Iopidine 1.0% Ophthalmic Solution

1. Name Of The Medicinal Product

IOPIDINE 1.0% Eye Drops, Solution

2. Qualitative And Quantitative Composition

Apraclonidine 1.0% w/v (10mg/ml)

(as hydrochloride)

For a full list of excipients see section 6.1.

3. Pharmaceutical Form

Eye Drops, Solution

IOPIDINE 1.0% is a pale yellow solution.

4. Clinical Particulars

4.1 Therapeutic Indications

IOPIDINE 1.0% is indicated to control or prevent postsurgical elevations in intraocular pressure that occur in patients after anterior segment laser surgery. (Clinical trials have been conducted in trabeculoplasty, iridotomy and capsulotomy).

4.2 Posology And Method Of Administration

Adults(including the elderly):

One drop of IOPIDINE 1.0% should be instilled into the eye scheduled for operation one hour before initiating anterior segment laser surgery. A second drop should be instilled into the same eye immediately upon completion of the laser surgical procedure.

If for any reason, the drop of IOPIDINE 1.0% does not remain in the eye, repeat the dose by placing another drop in the eye.

Nasolacrimal occlusion or gently closing the eyelid after instillation is recommended. This may reduce the systemic absorption of medications administered via the ocular route and result in a decrease in systemic side effects.

There are no special precautions for administration to the elderly.

Children:

Safety and effectiveness of IOPIDINE in children have not been established and therefore IOPIDINE 1.0% is not recommended for use in children.

4.3 Contraindications

IOPIDINE 1.0% is contraindicated in patients with a history of severe or unstable and uncontrolled cardiovascular disease.

IOPIDINE 1.0% is contraindicated for children, for patients receiving monamine oxidase inhibitor therapy, systemic sympathomimetic agents, tricyclic antidepressants, and for patients with hypersensitivity to any component of the preparation or to clonidine.

4.4 Special Warnings And Precautions For Use

Warnings:

For topical ophthalmic use only. Not for injection or oral ingestion.

While the topical administration of two drops of IOPIDINE 1.0% had minimal effect on heart rate or blood pressure in clinical studies evaluating patients undergoing anterior segment laser surgery, including those with cardiovascular disease, the possibility of a vasovagal attack should be considered and caution should be exercised in patients with a history of such episodes. IOPIDINE 1.0% should be used with caution in patients with a history of angina, severe coronary insufficiency, recent myocardial infarction, overt cardiac failure, cerebrovascular disease, chronic renal failure, Raynaud's disease or thromboangiitis obliterans. Caution in and monitoring of depressed patients are advised since apraclonidine has been rarely associated with depression.

Precautions:

No data are available on the topical use of apraclonidine in patients with renal or hepatic failure. Systemic absorption of apraclonidine following topical administration is low, resulting in plasma levels less than 1.0 ng/ml. Nonetheless, monitoring of patients with impaired renal or hepatic function is advised. Close monitoring of cardiovascular parameters in patients with impaired liver function is also advised as the systemic dosage form of clonidine is partly metabolised in the liver.

Since apraclonidine is a potent depressor of intraocular pressure, patients who develop an exaggerated reduction in intraocular pressure should be closely monitored.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The risk of clinically relevant interactions appears low considering the plasma levels of apraclonidine given by the ocular route.

Although no specific drug interactions with topical glaucoma drugs or systemic medicaments were identified in clinical studies of IOPIDINE 1.0%, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, anaesthetics) should be considered. There is a theoretical possibility that use of IOPIDINE 1.0% in conjunction with topical sympathomimetics may give rise to a systemic pressor response and blood pressure should be checked initially in patients receiving these drug combinations.

Caution,is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

An additive hypotensive effect has been reported with the combination of systemic clonidine and neuroleptic therapy. Systemic clonidine may inhibit the production of catecholamine in response to insulin-induced hypoglycaemia and mask the signs and symptoms of hypoglycaemia.

Since apraclonidine may reduce pulse and blood pressure, caution in using drugs such as beta-blockers (ophthalmic and systemic), antihypertensives, and cardiac glycosides is advised. Patients using cardiovascular drugs concurrently with IOPIDINE 1.0% should have pulse and blood pressure frequently monitored. Caution should be exercised with simultaneous use of clonidine and other similar pharmacologic agents.

4.6 Pregnancy And Lactation

There are no adequate data from the use of Iopidine 1% in pregnant women. Preclinical studies with apraclonidine have shown embryotoxicity (see 5.3). The potential risk for humans is unknown.

It is not known if topically applied apraclonidine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when IOPIDINE 1.0% is administered to nursing women.

4.7 Effects On Ability To Drive And Use Machines

Clonidine-like drugs may cause drowsiness; patients if so affected should not drive or operate machinery.

4.8 Undesirable Effects

The following adverse events occurring in less than 2% of patients were reported in association with the use of IOPIDINE 1% in laser surgery:

Eye Disorders

Common (> 1/100 to < 1/10): Ocular hyperaemia.

Uncommon > 1/1000 to

Respiratory, Thoracic and Mediastinal Disorders

Uncommon (> 1/1000 to

Investigations

Uncommon (> 1/1000 to

The following adverse events were observed in non-laser investigational studies dosing IOPIDINE 1% once or twice daily for up to 28 days:

Psychiatric Disorders

Uncommon (> 1/1000 to

Nervous System Disorders

Uncommon (> 1/1000 to

Rare (> 1/10,000 to

Eye Disorders

Uncommon (> 1/1000 to

Cardiac Disorders

Uncommon (> 1/1000 to

Vascular Disorders

Uncommon (> 1/1000 to

Respiratory, Thoracic and Mediastinal Disorders

Rare (> 1/10,000 to

Gastrointestinal Disorders

Uncommon (> 1/1000 to

Rare (> 1/10,000 to

Skin and Subcutaneous Tissue Disorders

Rare (> 1/10,000 to

Musculoskeletal, Connective Tissue and Bone Disorders

Rare (> 1/10,000 to

General Disorders and Administration Site Conditions

Rare (> 1/10,000 to

4.9 Overdose

In the case of accidental overdose, Iopidine 1% can be removed by rinsing the eye with water or sterile saline solution.

A 2 month old female child received IOPIDINE 1% 1 drop in each eye. Two to three hours later, the infant presented with extreme pallor, hypothermia and miosis. She became comatose and was treated with glucose perfusion. The infant became responsive, but lethargic and heart rate was noted to be slow but regular. The infant made a full recovery with no sequelae.

