Typherix

1. Name Of The Medicinal Product

Typherix, solution for injection in a pre-filled syringe

Typhoid Polysaccharide vaccine.

2. Qualitative And Quantitative Composition

Each 0.5 ml dose of vaccine contains:

Vi polysaccharide of Salmonella typhi (Ty2 strain) 25 micrograms

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection in a pre-filled syringe.

Clear isotonic colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Typherix is indicated for active immunisation against typhoid fever for both adults and children two years of age and older.

4.2 Posology And Method Of Administration

Posology

A single dose of 0.5 ml is recommended for both adults and children two years of age and older.

The vaccine should be administered at least two weeks prior to risk of exposure to typhoid fever.

Subjects who remain at risk of typhoid fever should be revaccinated using a single dose of vaccine with an interval of not more than 3 years.

Method of administration

Typherix is for intramuscular injection.

Typherix should under no circumstances be administered intravascularly.

4.3 Contraindications

Typherix should not be administered to subjects with known hypersensitivity to any component of the vaccine or to subjects having shown signs of hypersensitivity after previous administration.

As with other vaccines, the administration of Typherix should be postponed in subjects suffering from acute febrile illness. The presence of a minor infection, however, is not a contraindication for vaccination.

4.4 Special Warnings And Precautions For Use

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic reaction following administration of the vaccine.

The vaccine protects against typhoid fever caused by Salmonella typhi. Protection is not conferred against disease caused by Salmonella paratyphi and other non-typhoidal Salmonellae.

Typherix has not been evaluated in children under 2 years of age. Polysaccharide vaccines in general have lower immunogenicity under this age.

Different injectable vaccines should always be administered at different injection sites.

Typherix should be administered with caution to subjects with thrombocytopenia or bleeding disorders since bleeding may occur following an intramuscular administration to these subjects: following injection, firm pressure should be applied to the site (without rubbing) for at least two minutes.

It may be expected that in patients receiving immunosuppressive treatment or patients with immunodeficiency, an adequate response may not be achieved.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In clinical studies in adults aged over 18 years, Typherix has been administered concomitantly in opposite arms with Havrix Monodose (1440), GlaxoSmithKline's inactivated hepatitis A vaccine.

There was no adverse impact on either the reactogenicity or immunogenicity of the vaccines when they were administered simultaneously in opposite arms.

No interaction studies with other vaccines have been performed.

4.6 Pregnancy And Lactation

Pregnancy

The effect of Typherix on fetal development has not been assessed.

Typherix should only be used during pregnancy when there is a high risk of infection.

Lactation

The effect on breastfed infants of the administration of Typherix to their mothers has not been evaluated.

Typherix should therefore only be used in breastfeeding women when there is a high risk of infection.

4.7 Effects On Ability To Drive And Use Machines

Some of the effects mentioned under section 4.8 “Undesirable Effects” may affect the ability to drive or operate machinery.

4.8 Undesirable Effects

During clinical studies, the most commonly reported adverse events after the first dose were reactions at the injection site, including soreness, redness and swelling.

Frequencies are reported as:

Common:	(
Very rare:	(< 1/10,000)

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

General reactions that may occur in temporal association with Typherix vaccination include:

Clinical studies

Nervous system disorders:

Common: headache

Gastrointestinal disorders:

Common: nausea

Skin and subcutaneous tissue disorders:

Common: itching

General disorders and administration site conditions:

Common: fever, general aches, malaise

Following a second dose, there was an increased incidence of redness and soreness (>10%).

Local reactions were usually reported during the first 48 hours and systemic reactions were also transient.

Post-marketing

The following reactions have been reported in post-marketing experience:

Skin and subcutaneous tissue disorders:

Very rare: urticaria

Immune system disorders:

Very rare: anaphylaxis, allergic reactions, including anaphylactoid reactions

4.9 Overdose

Occasional reports of overdose have been received. The symptoms reported in these cases are not different from those reported following normal dosage.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Bacterial vaccine, ATC code: J07AP03

In comparative clinical studies, the immune response to Typherix was shown to be equivalent to a licensed comparator Vi polysaccharide vaccine. Seroconversion was observed in >95% of Typherix recipients when measured at two weeks after administration. Two years after vaccination 61% were seropositive, and at three years 46%.

The protective efficacy of Typherix has not been investigated in clinical trials.

For individuals who remain at - or who may be reexposed to - risk of typhoid fever, it is recommended that they be revaccinated using a single dose of vaccine with an interval of not more than 3 years.

5.2 Pharmacokinetic Properties

Evaluation of pharmacokinetic properties is not required for vaccines and formal pharmacokinetic studies have not been performed.

