or difficult breathing, confusion, and seizures, may be increased


• Azole antifungals (eg, itraconazole, ketoconazole), beta-blockers (eg, propranolol), clarithromycin, isoniazid, nefazodone, protease inhibitors (eg, boceprevir, ritonavir), or telithromycin because they may increase the risk of Endocet's side effects


• Buprenorphine, butorphanol, nalbuphine, naltrexone, pentazocine, or rifamycins (eg, rifampin) because they may decrease Endocet's effectiveness


• Lamotrigine, loop diuretics (eg, furosemide), or zidovudine because their effectiveness may be decreased by Endocet


• Anticoagulants (eg, warfarin) or sodium oxybate (GHB) because the risk of their side effects may be increased by Endocet


• Medicines that may harm the liver (eg, acetaminophen, methotrexate, certain medicines for HIV infection) because the risk of liver side effects may be increased. Ask your doctor if you are unsure if any of your medicines might harm the liver

This may not be a complete list of all interactions that may occur. Ask your health care provider if Endocet 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 Endocet:

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

• Take Endocet by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation.


• If you have been taking Endocet regularly or for longer than a few weeks, do not suddenly stop taking it without checking with your doctor. Your doctor may need to gradually lower your dose.


• If Endocet is no longer needed, dispose of the unused tablets by flushing them down the toilet.


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

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

Important safety information:

• Endocet may cause dizziness, light-headedness, blurred vision, or drowsiness. These effects may be worse if you take it with alcohol or certain medicines. Use Endocet with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Endocet may cause dizziness, light-headedness, or fainting; alcohol, hot weather, exercise, or fever may increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects.


• Do not drink alcohol while you are using Endocet.


• Check with your doctor before you use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers, narcotic pain medicines) while you are using Endocet; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.


• Do NOT take more than the recommended dose or take more often than prescribed without checking with your doctor.


• Tell your doctor or dentist that you take Endocet before you receive any medical or dental care, emergency care, or surgery.


• Endocet may cause constipation. Talk with your doctor or pharmacist about using a stool softener or laxative to prevent constipation. It is also important to maintain a diet adequate in fiber, drink plenty of water, and exercise to prevent constipation. If you become constipated while taking Endocet, talk with your doctor or pharmacist.


• Endocet may harm your liver. Your risk may be greater if you drink alcohol while you are using Endocet. Talk to your doctor before you take Endocet or other fever reducers if you drink alcohol.


• Endocet has acetaminophen in it. Before you start any new medicine, check the label to see if it has acetaminophen in it too. If it does or if you are not sure, check with your doctor or pharmacist.


• Contact your doctor right away if you take more than 4,000 mg of acetaminophen per day, even if you feel well.


• Endocet may interfere with certain lab tests. Be sure your doctor and lab personnel know you are taking Endocet.


• Use Endocet with caution in the ELDERLY; they may be more sensitive to its side effects, especially breathing problems and drowsiness.


• Endocet should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


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

When used for long periods of time or at high doses, Endocet may not work as well and may require higher doses to obtain the same effect as when originally taken. This is known as TOLERANCE. Talk with your doctor if Endocet stops working well. Do not take more than prescribed.

Some people who use Endocet for a long time may develop a need to continue taking it. People who take high doses are also at risk. This is known as DEPENDENCE or addiction. If you suddenly stop taking Endocet, you may experience WITHDRAWAL symptoms including anxiety; diarrhea; fever, runny nose, or sneezing; goose bumps and abnormal skin sensations; nausea; vomiting; pain; rigid muscles; rapid heartbeat; seeing, hearing, or feeling things that are not there; shivering or tremors; sweating; and trouble sleeping.

Possible side effects of Endocet:

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:

Constipation; dizziness; drowsiness; flushing; light-headedness; nausea; vomiting.

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

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, throat, or tongue; unusual hoarseness); burning, numbness, or tingling; change in amount of urine produced; confusion; fainting; fast, slow, or irregular heartbeat; fever, chills, or persistent sore throat; hallucinations; hearing loss; mental or mood changes (eg, agitation, anxiety, depression); seizures; severe or persistent constipation; severe or persistent dizziness, headache, or light-headedness; shortness of breath; slow or difficult breathing; stomach or back pain; symptoms of liver problems (eg, yellowing of the skin or eyes, pale stools, dark urine, persistent loss of appetite); tremors; trouble urinating; unusual bruising or bleeding; unusual tiredness or weakness; vision changes.