A 23 month old male child ingested orally an unknown amount of IOPIDINE 5 mg/ml. The child was admitted to the hospital with hypothermia, bradycardia and drowsiness. Blood analysis revealed an apraclonidine serum level of 2.9ng/ml. The child was warmed and treated with atropine and dopamine with resolution of hypothermia and bradycardia within 4 hours. The child remained somnolent for 24 hours and was discharged 48 hours after admission with no reported sequelae.

Overdose with the oral form of clonidine has been reported to cause hypotension, transient hypertension, asthenia, vomiting, irritability, diminished or absent reflexes, lethargy, somnolence, sedation or coma, pallor, hypothermia, bradycardia, conduction defects, arrhythmias, dryness of the mouth, miosis, apnoea, respiratory depression, hypoventilation, and seizure. Treatment of an oral overdose includes supportive and symptomatic therapy, a patent airway should be maintained. Haemodialysis is of limited value since a maximum of 5% of circulating drug is removed.

5. Pharmacological Properties

Ophthalmologicals; Antiglaucoma Preparation and Miotics.

ATC Code: SO1E A03

5.1 Pharmacodynamic Properties

Apraclonidine is a relatively selective alpha-2-adrenergic agonist which does not possess significant membrane stabilising (local anaesthetic) activity. When instilled into the eye, apraclonidine has the action of reducing intraocular pressure. Ophthalmic apraclonidine has minimal effect on cardiovascular parameters. Aqueous fluorophotometry studies in man suggest that the mechanism of the ocular hypotensive action of apraclonidine is related to a reduction in aqueous formation.

The onset of action of IOPIDINE 1.0% can usually be noted within one hour and the maximum intraocular pressure reduction usually occurs three to five hours after application of a single dose.

5.2 Pharmacokinetic Properties

Following topical ocular administration to New Zealand albino rabbits, apraclonidine reached peak concentrations after two hours in the aqueous humor, iris, ciliary body and lens. The cornea exhibited the greatest concentration and peaked at the earliest time point (20 minutes). The tissue distribution of apraclonidine from highest to lowest concentration in microgram equivalents per gram of tissue was cornea, iris-ciliary body, aqueous humor, lens and vitreous humor. The elimination half-life of apraclonidine from the aqueous humor was determined to be approximately two hours.

Plasma concentration of apraclonidine following three times daily, bilateral, topical ocular dosing of 0.5% apraclonidine ophthalmic solution to normal human volunteers was less than 1.0 ng/ml. A steady state level was attained after five days of dosing. The systemic elimination half-life of apraclonidine was approximately 8 hours.

5.3 Preclinical Safety Data

Administration of apraclonidine intravenously and via the topical ocular route to both cats and monkeys resulted in a reduced anterior segment blood flow whereas flow to the posterior segment (i.e., retina, choroid or optic nerve head) was not affected. Chronic treatment of primates with apraclonidine hydrochloride 1.5% ocularly three times a day for one year did not result in morphological effects.

Acute Toxicity

Acute toxicity was evaluated intravenously and orally in rats and mice and orally in primates. The approximate oral LD₅₀ ranged from 5.04 mg/kg (mice) to 63.9 mg/kg (rats); no lethalities were observed in primates at 55 mg/kg. In rodents toxic signs included lethargy, hypothermia, cornea cloudiness, and haemorrhagic areas as well as distension of the gastrointestinal tract. Pronounced inhibition of gastrointestinal motility is considered the cause of mortality in mice. The reduced intestinal motility was observed in mice after intravenous administration of 0.1 mg/kg. Lethargy and disturbed defecation were found in monkeys after oral administration of 55 mg/kg. The normal human dose from ophthalmic use is approximately 0.01 mg/kg/d.

Subchronic and Chronic Toxicity

Rabbits tolerated apraclonidine hydrochloride solutions of 0.5%, 1% or 1.5% (2 drops t.i.d.) over a period of one month without signs of systemic toxicity. Minimal corneal cloudiness was observed sporadically in some eyes receiving the 1.5% apraclonidine hydrochloride solution.

Rats and mice received daily oral doses of up to 1.2 mg/kg and 2 mg/kg, respectively, over a period of 13 weeks. Mortalities occurred in rats at 1.2 mg/kg/d and in mice at 1.6 mg/kg/d. Pharmacotoxic reactions included disturbed defecation and distended abdomen plus corneal cloudiness predominantly in female mice of the high-dose group. Rats in the high-dose group that died before the end of the study showed lymphocytic effects in the spleen and thymus, but these effects were not seen in animals which survived to the end of the study. No drug-related toxic or ophthalmic findings were observed when monkeys received apraclonidine hydrochloride solutions of 0.5%, 1% and 1.5% by topical ocular administration t.i.d. for one year.

Local Tolerance

The topical ocular administration of apraclonidine hydrochloride solutions of 0.5%, 1% and 1.5% (2 drops instilled at 30 min intervals into one eye for 6 h) led to dose-dependent conjunctival and corneal irritation in the rabbit.

Assessment of the sensitization potential in the guinea pig proved apraclonidine hydrochloride to be moderately sensitizing.

Mutagenic and Tumorigenic Potential

Mutagenicity testing of apraclonidine hydrochloride using different standard systems all produced negative results.

Two-year long-term studies evaluating the carcinogenic potential in rats (at doses of 0.1, 0.3 and 1.0 mg/kg/d) and mice (at doses of 0.1, 0.3 and 0.6 mg/kg/d) revealed no signs of a carcinogenic potential of apraclonidine hydrochloride.

Both species showed an increased incidence of ocular changes (mineralization and neo-vascularization of the cornea, and keratitis), which are considered related to the pharmacological effect of the drug in reducing the tear film. In addition, renal changes (mineralisation) were found in rats from 0.3 mg/kg/d onward.

Reproduction Toxicity

Studies performed in rats and rabbits did not suggest any teratogenic effects of apraclonidine. Embryotoxicity has been observed when pregnant rabbits were dosed orally with doses of apraclonidine (doses > 1.25 mg/kg/day) that were maternally toxic, and administered over the entire period of organogenesis at exposure levels > 100 times the recommended daily dosage regimen for IOPIDINE 1.0% based on a 50 kg person.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium acetate, sodium chloride, hydrochloric acid and/or sodium hydroxide (to adjust pH) and purified water.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Unopened: 2 years.

Use immediately after first opening the container.

6.4 Special Precautions For Storage

Do not store above 25°C. Keep the container in the outer carton

6.5 Nature And Contents Of Container

Two sealed LDPE form/fill/seal single-dose containers each containing 0.25 mL and wrapped in a foil pouch.