5.3 Preclinical Safety Data

No preclinical safety testing with the vaccine has been conducted.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium dihydrogen phosphate dihydrate

Disodium phosphate dihydrate

Sodium chloride

Phenol

Water for injection

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C

Do not freeze.

Store in the original package, in order to protect from light.

6.5 Nature And Contents Of Container

0.5 ml of solution in a pre-filled syringe (Type I glass) with a plunger stopper (elastomer rubber butyl) in pack sizes of 1, 10, 50 or 100.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Vaccines should be inspected for any foreign particulate matter and/or variation of physical aspect. In the event of either being observed, discard the vaccine.

Shake before use.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

SmithKline Beecham plc

980 Great West Road

Brentford

Middlesex TW8 9BD

Trading as:

GlaxoSmithKline UK

Stockley Park West

Uxbridge

Middlesex, UB11 1BT

8. Marketing Authorisation Number(S)

PL 10592/0126

9. Date Of First Authorisation/Renewal Of The Authorisation

05/07/2008

10. Date Of Revision Of The Text

3/11/09

POM

Tygacil 50mg powder for solution for infusion

1. Name Of The Medicinal Product

Tygacil^® 50 mg powder for solution for infusion.

2. Qualitative And Quantitative Composition

Each 5 ml Tygacil vial contains 50 mg of tigecycline. After reconstitution, 1 ml contains 10 mg of tigecycline.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for solution for infusion (powder for infusion).

Lyophilised orange cake or powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Tygacil is indicated in adults for the treatment of the following infections (see sections 4.4 and 5.1):

• Complicated skin and soft tissue infections, excluding diabetic foot infections (see section 4.4)

• Complicated intra-abdominal infections

Tygacil should be used only in situations where it is known or suspected that other alternatives are not suitable (see sections 4.4 and 4.8).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology And Method Of Administration

Posology

The recommended dose for adults is an initial dose of 100 mg followed by 50 mg every 12 hours for 5 to 14 days.

The duration of therapy should be guided by the severity, site of the infection, and the patient's clinical response.

Hepatic insufficiency

No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B).

In patients with severe hepatic impairment (Child Pugh C), the dose of Tygacil should be reduced to 25 mg every 12 hours following the 100 mg loading dose. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response (see sections 4.4 and 5.2).

Renal insufficiency

No dosage adjustment is necessary in patients with renal impairment or in patients undergoing haemodialysis (see section 5.2).

Elderly patients

No dosage adjustment is necessary in elderly patients (see section 5.2).

Paediatric population

The safety and efficacy of Tygacil in children below 18 years have not yet been established. (see section 4.4). Currently available data are described in section 5.2, but no recommendation on a posology can be made.

Method of administration:

Tygacil is administered only by intravenous infusion over 30 to 60 minutes (see section 6.6).

For instructions on reconstitution & dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients. Patients hypersensitive to tetracycline class antibiotics may be hypersensitive to tigecycline.

4.4 Special Warnings And Precautions For Use

In clinical studies in complicated skin and soft tissue infections, complicated intra-abdominal infections, diabetic foot infections, nosocomial pneumonia and studies in resistant pathogens, a numerically higher mortality rate among Tygacil treated patients has been observed as compared to the comparator treatment. The causes of these findings remain unknown, but poorer efficacy and safety than the study comparators cannot be ruled out.

Patients who develop super-infections, in particular nosocomial pneumonia, appear to be associated with poorer outcomes. Patients should be closely monitored for the development of super-infection. If a focus of infection other than cSSTI or cIAI is identified after initiation of Tygacil therapy consideration should be given to instituting alternative antibacterial therapy that has been demonstrated to be efficacious in the treatment of the specific type of infection(s) present.

Tygacil is not approved for clinical indications other than complicated skin and soft tissue infections, and complicated intra-abdominal infections. The use of Tygacil in non-approved indications is not recommended.

Anaphylaxis/anaphylactoid reactions, potentially life-threatening, have been reported with tigecycline (see sections 4.3 and 4.8).

Cases of liver injury with a predominantly cholestatic pattern have been reported in patients receiving tigecycline treatment, including some cases of hepatic failure with a fatal outcome. Although hepatic failure may occur in patients treated with tigecycline due to the underlying conditions or concomitant medicinal products, a possible contribution of tigecycline should be considered (see section 4.8).

Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics. Tigecycline may have adverse reactions similar to tetracycline class antibiotics. Such reactions may include photosensitivity, pseudotumor cerebri, pancreatitis, and anti-anabolic action which has led to increased BUN, azotaemia, acidosis, and hyperphosphataemia (see section 4.8).