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: Endocet 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. Symptoms may include cold or clammy skin; fainting; limp muscles; loss of consciousness; persistent nausea or vomiting; pinpoint pupils; severe dizziness, drowsiness, or light-headedness; slow heartbeat; slow, shallow, or abnormal breathing; stomach pain; symptoms of liver problems (eg, yellowing of the skin or eyes, pale stools, dark urine, loss of appetite); unusual sweating.

Proper storage of Endocet:

Store Endocet at room temperature, between 68 and 77 degrees F (20 and 25 degrees C), in a tightly closed container away from heat, moisture, and light. Do not store in the bathroom. Keep Endocet out of the reach of children and away from pets.

General information:

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


• Endocet 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 Endocet. 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 Endocet resources

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

• Endocet Consumer Overview


• Endocet Advanced Consumer (Micromedex) - Includes Dosage Information


• Endocet Prescribing Information (FDA)


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• Pain

Noriday Tablets

1. Name Of The Medicinal Product

Noriday®

2. Qualitative And Quantitative Composition

Each tablet contains 350 micrograms norethisterone.

3. Pharmaceutical Form

White, flat, circular, bevel-edged tablet inscribed 'SEARLE' on one side and 'NY' on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

Noriday is a progestogen-only oral contraceptive. It is particularly useful for women for whom oestrogens may not be appropriate.

4.2 Posology And Method Of Administration

Oral Administration

Starting on the first day of menstruation, one pill every day without a break in medication for as long as contraception is required. Additional contraceptive precautions (such as a condom) should be taken for the first 7 days of the first pack. Pills should be taken at the same time each day.

Missed Pills

If a pill is missed within 3 hours of the correct dosage time then the missed pill should be taken as soon as possible; this will ensure that contraceptive protection is maintained. If a pill is taken 3 or more hours late it is recommended that the woman takes the last missed pill as soon as possible and then continues to take the rest of the pills in the normal manner. However, to provide continued contraceptive protection it is recommended that an alternative method of contraception, such as a condom, is used for the next 7 days.

Changing from another oral contraceptive

In order to ensure that contraception is maintained it is advised that the first pill is taken on the day immediately after the patient has finished the previous pack.

Use after childbirth, miscarriage or abortion

The first pill should be taken on the 21st day after childbirth. This will ensure the patient is protected immediately. If there is any delay in taking the first pill, contraception may not be established until 7 days after the first pill has been taken. In these circumstances women should be advised that extra contraceptive methods will be necessary.

After a miscarriage or abortion patients can take the first pill on the next day; in this way they will be protected immediately.

Vomiting and diarrhoea

Gastrointestinal upsets, such as vomiting and diarrhoea, may interfere with the absorption of the pill leading to a reduction in contraceptive efficacy. Women should continue to take Noriday, but they should also be advised to use another contraceptive method during the period of gastrointestinal upset and for the next 7 days.

4.3 Contraindications

The contraindications for progestogen-only oral contraceptives are:

(i) known, suspected, or a past history of breast, genital or hormone dependent cancer;

(ii) acute or severe chronic liver diseases including past or present liver tumours, Dubin-Johnson or Rotor syndrome;

(iii) active liver disease;

(iv) history during pregnancy of idiopathic jaundice or severe pruritus;

(v) disorders of lipid metabolism;

(vi) undiagnosed abnormal vaginal bleeding ;

(vii) known or suspected pregnancy;

(viii) hypersensitivity to any component.

Combined oestrogen/progestogen preparations have been associated with an increase in the risk of thromboembolic and thrombotic disease. Risk has been reported to be related to both oestrogenic and progestogenic activity. In the absence of long term epidemiological studies with progestogen-only oral contraceptives, it is required that the existence, or history of thrombophlebitis, thromboembolic disorders, cerebral vascular disease, myocardial infarction, angina, or coronary artery disease be described as a contraindication to Noriday as it is to oestrogen containing oral contraceptives.