The following pack sizes are available:

1 box containing 1 pouch of 2 single dose containers

1 box containing 5 pouches of 2 single dose containers

1 box containing 6 pouches of 2 single dose containers

1 box containing 10 pouches of 2 single dose containers

1 box containing 15 pouches of 2 single dose containers

1 box containing 20 pouches of 2 single dose containers

1 box containing 25 pouches of 2 single dose containers

Not all the pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

For single use only.

Discard any unused contents immediately after use.

7. Marketing Authorisation Holder

Alcon Laboratories (U.K.) Ltd

Pentagon Park

Boundary Way

Hemel Hempstead

Herts. HP2 7UD

United Kingdom

8. Marketing Authorisation Number(S)

PL 0649/0120

9. Date Of First Authorisation/Renewal Of The Authorisation

09/04/2006

10. Date Of Revision Of The Text

09/04/2006

Isentress 400 mg Film-coated Tablets

1. Name Of The Medicinal Product

ISENTRESS® 400 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 400 mg of raltegravir (as potassium).

Excipient: Each tablet contains 26.06 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Pink, oval tablet, marked with "227" on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

ISENTRESS is indicated in combination with other anti-retroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients.

This indication is based on safety and efficacy data from two double-blind, placebo-controlled trials in treatment-experienced patients and one double-blind, active-controlled trial in treatment-naïve patients (see sections 4.4 and 5.1).

4.2 Posology And Method Of Administration

Therapy should be initiated by a physician experienced in the management of HIV infection. ISENTRESS should be used in combination with other active anti-retroviral therapies (ARTs) (see sections 4.4 and 5.1). The use of raltegravir in previously ART-naïve patients is based on a study in which it was co-administered with two NRTIs (see sections 4.4 and 5.1).

Posology

Adults

The recommended dosage of ISENTRESS is 400 mg administered twice daily with or without food. The effect of food on absorption of raltegravir is uncertain (see section 5.2). It is not recommended to chew, crush or split the tablets.

Elderly

There is limited information regarding the use of ISENTRESS in the elderly (see section 5.2). Therefore ISENTRESS should be used with caution in this population.

Children and adolescents

Safety and efficacy have not been established in patients below 16 years of age (see sections 5.1 and 5.2).

Renal impairment

No dosage adjustment is required for patients with renal impairment (see section 5.2).

Hepatic impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment. The safety and efficacy of ISENTRESS have not been established in patients with severe underlying liver disorders. Therefore ISENTRESS should be used with caution in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Method of administration

Oral

4.3 Contraindications

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

4.4 Special Warnings And Precautions For Use

Patients should be advised that current anti-retroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be employed.

Overall, considerable inter- and intra-subject variability was observed in the pharmacokinetics of raltegravir (see sections 4.5 and 5.2).

Raltegravir has a relatively low genetic barrier to resistance. Therefore, whenever possible, raltegravir should be administered with two other active ARTs to minimise the potential for virological failure and the development of resistance (see section 5.1).

In treatment-naïve patients, the clinical study data on use of raltegravir are limited to use in combination with two nucleotide reverse transcriptase inhibitors (NRTIs) (emtricitabine and tenofovir disoproxil fumarate).

The safety and efficacy of ISENTRESS have not been established in patients with severe underlying liver disorders. Therefore ISENTRESS should be used with caution in patients with severe hepatic impairment (see sections 4.2 and 5.2).

Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination anti-retroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.

There are very limited data on the use of raltegravir in patients co-infected with HIV and hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients with chronic hepatitis B or C and treated with combination anti-retroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination anti-retroviral therapy. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination anti-retroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Caution should be used when co-administering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.5).

Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinal products associated with these conditions (see section 4.8).

Severe skin and hypersensitivity reactions

Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking ISENTRESS, in most cases concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping ISENTRESS treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

Rash occurred more commonly in treatment-experienced patients receiving regimens containing ISENTRESS + darunavir compared to patients receiving ISENTRESS without darunavir or darunavir without ISENTRESS (see section 4.8).

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In vitro studies indicated that raltegravir is not a substrate of cytochrome P450 (CYP) enzymes, does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, does not induce CYP3A4 and does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or P-glycoprotein.

Based on in vitro and in vivo studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.

Although in vitro studies indicated that raltegravir is not an inhibitor of the UDP glucuronosyltransferases (UGTs) 1A1 and 2B7, one clinical study has suggested that some inhibition of UGT1A1 may occur in vivo based on effects observed on bilirubin glucuronidation. However, the magnitude of the effect seems unlikely to result in clinically important drug-drug interactions.

Considerable inter- and intra-individual variability was observed in the pharmacokinetics of raltegravir. The following drug interaction information is based on Geometric Mean values; the effect for an individual patient cannot be predicted precisely.

Effect of raltegravir on the pharmacokinetics of other medicinal products

In interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone, or midazolam.

Effect of other agents on the pharmacokinetics of raltegravir

Given that raltegravir is metabolised primarily via UGT1A1, caution should be used when co-administering ISENTRESS with strong inducers of UGT1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.4). The impact of other strong inducers of drug metabolising enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Less potent inducers (e.g., efavirenz, nevirapine, etravirine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) may be used with the recommended dose of ISENTRESS.

Co-administration of ISENTRESS with medicinal products that are known to be potent UGT1A1 inhibitors (e.g., atazanavir) may increase plasma levels of raltegravir. Less potent UGT1A1 inhibitors (e.g., indinavir, saquinavir) may also increase plasma levels of raltegravir, but to a lesser extent compared with atazanavir. In addition, tenofovir may increase plasma levels of raltegravir, however, the mechanism for this effect is unknown (see Table 1). From the clinical trials, a large proportion of patients used atazanavir and / or tenofovir, both agents that result in increases in raltegravir plasma levels, in the optimised background regimens. The safety profile observed in patients who used atazanavir and / or tenofovir was generally similar to the safety profile of patients who did not use these agents. Therefore no dose adjustment is required.

In healthy subjects, co-administration of ISENTRESS with omeprazole increases raltegravir plasma levels. As the effects of increasing gastric pH on the absorption of raltegravir in HIV-infected patients are uncertain, use ISENTRESS with medicinal products that increase gastric pH (e.g., proton pump inhibitors and H2 antagonists) only if unavoidable.