Acute pancreatitis, which can be serious, has occurred (frequency: uncommon) in association with tigecycline treatment (see section 4.8). The diagnosis of acute pancreatitis should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Most of the reported cases developed after at least one week of treatment. Cases have been reported in patients without known risk factors for pancreatitis. Patients usually improve after tigecycline discontinuation. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis.

Experience in the use of tigecycline for treatment of infections in patients with severe underlying diseases is limited.

In clinical trials in complicated skin and soft tissue infections, the most common type of infection in tigecycline treated-patients was cellulitis (59 %), followed by major abscesses (27.5 %). Patients with severe underlying disease, such as those that were immunocompromised, patients with decubitus ulcer infections, or patients that had infections requiring longer than 14 days of treatment (for example, necrotizing fasciitis), were not enrolled. A limited number of patients were enrolled with co-morbid factors such as diabetes (20 %), peripheral vascular disease (7 %), intravenous drug abuse (2 %), and HIV-positive infection (1 %). Limited experience is also available in treating patients with concurrent bacteraemia (3 %). Therefore, caution is advised when treating such patients. The results in a large study in patients with diabetic foot infection, showed that tigecycline was less effective than comparator, therefore, tigecycline is not recommended for use in these patients (see section 4.1)

In clinical trials in complicated intra-abdominal infections, the most common type of infection in tigecycline treated-patients was complicated appendicitis (51 %), followed by other diagnoses less commonly reported such as complicated cholecystitis (14 %), intra-abdominal abscess (10 %), perforation of intestine (10 %) and gastric or duodenal ulcer perforation less than 24 hours (5 %). Of these patients, 76 % had associated diffuse peritonitis (surgically-apparent peritonitis). There were a limited number of patients with severe underlying disease such as immunocompromised patients, patients with APACHE II scores > 15 (4 %), or with surgically apparent multiple intra-abdominal abscesses (10 %). Limited experience is also available in treating patients with concurrent bacteraemia (6 %). Therefore, caution is advised when treating such patients.

Consideration should be given to the use of combination antibacterial therapy whenever tigecycline is to be administered to severely ill patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation or patients with incipient sepsis or septic shock (see section 4.8).

The effect of cholestasis in the pharmacokinetics of tigecycline has not been properly established. Biliary excretion accounts for approximately 50 % of the total tigecycline excretion. Therefore, patients presenting with cholestasis should be closely monitored.

Prothrombin time or other suitable anticoagulation test should be used to monitor patients if tigecycline is administered with anticoagulants (see section 4.5).

Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibacterial agent (see section 4.8).

The use of tigecycline may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If super infection occurs, appropriate measures should be taken (see section 4.8).

Results of studies in rats with tigecycline have shown bone discolouration. Tigecycline may be associated with permanent tooth discolouration in humans if used during tooth development (see section 4.8).

Paediatric population

Tygacil should not be used in children under 8 years of age because of teeth discolouration, and is not recommended in adolescents below 18 years due to the lack of data on safety and efficacy (see sections 4.2 and 4.8).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

Concomitant administration of tigecycline and warfarin (25 mg single-dose) to healthy subjects resulted in a decrease in clearance of R-warfarin and S-warfarin by 40 % and 23 %, and an increase in AUC by 68 % and 29 %, respectively. The mechanism of this interaction is still not elucidated. Available data does not suggest that this interaction may result in significant INR changes. However, since tigecycline may prolong both prothrombin time (PT) and activated partial thromboplastin time (aPTT), the relevant coagulation tests should be closely monitored when tigecycline is co-administered with anticoagulants (see section 4.4). Warfarin did not affect the pharmacokinetic profile of tigecycline.

Tigecycline is not extensively metabolised. Therefore, clearance of tigecycline is not expected to be affected by active substances that inhibit or induce the activity of the CYP450 isoforms. In vitro, tigecycline is neither a competitive inhibitor nor an irreversible inhibitor of CYP450 enzymes (see section 5.2).

Tigecycline in recommended dosage did not affect the rate or extent of absorption, or clearance of digoxin (0.5 mg followed by 0.25 mg daily) when administered in healthy adults. Digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore, no dosage adjustment is necessary when tigecycline is administered with digoxin.

In in vitro studies, no antagonism has been observed between tigecycline and other commonly used antibiotic classes.

Concurrent use of antibiotics with oral contraceptives may render oral contraceptives less effective.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of tigecycline in pregnant women. Results from animal studies have shown tigecycline may cause foetal harm when administered during pregnancy (see section 5.3). The potential risk for humans is unknown. As it is known for tetracycline class antibiotics, tigecycline may also induce permanent dental defects (discolouration and enamel defects) and a delay in ossification processes in foetuses, exposed in utero during the last half of gestation, and in children under eight years of age due to the enrichment in tissues with a high calcium turnover and formation of calcium chelate complexes (see section 4.4). Tigecycline should not be used during pregnancy unless clearly necessary.