4.4 Special Warnings And Precautions For Use

Assessment of women prior to starting oral contraceptives (and at regular intervals thereafter) should include a personal and family medical history of each woman. Physical examination should be guided by this and by the contraindications (section 4.3) and warnings (section 4.4) for this product. The frequency and nature of these assessments should be based upon relevant guidelines and should be adapted to the individual woman, but should include measurement of blood pressure and, if judged appropriate by the clinician, breast, abdominal and pelvic examination including cervical cytology.

Malignant hepatic tumours have been reported on rare occasions in long-term users of contraceptives. Benign hepatic tumours have also been associated with oral contraceptive usage. A hepatic tumour should be considered in the differential diagnosis when upper abdominal pain, enlarged liver or signs of intra-abdominal haemorrhage occur.

A statistical association between the use of oral contraceptives and the occurrence of thrombosis, embolism or haemorrhage has been reported. Patients receiving oral contraceptives should be kept under regular surveillance, in view of the possibility of development of conditions such as thrombo-embolism.

The risk of coronary artery disease in women taking oral contraceptives is increased by the presence ofother predisposing factors such as cigarette smoking, hypercholesterolaemia, obesity, diabetes, history of pre-eclamptic toxaemia and increasing age. After the age of thirty-five years, the patient and physician should carefully re-assess the risk/benefit ratio of using oral contraceptives as opposed to alternative methods of contraception.

Noriday should be discontinued at least 4 weeks before elective surgery or during periods of prolonged immobilisation. It would be reasonable to resume Noriday 2 weeks after surgery provided the woman is ambulant. However, every woman should be considered individually with regard to the nature of the operation, the extent of immobilisation, the presence of additional risk factors and the chance of unwanted conception.

Noriday should be discontinued if there is a gradual or sudden, partial or complete loss of vision or any evidence of ocular changes, onset or aggravation of migraine or development of headache of a new kind which is recurrent, persistent or severe, suspicion of thrombosis or infarction, significant rise in blood pressure or if jaundice occurs.

Caution should be exercised where there is the possibility of an interaction between a pre-existing disorder and a known or suspected side effect. The use of Noriday in women suffering from epilepsy, or with a history of migraine or cardiac or renal dysfunction may result in exacerbation of these disorders because of fluid retention. Caution should also be observed in women who wear contact lenses, women with impaired carbohydrate tolerance, depression, gallstones, a past history of liver disease, varicose veins, hypertension, asthma or any disease that is prone to worsen during pregnancy (e.g. multiple sclerosis, porphyria, tetany and otosclerosis).

An increased risk of congenital abnormalities, including heart defects and limb defects, has been reported following the use of sex hormones, including oral contraceptives, in pregnancy. If the patient does not adhere to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and further use of oral contraceptives should be withheld until pregnancy has been ruled out. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen. If pregnancy is confirmed the patient should be advised of the potential risks to the foetus and the advisability of continuing the pregnancy should be discussed in the light of these risks. It is advisable to discontinue Noriday three months before a planned pregnancy.

Progestogen-only oral contraceptives may offer less protection against ectopic pregnancy, than against intrauterine pregnancy.

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk of having breast cancer diagnosed in women who are currently using oral contraceptives (OC). The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in OC users, the biological effects of OCs or a combination of both. The additional breast cancers diagnosed in current users of OCs or in women who have used OCs in the last ten years are more likely to be localised to the breast than those in women who never used OCs.

Breast cancer is rare among women under 40 years of age whether or not they take OCs. Whilst the background risk increases with age, the excess number of breast cancer diagnoses in current and recent progesterone-only pill (POP) users is small in relation to the overall risk of breast cancer, possibly of similar magnitude to that associated with combined OCs. However, for POPs, the evidence is based on much smaller populations of users and so is less conclusive than that for combined OCs.

The most important risk factor for breast cancer in POP users is the age women discontinue the POP; the older the age at stopping, the more breast cancers are diagnosed. Duration of use is less important and the excess risk gradually disappears during the course of the 10 years after stopping POP use, such that by 10 years there appears to be no excess.