Table 1

Pharmacokinetic Interaction Data

Medicinal products by therapeutic area	Interaction (mechanism, if known)	Recommendations concerning co-administration
ANTI-RETROVIRAL
Protease inhibitors (PI)
atazanavir /ritonavir (raltegravir 400 mg Twice Daily)	raltegravir AUC ↑41% raltegravir C12hr ↑77% raltegravir Cmax ↑24% (UGT1A1 inhibition)	No dose adjustment required for ISENTRESS.
tipranavir /ritonavir (raltegravir 400 mg Twice Daily)	raltegravir AUC raltegravir C12hr raltegravir Cmax (UGT1A1 induction)	No dose adjustment required for ISENTRESS.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
efavirenz (raltegravir 400 mg Single Dose)	raltegravir AUC raltegravir C12hr raltegravir Cmax (UGT1A1 induction)	No dose adjustment required for ISENTRESS.
etravirine (raltegravir 400 mg Twice Daily)	raltegravir AUC raltegravir C12hr raltegravir Cmax (UGT1A1 induction) etravirine AUC ↑ 10% etravirine C12hr ↑ 17% etravirine Cmax ↑ 4%	No dose adjustment required for ISENTRESS or etravirine.
Nucleoside/tide reverse transcriptase inhibitors
tenofovir (raltegravir 400 mg Twice Daily)	raltegravir AUC ↑49% raltegravir C12hr ↑3% raltegravir Cmax ↑64% (mechanism of interaction unknown) tenofovir AUC tenofovir C12hr tenofovir Cmax	No dose adjustment required for ISENTRESS or tenofovir disoproxil fumarate.
CCR5 inhibitors
maraviroc (raltegravir 400 mg Twice Daily)	raltegravir AUC raltegravir C12hr raltegravir Cmax (mechanism of interaction unknown) maraviroc AUC maraviroc C12hr maraviroc Cmax	No dose adjustment required for ISENTRESS or maraviroc.
ANTIMICROBIALS
Antimycobacterial
rifampicin (raltegravir 400 mg Single Dose)	raltegravir AUC raltegravir C12hr raltegravir Cmax (UGT1A1 induction)	Rifampicin reduces plasma levels of ISENTRESS. If co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.4).
SEDATIVE
midazolam (raltegravir 400 mg Twice Daily)	midazolam AUC midazolam Cmax↑3%	No dosage adjustment required for ISENTRESS or midazolam. These results indicate that raltegravir is not an inducer or inhibitor of CYP3A4, and raltegravir is thus not anticipated to affect the pharmacokinetics of medicinal products which are CYP3A4 substrates.
ANTI-ULCER
omeprazole (raltegravir 400 mg Single Dose)	raltegravir AUC ↑ 212% raltegravir C12 hr↑ 46% raltegravir Cmax↑ 315%	Co-administration of proton pump inhibitors or other antiulcer medicinal products may increase plasma levels of raltegravir. Do not use ISENTRESS with medicinal products that increase gastric pH unless this is unavoidable.
HORMONAL CONTRACEPTIVES
Ethinyl Estradiol Norelgestromin (raltegravir 400 mg Twice Daily)	Ethinyl Estradiol AUC Ethinyl Estradiol Cmax↑ 1% Norelgestromin AUC ↑ 14% Norelgestromin Cmax↑ 29%	No dosage adjustment required for ISENTRESS or hormonal contraceptives (estrogen- and/or progesterone-based)
OPIOID ANALGESICS
methadone (raltegravir 400 mg Twice Daily)	methadone AUC ↔ methadone Cmax↔	No dose adjustment required for ISENTRESS or methadone.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of raltegravir in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. ISENTRESS should not be used during pregnancy.

Anti-retroviral Pregnancy Registry

To monitor maternal-foetal outcomes in patients inadvertently administered ISENTRESS while pregnant, an Anti-retroviral Pregnancy Registry has been established. Physicians are encouraged to register patients in this registry.

Lactation

It is not known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the milk of lactating rats. In rats, at a maternal dose of 600 mg/kg/day, mean active substance concentrations in milk were approximately 3-fold greater than in maternal plasma. Breastfeeding is not recommended while taking ISENTRESS. In addition, it is recommended that HIV-infected mothers should not breastfeed their infants to avoid risking postnatal transmission of HIV.

4.7 Effects On Ability To Drive And Use Machines

No studies have been performed on the effects of ISENTRESS on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing ISENTRESS, which may influence some patients' ability to drive and use machines (see section 4.8).

4.8 Undesirable Effects

The safety profile of ISENTRESS was based on the pooled safety data from two Phase III clinical studies in treatment-experienced patients and one Phase III clinical study in treatment-naïve patients; described below.

In treatment-experienced patients, the two randomised clinical studies used the recommended dose of 400 mg twice daily in combination with optimised background therapy (OBT) in 462 patients, in comparison to 237 patients taking placebo in combination with OBT. During double-blind treatment, the total follow-up was 708 patient-years in the group receiving ISENTRESS 400 mg twice daily, and 244 patient-years in the group receiving placebo.

In treatment-naïve patients, the multi-centre, randomised, double-blind, active-controlled clinical study used the recommended dose of 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir 245 mg in 281 patients, in comparison to 282 patients taking efavirenz (EFV) 600 mg (at bedtime) in combination with emtricitabine (+) tenofovir. During double-blind treatment, the total follow-up was 480 patient-years in the group receiving ISENTRESS 400 mg twice daily, and 463 patient-years in the group receiving efavirenz 600 mg at bedtime.

In the pooled analysis of treatment-experienced patients, the rates of discontinuation of therapy due to adverse reactions were 3.9 % in patients receiving ISENTRESS + OBT and 4.6 % in patients receiving placebo + OBT. The rates of discontinuation of therapy in naïve patients due to adverse reactions were 3.6 % in patients receiving ISENTRESS + emtricitabine (+) tenofovir and 6.7 % in patients receiving efavirenz + emtricitabine (+) tenofovir.

Adverse reactions considered by investigators to be causally related to ISENTRESS (alone or in combination with other ART) are listed below by System Organ Class. Any term that includes at least one serious adverse reaction is identified with a dagger (^†). Adverse reactions identified from post-marketing experience are included in italics.