Breastfeeding

It is not known whether this medicinal product is excreted in human milk. In animal studies tigecycline is excreted into milk of lactating rats. Because a potential risk to the breast-feeding infant cannot be ruled out, when treating with tigecycline, caution should be exercised and interruption of breast-feeding should be considered (see section 5.3).

Fertility

Tigecycline did not affect mating or fertility in rats at exposures up to 4.7 times the human daily dose based on AUC. In female rats, there were no compound-related effects on ovaries or oestrus cycles at exposures up to 4.7 times the human daily dose based on AUC.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects of tigecycline on the ability to drive and use machines have been performed. Dizziness may occur and this may have an effect on driving and use of machines (see section 4.8).

4.8 Undesirable Effects

a. Summary of safety profile

The total number of patients treated with tigecycline in Phase 3 clinical studies was 1415. Adverse reactions were reported in approximately 41 % of patients treated with tigecycline. Treatment was discontinued due to adverse reactions in 5 % of patients.

In clinical trials, the most common drug-related treatment emergent adverse reactions were reversible nausea (20 %) and vomiting (14 %), which usually occurred early (on treatment days 1-2) and were generally mild or moderate in severity.

Adverse reactions reported with Tygacil, including clinical trials and post-marketing experience, are listed below.

Frequency categories are expressed as: Very common (

For adverse reactions identified from post-marketing experience with Tygacil derived from spontaneous reports for which the frequency cannot be estimated, the frequency grouping is categorized as not known.

b. Tabulated summary of adverse reactions

Infections and infestations:

Common: Pneumonia, abscess, infections

Uncommon: Sepsis/septic shock

Blood and the lymphatic system disorders:

Common: Prolonged activated partial thromboplastin time (aPTT), Prolonged prothrombin time (PT)

Uncommon: Increased International Normalised Ratio (INR)

Not known: thrombocytopenia

Immune system disorders:

Not known: Anaphylaxis/anaphylactoid reactions (see sections 4.3 and 4.4)

Metabolism and nutrition disorders:

Common: Hypoglycaemia

Uncommon: Hypoproteinaemia

Nervous system disorders:

Common: Dizziness

Vascular disorders:

Common: Phlebitis

Uncommon: Thrombophlebitis

Gastrointestinal disorders:

Very common: Nausea, vomiting, diarrhoea

Common: Abdominal pain, dyspepsia, anorexia

Uncommon: Acute pancreatitis (see section 4.4)

Hepato-biliary disorders:

Common: Elevated aspartate aminotransferase (AST) in serum, and elevated alanine aminotransferase (ALT) in serum, hyperbilirubinaemia

Uncommon: Jaundice, liver injury, mostly cholestatic

Not known: Hepatic failure (see section 4.4)

Skin and subcutaneous tissue disorders:

Common: Pruritus, rash

Not known: Severe skin reactions, including Stevens-Johnson Syndrome

General disorders and administration site conditions:

Common: Headache

Uncommon: Injection site reaction, injection site inflammation, injection site pain, injection site oedema, injection site phlebitis

Investigations:

Common: Elevated amylase in serum, increased blood urea nitrogen (BUN)

c. Description of selected adverse reactions

Antibiotic Class Effects:

Pseudomembranous colitis which may range in severity from mild to life threatening (see section 4.4)

Overgrowth of non-susceptible organisms, including fungi (see section 4.4)

Tetracycline Class Effects:

Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics. Tetracycline class adverse reactions may include photosensitivity, pseudotumour cerebri, pancreatitis, and anti-anabolic action which has led to increased BUN, azotaemia, acidosis, and hyperphosphataemia (see section 4.4).

Tigecycline may be associated with permanent tooth discolouration if used during tooth development (see section 4.4).

In Phase 3 clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with tigecycline (6.7 %) vs comparators (4.6 %). Significant differences in sepsis/septic shock with tigecycline (1.5 %) vs comparators (0.5 %) were observed.

AST and ALT abnormalities in Tygacil-treated patients were reported more frequently in the post therapy period than in those in comparator-treated patients, which occurred more often on therapy.

In all Phase 3 and 4 (cSSSI and cIAI) studies, death occurred in 2.4 % (54/2216) of patients receiving tigecycline and 1.7% (37/2206) of patients receiving comparator drugs.

Paediatric population

Very limited safety data were available from a multiple dose PK study (see section 5.2). No new or unexpected safety concerns were observed with tigecycline in this study.