The evidence suggests that compared with never-users, among 10,000 women who use POPs for up to 5 years but stop by age 20, there would be much less than 1 extra case of breast cancer diagnosed up to 10 years afterwards. For those stopping by age 30 after 5 years use of the POP, there would be an estimated 2-3 extra cases (additional to the 44 cases of breast cancer per 10,000 women in this age group never exposed to oral contraceptives). For those stopping by age 40 after 5 years use, there would be an estimated 10 extra cases diagnosed up to 10 years afterwards (additional to the 160 cases of breast cancer per 10,000 never-exposed women in this age group).

It is important to inform patients that users of all contraceptive pills appear to have a small increase in the risk of being diagnosed with breast cancer, compared with non-users of oral contraceptives, but this has to be weighed against the known benefits.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The herbal remedy St John's wort (Hypericum perforatum) should not be taken concomitantly with this medicine as this could potentially lead to a loss of contraceptive effect.

Some drugs may modify the metabolism of Noriday reducing its effectiveness; these include certain sedatives, antibiotics, and antiepileptics. During the time such agents are used concurrently, it is advised that an alternative method of contraception, such as a condom, is also used.

The serum levels of prednisone, prednisolone, cloprednol and possibly other corticosteroids are considerably increased in those taking oral contraceptives. Both the therapeutic and toxic effects may be expected to increase accordingly.

4.6 Pregnancy And Lactation

Noriday is contraindicated in women with suspected pregnancy. Several reports suggest an association between foetal exposure to female sex hormones, including oral contraceptives, and congenital anomalies.

There is no evidence that Noriday tablets diminish the yield of breast milk. Small amounts of steroid materials appear in the milk; their effect on the breast-fed child has not been determined.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

The incidence of side effects in clinical trials was lower than that experienced with oestrogen-containing oral contraceptives. Side effects which did occur included some cycle irregularity during the first few months of therapy, spotting or breakthrough bleeding, amenorrhoea, breast discomfort, gastrointestinal symptoms, rash, headaches, migraine, depression, fatigue, nervousness, disturbance of appetite and changes in weight and libido.

Hypertension, which is usually reversible on discontinuing treatment, has occurred in a small percentage of women taking oral contraceptives.

Menstrual pattern: Women taking Noriday for the first time should be informed that they may initially experience menstrual irregularity. This may include amenorrhoea, prolonged bleeding and/or spotting but such irregularity tends to decrease with time. If a woman misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.

4.9 Overdose

Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may be manifested by nausea, vomiting, breast enlargement and vaginal bleeding. There is no specific antidote and treatment should be symptomatic. Gastric lavage may be employed if the overdose is large and the patient is seen sufficiently early (within four hours).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Norethisterone administration increases the protein and sialic acid content of cervical mucus which prevents penetration of the mucus by spermatozoa. It causes changes in the structure of the endometrium such that implantation of blastocysts is impaired. It also reduces numbers and height of cilia on cells lining the fallopian tube, which could delay tubal transport of ova.

5.2 Pharmacokinetic Properties

Norethisterone is rapidly and completely absorbed after oral administration, peak plasma concentrations occurring in the majority of subjects between 1 and 3 hours. Due to first-pass metabolism, blood levels after oral administration are 60% of those after i.v. administration. The half life of elimination varies from 5 to 12 hours, with a mean of 7.6 hours. Norethisterone is metabolised mainly in the liver. Approximately 60% of the administered dose is excreted as metabolites in urine and faeces.

5.3 Preclinical Safety Data

The toxicity of norethisterone is very low. Reports of teratogenic effects in animals are uncommon. No carcinogenic effects have been found even in long-term studies. In subacute and chronic studies only minimal differences between treated and control animals are observed.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Noriday tablets contain:

Maize starch, polyvidone, magnesium stearate and lactose.

6.2 Incompatibilities

None known.

6.3 Shelf Life

The shelf life of Noriday tablets is 5 years.

6.4 Special Precautions For Storage

Store in a cool, dry place away from direct sunlight.

6.5 Nature And Contents Of Container

Noriday tablets are supplied in pvc/foil blister packs of 28 and 84 tablets.

Blister packaging consists of 250 micron PVC and 20 micron aluminium foil.

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Pfizer Limited

Ramsgate Road

Sandwich

Kent, CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

PL 00057/1019

9. Date Of First Authorisation/Renewal Of The Authorisation

26^th July 2002

10. Date Of Revision Of The Text

June 2010

11. LEGAL CATEGORY

POM

Ref: NO 2_0 UK