Frequencies are defined as common (

System Organ Class	Frequency	Adverse reactions ISENTRESS (alone or in combination with other ART)
Infections and infestations	uncommon	genital herpes†, folliculitis, gastro-enteritis, herpes simplex, herpes virus infection, herpes zoster, influenza, molluscum contagiosum, nasopharyngitis, upper respiratory tract infection
Neoplasms benign, malignant and unspecified (including cysts and polyps)	uncommon	skin papilloma
Blood and lymphatic system disorders	uncommon	anaemia†, iron deficiency anaemia, lymph node pain, lymphadenopathy, neutropenia
uncommon	thrombocytopenia‡‡
Immune system disorders	uncommon	immune reconstitution syndrome†, drug hypersensitivity, hypersensitivity
Metabolism and nutrition disorders	uncommon	anorexia, cachexia, decreased appetite, diabetes mellitus, dyslipidaemia, hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hyperphagia, increased appetite, polydipsia
Psychiatric disorders	common uncommon uncommon	abnormal dreams, insomnia mental disorder†, suicide attempt†, anxiety, confusional state, depressed mood, depression, major depression, middle insomnia, mood altered, nightmare, panic attack, sleep disorder suicidal ideation‡‡, suicidal behaviour (particularly in patients with a pre-existing history of psychiatric illness) ‡‡
Nervous system disorders	common uncommon	dizziness, headache amnesia, carpal tunnel syndrome, cognitive disorder, disturbance in attention, dizziness postural, dysgeusia, hypersomnia, hypoaesthesia, lethargy, memory impairment, migraine, neuropathy peripheral, paraesthesia, somnolence, tension headache, tremor
Eye disorders	uncommon	visual impairment
Ear and labyrinth disorders	common uncommon	vertigo tinnitus
Cardiac disorders	uncommon	palpitations, sinus bradycardia, ventricular extrasystoles
Vascular disorders	uncommon	hot flush, hypertension
Respiratory, thoracic and mediastinal disorders	uncommon	dysphonia, epistaxis, nasal congestion
Gastro-intestinal disorders	common uncommon	abdominal distention, abdominal pain, diarrhoea, flatulence, nausea, vomiting gastritis†, abdominal discomfort, abdominal pain upper, abdominal tenderness, anorectal discomfort, dry mouth, constipation, dyspepsia, epigastric discomfort, erosive duodenitis, eructation, gastro-oesophageal reflux disease, gingivitis, glossitis, odynophagia, pancreatitis acute, peptic ulcer, rectal haemorrhage
Hepato-biliary disorders	uncommon	hepatitis†, hepatic steatosis
Skin and subcutaneous tissue disorders	common uncommon   uncommon	rash‡ acne, alopecia, dermatitis acneiforme, dry skin, erythema, facial wasting, hyperhidrosis, lipodystrophy acquired, lipohypertrophy, night sweats, prurigo, pruritus, pruritus generalised, rash macular, rash maculo-papular, rash pruritic, skin lesion, urticaria, xeroderma Stevens Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS) ‡‡
Musculoskeletal and connective tissue disorders	uncommon	arthralgia, arthritis, back pain, flank pain, musculoskeletal pain, myalgia, neck pain, osteopenia, pain in extremity, tendonitis
Uncommon	rhabdomyolysis‡‡
Renal and urinary disorders	uncommon	renal failure†, nephritis, nephrolithiasis, nocturia, renal cyst, renal impairment, tubulointerstitial nephritis
Reproductive system and breast disorders	uncommon	erectile dysfunction, gynaecomastia, menopausal symptoms
General disorders and administration site conditions	common uncommon	asthenia, fatigue, pyrexia chest discomfort, chills, face oedema, fat tissue increased, feeling jittery, malaise, oedema peripheral, pain
Investigations	common uncommon	alanine aminotransferase increased, atypical lymphocytes, aspartate aminotransferase increased, blood triglycerides increased, lipase increased absolute neutrophil count decreased, alkaline phosphatase increased, blood albumin decreased, blood amylase increased, blood bilirubin increased, blood cholesterol increased, blood creatinine increased, blood glucose increased, blood urea nitrogen increased, creatine phosphokinase increased, fasting blood glucose increased, glucose urine present, high density lipoprotein increased, low density lipoprotein decreased, low density lipoprotein increased, platelet count decreased, red blood cells urine positive, waist circumference increased, weight increased, white blood cell count decreased
Injury, poisoning and procedural complications	uncommon	accidental overdose†
† Includes at least one serious adverse reaction ‡ In clinical studies of treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing ISENTRESS + darunavir compared to those containing ISENTRESS without darunavir or darunavir without ISENTRESS. Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section 4.4). ‡‡ This adverse reaction was identified through post-marketing surveillance but not reported as drug-related in randomised controlled Phase III clinical trials (Protocols 018, 019, and 021). The frequency category of "uncommon" was defined per the Summary of Product Characteristics (SmPC) guidance (rev. 2, Sept 2009) on the basis of an estimated upper bound of the 95% confidence interval for 0 events given the number of subjects treated with ISENTRESS in the Phase III clinical program (n=743).

Cancers were reported in treatment-experienced and treatment-naïve patients who initiated ISENTRESS in conjunction with other antiretroviral agents. The types and rates of specific cancers were those expected in a highly immunodeficient population. The risk of developing cancer in these studies was similar in the groups receiving ISENTRESS and in the groups receiving comparators.

Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS. Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinal products associated with these conditions (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

Patients co-infected with hepatitis B and/or hepatitis C virus

In Phase III studies, treatment-experienced patients (N = 114/699 or 16%; HBV=6 %, HCV=9 %, HBV+HCV=1%) and treatment-naïve patients (N = 34/563 or 6 %; HBV=4 %, HCV=2 %, HBV+HCV=0.2 %) with chronic (but not acute) active hepatitis B and/or hepatitis C co-infection were permitted to enrol provided that baseline liver function tests did not exceed 5 times the upper limit of normal. In general the safety profile of ISENTRESS in patients with hepatitis B and/or hepatitis C virus co-infection was similar to that in patients without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were somewhat higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for both treatment groups. In treatment-experienced patients, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29 %, 34 % and 13 %, respectively, of co-infected subjects treated with ISENTRESS as compared to 11 %, 10 % and 9 % of all other subjects treated with ISENTRESS. In treatment-naïve patients, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 17 %, 28 % and 17 %, respectively, of co-infected subjects treated with ISENTRESS as compared to 6 %, 6 % and 3 % of all other subjects treated with ISENTRESS.

4.9 Overdose

No specific information is available on the treatment of overdosage with ISENTRESS.

In the event of an overdose, it is reasonable to employ the standard supportive measures, e.g., remove unabsorbed material from the gastro-intestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required. It should be taken into account that raltegravir is presented for clinical use as the potassium salt. The extent to which ISENTRESS may be dialysable is unknown.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiviral for systemic use, Other Antivirals, ATC code: J05AX08.

Mechanism of action

Raltegravir is an integrase strand transfer inhibitor active against the Human Immunodeficiency Virus (HIV-1). Raltegravir inhibits the catalytic activity of integrase, an HIV-encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of the HIV genome into the host cell genome. HIV genomes that fail to integrate cannot direct the production of new infectious viral particles, so inhibiting integration prevents propagation of the viral infection.

Antiviral activity in vitro

Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (IC₉₅) of HIV-1 replication (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, raltegravir inhibited viral replication in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates from 5 non-B subtypes, and isolates resistant to reverse transcriptase inhibitors and protease inhibitors. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV isolates representing 5 non-B subtypes and 5 circulating recombinant forms with IC50 values ranging from 5 to 12 nM.