4.9 Overdose

No specific information is available on the treatment of overdosage. Intravenous administration of tigecycline at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. Tigecycline is not removed in significant quantities by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antibacterials for systemic use, Tetracyclines, ATC code: J01AA12.

Mode of action

Tigecycline, a glycylcycline antibiotic, inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains.

In general, tigecycline is considered bacteriostatic. At 4 times the minimum inhibitory concentration (MIC), a 2-log reduction in colony counts was observed with tigecycline against Enterococcus spp., Staphylococcus aureus, and Escherichia coli.

Mechanism of resistance

Tigecycline is able to overcome the two major tetracycline resistance mechanisms, ribosomal protection and efflux. Cross-resistance between tigecycline and minocycline-resistant isolates among the Enterobacteriacae due to multi-drug resistance (MDR) efflux pumps has been shown. There is no target-based cross-resistance between tigecycline and most classes of antibiotics.

Tigecycline is vulnerable to chromosomally-encoded multi-drug efflux pumps of Proteeae and Pseudomonas aeruginosa. Pathogens of the family Proteeae (Proteus spp., Providencia spp., and Morganella spp.) are generally less susceptible to tigecycline than other members of the Enterobacteriaceae.Decreased susceptibility in both groups has been attributed to the overexpression of the non-specific AcrAB multi-drug efflux pump. Decreased susceptibility in Acinetobacter baumannii has been attributed to the overexpression of the AdeABC efflux pump.

Breakpoints

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

Staphylococcus spp. S

Streptococcus spp. other than S. pneumoniae S

Enterococcus spp. S

Enterobacteriaceae S ^{(^)} mg/L and R > 2 mg/L

^{(^)}Tigecycline has decreased in vitro activity against Proteus, Providencia, and Morganella spp.

For anaerobic bacteria there is clinical evidence of efficacy in polymicrobial intra-abdominal infections, but no correlation between MIC values, PK/PD data and clinical outcome. Therefore, no breakpoint for susceptibility is given. It should be noted that the MIC distributions for organisms of the genera Bacteroides and Clostridium are wide and may include values in excess of 2 mg/L tigecycline.

There is limited evidence of the clinical efficacy of tigecycline against enterococci. However, polymicrobial intra-abdominal infections have shown to respond to treatment with tigecycline in clinical trials.

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Pathogen

Commonly Susceptible Species

Gram-positive Aerobes Enterococcus spp.† Staphylococcus aureus* Staphylococcus epidermidis Staphylococcus haemolyticus Streptococcus agalactiae* Streptococcus anginosus group* (includes S. anginosus, S. intermedius and S. constellatus) Streptococcus pyogenes* Viridans group streptococci Gram-negative Aerobes Citrobacter freundii* Citrobacter koseri Escherichia coli* Klebsiella oxytoca* Anaerobes Clostridium perfringens† Peptostreptococcus spp. † Prevotella spp.

Species for which acquired resistance may be a problem

Gram-negative Aerobes Acinetobacter baumannii Burkholderia cepacia Enterobacter aerogenes Enterobacter cloacae* Klebsiella pneumoniae* Morganella morganii Proteus spp. Providencia spp. Serratia marcescens Stenotrophomonas maltophilia Anaerobes Bacteroides fragilis group†

Inherently resistant organisms

Gram-negative Aerobes Pseudomonas aeruginosa

* denotes species against which it is considered that activity has been satisfactorily demonstrated in clinical studies.

† see section 5.1, Breakpoints above.

5.2 Pharmacokinetic Properties

Absorption

Tigecycline is administered intravenously and therefore has 100 % bioavailability.

Distribution

The in vitro plasma protein binding of tigecycline ranges from approximately 71 % to 89 % at concentrations observed in clinical studies (0.1 to 1.0 μg/mL). Animal and human pharmacokinetic studies have demonstrated that tigecycline readily distributes to tissues.

In rats receiving single or multiple doses of ¹⁴C-tigecycline, radioactivity was well distributed to most tissues, with the highest overall exposure observed in bone marrow, salivary glands, thyroid gland, spleen, and kidney. In humans, the steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating that tigecycline is extensively distributed beyond the plasma volume and concentrates into tissues.

No data are available on whether tigecycline can cross the blood-brain barrier in humans.

In clinical pharmacology studies using the therapeutic dosage regimen of 100 mg followed by 50 mg q12h, serum tigecycline steady-state C_max was 866±233 ng/mL for 30-minute infusions and 634±97 ng/mL for 60-minute infusions. The steady-state AUC_0-12h was 2349±850 ng•h/mL.