Resistance

Most viruses isolated from patients failing raltegravir had high-level raltegravir resistance resulting from the appearance of two or more mutations. Most had a signature mutation at amino acid 155 (N155 changed to H), amino acid 148 (Q148 changed to H, K, or R), or amino acid 143 (Y143 changed to H, C, or R), along with one or more additional integrase mutations (e.g., L74M, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, S230R). The signature mutations decrease viral susceptibility to raltegravir and addition of other mutations results in a further decrease in raltegravir susceptibility. Factors that reduced the likelihood of developing resistance included lower baseline viral load and use of other active anti-retroviral agents. Preliminary data indicate that there is potential for at least some degree of cross-resistance to occur between raltegravir and other integrase inhibitors.

Clinical experience

The evidence of efficacy of ISENTRESS is based on the analyses of 96-week data from two ongoing, randomised, double-blind, placebo-controlled trials, (BENCHMRK 1 and BENCHMRK 2, Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult patients and the analysis of 96-week data from an ongoing, randomised, double-blind, active-control trial, (STARTMRK, Protocol 021) in antiretroviral treatment-naïve HIV-1 infected adult patients.

Efficacy

Treatment-experienced patients

BENCHMRK 1 and BENCHMRK 2 (ongoing multi-centre, randomised, double-blind, placebo-controlled trials) evaluate the safety and anti-retroviral activity of ISENTRESS 400 mg twice daily vs. placebo in a combination with optimised background therapy (OBT), in HIV-infected patients, 16 years or older, with documented resistance to at least 1 drug in each of 3 classes (NRTIs, NNRTIs, PIs) of anti-retroviral therapies. Prior to randomisation, OBT were selected by the investigator based on the patient's prior treatment history, as well as baseline genotypic and phenotypic viral resistance testing.

Patient demographics (gender, age and race) and baseline characteristics were comparable between the groups receiving ISENTRESS 400 mg twice daily and placebo. Patients had prior exposure to a median of 12 anti-retrovirals for a median of 10 years. A median of 4 ARTs was used in OBT.

Results 48-week and 96-week analyses

Durable outcomes (Week 48 and Week 96) for patients on the recommended dose ISENTRESS 400 mg twice daily from the pooled studies BENCHMRK 1 and BENCHMRK 2 are shown in Table 2.

Table 2

Efficacy Outcome at Weeks 48 and 96

BENCHMRK 1 and 2 Pooled Parameter	48 Weeks	96 Weeks
ISENTRESS 400 mg twice daily + OBT (N = 462)	Placebo + OBT (N = 237)	ISENTRESS 400 mg twice daily + OBT (N = 462)	Placebo + OBT (N = 237)
Percent HIV-RNA < 400 copies/ml (95% CI)
All patients†	72 (68, 76)	37 (31, 44)	62 (57, 66)

Isoflurane inhalation anaesthetic

ISOFLURANE

IMPORTANT INFORMATION

Read all of this leaflet carefully before you receive Isoflurane.

• Keep this leaflet as you may need to read it again.


• This leaflet provides a summary of the information currently available on Isoflurane.


• For further information or advice ask your ward doctor or anaesthetist.


• Tell your ward doctor or anaesthetist if you experience any side effects.

What is Isoflurane & what does it do?

Isoflurane belongs to a group of medicines called general anaesthetics. These work by temporarily reducing the activity of the body's central nervous system. This causes a complete loss of sensation in the body, including loss of consciousness allowing surgery to be carried out without pain or distress.

Isoflurane is a clear colourless liquid that when put into a special anaesthetic machine (vaporiser) becomes a gas. This mixes with the oxygen you will be breathing in.

Once breathed in (inhaled), Isoflurane will induce and maintain a deep, pain-free sleep (general anaesthesia) in adults and children.

What should you know before receiving Isoflurane?

TELL YOUR DOCTOR, SURGEON OR ANAESTHETIST if:

• You are currently taking any medicines.


• You have been told that you are allergic to Isoflurane or any other anaesthetic.


• You or any member of your family has experienced a rapid rise in body temperature during an operation (a condition called malignant hyperthermia).


• You have previously received general anaesthetics, particularly if repeated over a short period of time. Some anaesthetics
  can cause jaundice.


• You are suffering from any illness other than those connected with your operation, such as severe headaches, nausea, vomiting or a condition that affects muscles (a neuromuscular disease e.g. Duchenne muscular dystrophy).


• You are pregnant, could be pregnant or are breast feeding.

DRIVING & USING MACHINERY

You should NOT drive or operate machinery until your doctor advises that you may do so.

Your ability to drive or operate machinery may be impaired for some time.

How will you receive Isoflurane?

Isoflurane will ALWAYS be administered to you by an anaesthetist. They will decide on the dose you will receive, depending on your age, weight and the type of operation you are having.

Isoflurane has a strong smell, which is quite normal and will send you to sleep quickly.

Inducing sleep at the start of anaesthesia

Very occasionally you may be asked to breathe in the Isoflurane via a mask. Usually you will receive an injection of another anaesthetic to make you go to sleep before you receive Isoflurane.

Maintaining sleep during anaesthesia

Under the observation of the anaesthetist you will continue to breathe in Isoflurane during the operation via a mask.

Waking-up after anaesthesia

Once the anaesthetist stops you from inhaling Isoflurane you will wake up within a few minutes.

What will happen after receiving Isoflurane?

As with all anaesthetics, Isoflurane can cause side effects. These can occur both during and after your operation. Any side effects which may occur during your operation will be managed by your doctor, as necessary.

If you suffer from any unusual or unexpected symptoms after your operation tell your doctor or anaesthetist IMMEDIATELY.

SIDE EFFECTS AND THEIR FREQUENCIES where known:

During Anaesthesia:

Low blood pressure (hypotension), slow shallow breathing (respiratory depression), raised body temperature (malignant hyperthermia), palpitations or an irregular heart beat can occur.

Liver injury can occur and in very rare occasions this can be fatal. The potential for liver injury is increased if you have been previously exposed to this type of anaesthetic (halogenated hydrocarbon anaesthetic), especially if the interval is less than 3 months.

Levels of fluoride in the blood may be raised during and after anaesthesia, this is due to the body breaking down Isoflurane. These levels are not believed to be harmful and soon return to normal. An increase in the number of white blood cells has also been seen.

Dermatitis, rash, shortness of breath (dyspnoea), wheezing, chest discomfort, swelling face or severe allergic (anaphylactic) reaction have been reported rarely, especially in association with long-term exposure to inhaled anaesthetics, including Isoflurane.

After Anaesthesia:

On coming round you may experience shivering, nausea and vomiting.

How should Isoflurane be stored?

Isoflurane should be stored in a tightly closed container NOT above 25°C. Do NOT use after the expiry date printed on the packaging.

Further information about Isoflurane

Isoflurane ingredients:

The active ingredient is Isoflurane and it is supplied as a pure liquid containing no other ingredients.

Marketing Authorisation and Manufacturer's Details

Marketing Authorisation Holder:

Abbott Laboratories Ltd.

Abbott House

Vanwall Business Park

Vanwall Road

Maidenhead

Berkshire

SL6 4XE

United Kingdom

Manufacturer:

Aesica Queenborough Limited

Queenborough

Kent

ME11 5EL

United Kingdom

This leaflet was last approved in 01/2010

1000000863

Innohep syringe 10,000 IU / ML

innohep syringe 10,000 IU/ml

tinzaparin sodium

Please read all of this leaflet carefully before you start having 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 become serious, or you notice any side effects not listed in this leaflet please tell your doctor or pharmacist.


• In this leaflet innohep syringe 10,000 IU/ml will be called innohep.

In this leaflet:

• 1. What innohep is and what it is used for


• 2. Before you have innohep


• 3. How to use innohep


• 4. Possible side effects


• 5. How to store innohep


• 6. Further information

What Innohep Is And What It Is Used For

innohep belongs to a group of medicines called anticoagulants. It is a type of heparin called a low molecular weight heparin.

innohep changes the way your blood clots. This means your blood keeps flowing smoothly inside your blood vessels. These are the tubes that carry blood around your body and are called arteries and veins.

innohep is used to help stop:

• Harmful blood clots forming in your veins following an operation. An example is a clot in a vein deep inside your body. This is usually in your leg (deep vein thrombosis or DVT for short).


• Harmful blood clots forming in the tubing of an artificial kidney machine during kidney dialysis (haemodialysis).

Before You Have Innohep

Do not have innohep

• If you are allergic (hypersensitive) to tinzaparin or any of the other ingredients in your medicine. You can find a list of these ingredients in section 6 of this leaflet.


• If you know that you have, or have ever had, a big drop in the clotting cells (platelets) in your blood, caused by having any type of heparin (reaction called heparin-induced thrombocytopenia).


• If you have any condition which makes you bleed severely, such as haemophilia.


• If you have very high blood pressure.


• If you have severe liver problems.


• If you have a stomach ulcer.


• If you know that you have a condition called endocarditis (an inflammation of the lining of the heart and heart valves).


• If you have had a brain haemorrhage (bleeding inside your brain).


• If you have an injury to your spine, head, eyes or ears.


• If you have recently had, or are about to have an operation involving your spine, head, eyes or ears.


• If you may be having a miscarriage.

Important: If you are having an epidural or spinal anaesthetic

You must remind your doctor that you are having innohep before you receive any anaesthetic.

If you are pregnant please also read the section of this leaflet "Pregnancy and breast-feeding".

After you have the anaesthetic your doctor or nurse will make regular checks. This is to check if you are getting any major bleeding or bruising around your spine. This may cause paralysis that could be permanent. Any signs this may be happening to you include tingling, weakness or numbness in your lower legs or body, back pain or problems in going to the toilet. This happens very rarely.

After you have the anaesthetic your doctor will tell you when you can take your medicine again.

Take special care with innohep

Before you have innohep tell your doctor:

• If you have any condition which makes you more likely to bleed more easily. Ask your doctor if you are unsure.


• If you are allergic (hypersensitive) to heparin.


• If you are allergic to other low molecular weight heparins, such as enoxaparin or dalteparin.


• If you have kidney problems. Your doctor may need to adjust your dose.


• If you know you have a condition called diabetes mellitus.


• If you know you have a condition called metabolic acidosis.


• If you know you have any medical condition which may cause high levels of potassium in your blood (hyperkalaemia). Ask your doctor if you are unsure.


• If you are taking a medicine from the group called potassium-sparing diuretics, such as amiloride or spironolactone.


• If you are taking another medicine that may affect your blood clotting. For a list of these medicines see the section "Taking other medicines".


• If you have an artificial heart valve.

Your doctor may take a blood test before you start having this medicine, and while you are having it. This is to check the level of the clotting cells (platelets) and potassium in your blood.

This medicine may make you bleed more easily. The doctor or nurse should take care when giving you any other injections or procedures.

This medicine must not be injected into your muscles.

Taking other medicines

Please tell your doctor or pharmacist if you are taking, or have recently taken any other medicines. This includes any medicines which you have bought without a prescription.

You must tell your doctor or pharmacist if you are taking any of the following medicines:

• Non-steroidal anti-inflammatory drugs, such as ibuprofen or diclofenac: for arthritis or aches or pains. You may be likely to bleed more easily.


• Salicylates, such as aspirin: for reducing pain and inflammation, or for stopping harmful blood clots forming. You may be likely to bleed more easily.


• Platelet aggregation inhibitors, such as clopidogrel: for stopping harmful blood clots forming. You may be likely to bleed more easily.


• Thrombolytic agents, such as streptokinase: for dissolving blood clots. You may be likely to bleed more easily.


• Vitamin K antagonists, such as warfarin: for stopping harmful blood clots. You may be likely to bleed more easily.


• Activated protein C: for getting rid of blood clots. You may be likely to bleed more easily.


• Dextrans: for increasing your blood volume. You may be likely to bleed more easily.

Pregnancy and breast-feeding

Please ask your doctor or pharmacist for advice before having innohep:

• If you are pregnant, or think you are pregnant.


• If you are breast-feeding.

Tell your doctor if you become pregnant while having this medicine.

You must not have an epidural anaesthetic to help with your labour if you are having innohep.

Driving and using machines

Usually your medicine may have little effect on your ability to drive or use machines. However, you should check with your doctor if you feel any side effect that may stop you from driving or using machines.

Important information about some of the ingredients of innohep

innohep contains:

• Sodium. This medicine is nearly "sodium free". Your medicine contains less than 23 milligrams (mg) of sodium per dose.

Please ask your doctor if you are worried about any of the ingredients in this medicine.

How To Use Innohep

innohep is usually given to you by a doctor or nurse. innohep should not be mixed with any other injection.

How much innohep to have

Your doctor will prescribe the right dose for you.

To prevent harmful blood clots forming in the tubing of an artificial kidney machine during kidney dialysis (haemodialysis)

innohep will be given either into the artificial kidney machine or into your vein.

The usual dose depends on the length of dialysis.

To prevent harmful blood clots forming in your veins after an operation

Your doctor may decide that you or a carer may inject this medicine.