Biotransformation

On average, it is estimated that less than 20 % of tigecycline is metabolised before excretion. In healthy male volunteers, following the administration of ¹⁴C-tigecycline, unchanged tigecycline was the primary ¹⁴C-labelled material recovered in urine and faeces, but a glucuronide, an N-acetyl metabolite and a tigecycline epimer were also present.

In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 by competitive inhibition. In addition, tigecycline did not show NADPH-dependency in the inhibition of CYP2C9, CYP2C19, CYP2D6 and CYP3A, suggesting the absence of mechanism-based inhibition of these CYP enzymes.

Elimination

The recovery of the total radioactivity in faeces and urine following administration of ¹⁴C-tigecycline indicates that 59 % of the dose is eliminated by biliary/faecal excretion, and 33 % is excreted in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.

The total clearance of tigecycline is 24 L/h after intravenous infusion. Renal clearance is approximately 13 % of total clearance. Tigecycline shows a polyexponential elimination from serum with a mean terminal elimination half-life after multiple doses of 42 hours although high interindividual variability exists.

Special populations

Hepatic Insufficiency

The single-dose pharmacokinetic disposition of tigecycline was not altered in patients with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25 % and 55 % and the half-life of tigecycline was prolonged by 23 % and 43 % in patients with moderate or severe hepatic impairment (Child Pugh B and C), respectively (see section 4.2).

Renal Insufficiency

The single dose pharmacokinetic disposition of tigecycline was not altered in patients with renal insufficiency (creatinine clearance <30 mL/min, n=6). In severe renal impairment, AUC was 30 % higher than in subjects with normal renal function (see section 4.2).

Elderly Patients

No overall differences in pharmacokinetics were observed between healthy elderly subjects and younger subjects (see section 4.2).

Paediatric Population

The safety and efficacy of tigecycline in the paediatric population 8 to <18 years of age have not been established.

Tigecycline pharmacokinetics was investigated in two studies. The first study enrolled children aged 8-16 years (n=24) who received single doses of tigecycline (0.5, 1, or 2 mg/kg, with no dose limitation) administered intravenously over 30 minutes. The second study was performed in children aged 8 to 11 years (n=47) who received multiple doses of tigecycline (0.75, 1, or 1.25 mg/kg up to a maximum dose of 50 mg) every 12 hours administered intravenously over 30 minutes. No loading dose was administered in these studies. The pharmacokinetic parameters may be observed in the table below.

Dose Normalized to 1 mg/kg Mean ± SD Tigecycline Cmax and AUC in Children
Age (yr)	N	Cmax (ng/mL)	AUC (ng•h/mL)*
Single dose
8 – 11	8	3881 ± 6637	4034 ± 2874
12 - 16	16	8508 ± 11433	7026 ± 4088
Multiple dose
8 - 11	47	1899 ± 2954	2833 ± 1557
* single dose AUC0-œ, multiple dose AUC0-12h

The target AUC_0-12h in adults after the recommended dose of 100 mg loading and 50 mg every 12 hours, was approximately 2500 ng•h/mL.

Gender

There were no clinically relevant differences in the clearance of tigecycline between men and women. AUC was estimated to be 20 % higher in females than in males.

Race

There were no differences in the clearance of tigecycline based on race.

Weight

Clearance, weight-normalised clearance, and AUC were not appreciably different among patients with different body weights, including those weighing

5.3 Preclinical Safety Data

In repeated dose toxicity studies in rats and dogs, lymphoid depletion/atrophy of lymph nodes, spleen and thymus, decreased erythrocytes, reticulocytes, leukocytes, and platelets, in association with bone marrow hypocellularity, and adverse renal and gastrointestinal effects have been seen with tigecycline at exposures of 8 and 10 times the human daily dose based on AUC in rats and dogs, respectively. These alterations were shown to be reversible after two weeks of dosing.

Bone discolouring was observed in rats which was not reversible after two weeks of dosing.

Results of animal studies indicate that tigecycline crosses the placenta and is found in foetal tissues. In reproduction toxicity studies, decreased foetal weights in rats and rabbits (with associated delays in ossification) and foetal loss in rabbits have been observed with tigecycline. Tigecycline was not teratogenic in the rat or rabbit. Tigecycline did not affect mating or fertility in rats at exposures up to 4.7 times the human daily dose based on AUC. In female rats, there were no compound-related effects on ovaries or oestrus cycles at exposures up to 4.7 times the human daily dose based on AUC.

Results from animal studies using ¹⁴C-labelled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in the nursing pups as a result of exposure via maternal milk.

Lifetime studies in animals to evaluate the carcinogenic potential of tigecycline have not been performed, but short-term genotoxicity studies of tigecycline were negative.