Your doctor or nurse will show you how to inject yourself with the syringe. Only inject yourself if you have been instructed how.

The usual dose depends on the type of operation you are having. You will have one dose of innohep before your operation. Then usually you will have one dose of innohep once a day for 7 to 10 days afterwards. Your doctor will decide how long you should have innohep.

How to inject innohep

This section explains how to inject yourself with the innohep syringe.

Warning: Only give this injection to yourself after you have received instructions from your doctor or nurse.

Always use innohep exactly as your doctor has told you. You should check with your doctor or nurse if you are not sure about anything.

Where to inject

This injection goes under your skin. This may be called SC (subcutaneous). The usual place to inject yourself is on
the left or right side of your tummy.

Choose a place at least 5 cm (2 inches) from the belly button. Avoid the shaded area shown in the picture.

Choose a place away from any scars or bruises.

You should change the side you inject on each day. Pick a place on the opposite side from where your last injection went.

How to give the injection

• 1. Wash your hands thoroughly. Dry your hands well.


• 2. Decide where you are going to inject.


• 3. Put all the equipment you will need somewhere convenient to reach on a clean surface.


• 4. Check the expiry date on the syringe label. Do not use the injection after the expiry date. The expiry date is the last day of that month.


• 5. Look at the liquid inside the syringe. If you can see the liquid is cloudy or that it has any particles you must not use it.


• 6. Sit or lie in a comfortable position so you can see your skin where the injection will go. You may find using pillows or cushions will help.


• 7. Clean and dry the area of the skin as you have been told to do.


• 8. Bend the coloured lid on the plastic container all the way back. This will let you pull the syringe out. Only use one syringe for each injection. Never keep an opened one for later.


• 9. Only pull the cap off the needle when you are ready to use the syringe. It is important to keep the needle clean. Do not let it touch anything.


• 10. You may notice a small air bubble in the syringe. You do not need to remove this. The syringe is ready to use.


• 11. Hold the syringe in your writing hand like a pen.

• 12. Use your other hand to make a skin fold. Pinch your skin tight using your thumb and first finger. When you have made the skin fold keep holding on to it firmly.


• 13. It is important to hold your skin firmly until all the medicine has been injected. Hold the syringe upright with the needle pointing down. Push the needle down into the skin fold.


• 14. Press the plunger slowly down over 10-15 seconds. All the liquid should come out of the syringe.


• 15. Pull the needle right out of your skin. Then let go of the skin fold. The injection is complete.


• 16. Do not rub or massage the place where you have just put the injection. If you do this you may get a bruise.

How to get rid of syringes safely

You should have a sharps bin. Put the used syringe carefully into your sharps bin as you have been told to do. Put the needle end in first. Keep it out of the reach and sight of children.

When the bin is full give it to your nurse or pharmacist. Never throw syringes into the household waste.

If you have more innohep than you should

Your doctor or nurse will usually give you this medicine, if you think you may have injected yourself with too much, or been given too much, tell your doctor or nurse straight away.

You may start to haemorrhage (bleed severely). Please read section 4 so you can spot any signs this may be happening to you.

You may be given another injection of a medicine called protamine sulphate.

If you have missed a dose of innohep

Your doctor or nurse will usually give you this medicine. If you forget to inject yourself, or if you think that you have missed a dose, then tell your doctor or nurse.

If you have any further questions about taking this medicine, please ask your doctor or pharmacist.

Possible Side Effects

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

Important side effects to look out for

You must get urgent medical help if you have any of the following symptoms. You may be getting an allergic reaction:

• 
  You have difficulty breathing
  


• 
  Your face or throat swell
  


• 
  Your skin develops a severe rash
  


• 
  Your skin develops blisters at the site of your injection
  


• 
  Your skin peels.
  

You must get urgent medical help if you have any of the following symptoms after having an epidural or spinal anaesthetic. You may be developing paralysis:

• 
  Tingling, weakness or numbness in your legs or lower body
  


• 
  Back pain
  


• 
  Problems in going to the toilet.
  

You should tell your doctor straight away if you spot any of the following signs which mean you may be starting to bleed severely:

• 
  Red or brown urine
  


• 
  Black tarry stools
  


• 
  Unusual bruising
  


• 
  Bleeding from your nose, or mouth or any operation wound that will not stop.
  

Other possible side effects

The side effects most often reported are blood problems and skin reactions, especially where your injection has been given.

Very Common side effects (probably affect more than 1 in 10 people)

• Bleeding (haemorrhage). This may be more likely if you are taking a high dose of innohep.

Common side effects (probably affect less than 1 in 10 people)

• Bruising, pain or irritation at the site of the injection

Uncommon side effects (probably affect less than 1 in 100 people)

• Rash


• Itchy skin


• Hives


• Headache


• Blood tests results may show changes in the way your liver is working

Side effects where the number of people affected is not known

• Changes in your blood test results. This may lead to bruising or bleeding more easily, because of a reaction in your blood. Your blood may form more harmful clots. A drop in the number of clotting cells (platelets) in your blood may give you these symptoms. Your doctor can explain this more.


• Changes in your blood test results. The amount of potassium may be increased. This is more likely to happen if you have severe kidney problems or diabetes. Your doctor can explain this more.


• Problems with your heart if you have an artificial heart valve. This may be because you are not having the dose of innohep that is right for you.


• Your bones may weaken and break more easily. This is known as osteoporosis and has been seen in patients taking heparin for a long time.


• Prolonged, painful erections in men.

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

How To Store Innohep

• Keep out of the reach and the sight of children.


• Do not use after the expiry date on the syringe. The expiry date is the last day of that month.


• Do not store above 25°C.

Medicines should not be thrown away in waste water or in household waste. Please ask your pharmacist how to throw away any medicine you do not need anymore. If you do this you will help protect the environment.

Further Information

What innohep contains

• The active ingredient is tinzaparin sodium.
  
  innohep syringe 10,000 IU/ml contains 10,000 IU of tinzaparin sodium in each millilitre (ml).
  


• The other ingredients are sodium acetate, sodium hydroxide and water for injections.

You can find important information about some of the ingredients near the end of section 2, just before section 3.

What innohep looks like and contents of the pack

innohep is a straw coloured liquid.

innohep comes in glass syringe containing 0.25 ml, 0.35 ml or 0.45 ml.

There are 10 syringes in a carton.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

LEO Laboratories Limited

Princes Risborough

Bucks.

HP27 9RR

UK

Manufacturer:

Laboratoires LEO

28500 Vernouillet

France

This leaflet was last revised in July 2009.

This leaflet was approved in October 2009.

Registered Trade Mark

LEO

016447-09