Bolus intravenous administration of tigecycline has been associated with a histamine response in animal studies. These effects were observed at exposures of 14 and 3 times the human daily dose based on the AUC in rats and dogs respectively.

No evidence of photosensitivity was observed in rats following administration of tigecycline.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate

Hydrochloric acid, sodium hydroxide (for pH adjustment)

6.2 Incompatibilities

The following active substances should not be administered simultaneously through the same Y-site as Tygacil: Amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole, omeprazole and intravenous solutions that could result in an increase of pH above 7.

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

6.3 Shelf Life

2 years.

Once reconstituted and diluted in the bag or other suitable infusion container (e.g. glass bottle), tigecycline should be used immediately.

6.4 Special Precautions For Storage

Store below 25°C.

For storage conditions of the reconstituted product see section 6.3.

6.5 Nature And Contents Of Container

5 ml Type 1 clear glass vials fitted with grey butyl rubber stoppers and snap-off aluminium crimp seals. Tygacil is distributed in a ten vial tray pack.

6.6 Special Precautions For Disposal And Other Handling

The lyophilised powder should be reconstituted with 5.3 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection, dextrose 50 mg/ml (5 %) solution for injection, or Lactated Ringer's solution for injection to achieve a concentration of 10 mg/ml of tigecycline. The vial should be gently swirled until the medicinal product is dissolved. Thereafter, 5 ml of the reconstituted solution should be immediately withdrawn from the vial and added to a 100 ml intravenous bag for infusion or other suitable infusion container (e.g., glass bottle).

For a 100 mg dose, reconstitute using two vials into a 100 ml intravenous bag or other suitable infusion container (e.g., glass bottle). Note: The vial contains a 6 % overage. Thus, 5 ml of reconstituted solution is equivalent to 50 mg of the active substance. The reconstituted solution should be yellow to orange in colour; if not, the solution should be discarded. Parenteral products should be inspected visually for particulate matter and discolouration (e.g., green or black) prior to administration.

Tygacil may be administered intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several active substances, the line should be flushed before and after infusion of Tygacil with either sodium chloride 9 mg/ml (0.9 %) solution for injection or dextrose 50 mg/ml (5 %) solution for injection. Injection should be made with an infusion solution compatible with tigecycline and any other medicinal product(s) via this common line. (See section 6.2.)

This medicinal product is for single use only; any unused solution should be discarded.

Compatible intravenous solutions include: sodium chloride 9 mg/ml (0.9 %) solution for injection, dextrose 50 mg/ml (5 %) solution for injection and Lactated Ringer's solution for injection.

When administered through a Y-site, compatibility of Tygacil diluted in sodium chloride 0.9 % for injection is demonstrated with the following medicinal products or diluents: amikacin, dobutamine, dopamine HCl, gentamicin, haloperidol, Lactacted Ringers's, lidocaine HCl, metoclopramide, morphine, norepinephrine, piperacillin/tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine HCl, theophylline, and tobramycin.

7. Marketing Authorisation Holder

Wyeth Europa Ltd.

Huntercombe Lane South

Taplow, Maidenhead

Berkshire, SL6 0PH

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/06/336/001

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 24 April 2006

Date of last renewal: 06 May 2011

10. Date Of Revision Of The Text

27 October 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/

Ref TL 5_0

Tylex Effervescent

1. Name Of The Medicinal Product

Tylex Effervescent.

Medocodene 30/500 Effervescent

2. Qualitative And Quantitative Composition

Each effervescent tablet contains 500mg of paracetamol Ph. Eur and 30 mg of codeine phosphate Ph.Eur.

3. Pharmaceutical Form

Effervescent tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of severe pain.

4.2 Posology And Method Of Administration

ADULTS

The tablets are given orally and should be dissolved in at least half a tumblerful of water before taking. The usual dose is one or two tablets every four hours as required. The total daily dose should not exceed 240 mg of codeine phosphate (i.e., not more than eight tablets per 24 hours should be taken)

ELDERLY

A reduced dose may be required.

CHILDREN

Use in children under 12 years of age is not recommended.

Dosage should be adjusted according to the severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to codeine can develop with continued use and that the incidence of untoward effects is dose related. Doses of codeine higher than 60 mg fail to give commensurate relief of pain but merely prolong analgesia and are associated with an appreciably increased incidence of undesirable side effects.

4.3 Contraindications

TYLEX EFFERVESCENT should not be administered to patients who have previously exhibited hypersensitivity to either paracetamol or codeine, or to any of its excipients.

TYLEX EFFERVESCENT is not recommended for children under the age of 12 years.

4.4 Special Warnings And Precautions For Use

The risk-benefit of continued use should be assessed regularly by the prescriber.

Because safety and effectiveness in the administration of paracetamol with codeine in children under 12 years of age have not been established, such use is not recommended.

These tablets should be used with caution in patients with head injuries, increased intracranial pressure, acute abdominal conditions, the elderly and debilitated, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy or urethral stricture, myasthenia gravis, biliary tract disorders (including recent biliary tract surgery).

The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease.

Chronic heavy alcohol abusers may be at increased risk of liver toxicity from excessive paracetamol use, although reports of this event are rare. Reports almost invariably involve cases of severe chronic alcoholics and the dosages of paracetamol most often exceed recommended doses and often involve substantial overdose. Professionals should alert their patients who regularly consume large amounts of alcohol not to exceed recommended doses of paracetamol.

These tablets contain 326.6 mg sodium/tablet and this should be taken into account when prescribing for patients for whom sodium restriction is indicated. The product also contains 25 mg aspartame/tablet and therefore care should be taken in phenylketonuria.

At high doses codeine has most of the disadvantages of morphine, including respiratory depression. Codeine can produce drug dependence of the morphine type, and therefore has the potential for being abused. Codeine may impair the mental/or physical abilities required for the performance of potentially hazardous tasks.

Patients should be advised that immediate medical advice should be sought in the event of an overdose, because of the risk of delayed, serious liver damage. They should be advised not to exceed the recommended dose, not to take other paracetamol-containing products concurrently, to consult their doctor if symptoms persist and to keep the product out of the reach of children.

The leaflet will state in a prominent position in the 'before taking' section:

· Do not take for longer than directed by your prescriber

· Taking codeine regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop the tablets.

· Taking a painkiller for headaches too often or for too long can make them worse.

The label will state (To be displayed prominently on outer pack -not boxed):

· Do not take for longer than directed by your prescriber as taking codeine regularly for a long time can lead to addiction

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Patients receiving other central nervous system depressants (including other opioid analgesics, tranquillisers, sedative hypnotics and alcohol) concomitantly with TYLEX EFFERVESCENT may exhibit an additive depressant effect. When such therapy is contemplated, the dose of one or both agents should be reduced.

Concurrent use of MAO inhibitors or tricyclic antidepressants with codeine may increase the effect of either the antidepressant or codeine. Concurrent use of anticholinergics and codeine may produce paralytic ileus.

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

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

4.6 Pregnancy And Lactation

The use of TYLEX EFFERVESCENT is not recommended during pregnancy or lactation since safety in pregnant women or nursing mothers has not been established.

4.7 Effects On Ability To Drive And Use Machines

Patients should be advised not to drive or operate machinery if affected by dizziness or sedation.

4.8 Undesirable Effects

Regular prolonged use of codeine is known to lead to addiction and tolerance. Symptoms of restlessness and irritability may result when treatment is stopped.

Prolonged use of a painkiller for headaches can make them worse.

Reported adverse reactions seem more prominent in ambulatory than non-ambulatory patients and some of these effects may be alleviated if the patient lies down.

The most frequently observed reactions include light headedness, dizziness, sedation, shortness of breath, nausea and vomiting. These effects seem more prominent in ambulatory than nonambulatory patients and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include allergic reactions, (including skin rash), euphoria, dysphoria, constipation, abdominal pain and pruritus.

In clinical use of paracetamol-containing products, there have been a few reports of blood dyscrasias including thrombocytopenia and agranulocytosis but these were not necessarily causally related to paracetamol.

4.9 Overdose

Paracetamol

Liver damage is possible in adults who have taken 10g or more of paracetamol. The following groups are at risk of liver damage from paracetamol doses of 5g or more:

• patients on long-term treatment with drugs which induce liver enzymes (e.g. barbiturates, St John's Wort);

• people who regularly drink excessive amounts of alcohol;

• patients with depleted glutathione levels (e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia).

Symptoms of paracetamol overdose include:

• pallor, nausea, vomiting, anorexia and abdominal pain within 24 hours of ingestion;

• liver damage may become apparent 12 to 48 hours after ingestion;

• abnormalities of glucose metabolism and metabolic acidosis may occur;

• in severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death;

• Acute renal failure with acute tubular necrosis (loin pain, haematuria and proteinuria), may develop regardless of severe liver damage;

• Cardiac arrhythmias and pancreatitis have been reported.

Management

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

Treatment with activated charcoal should be considered within 1 hour of overdose. Plasma paracetamol concentration should be measured at 4 hours or more post-ingestion (to ensure the measurement is reliable). Treatment with N-acetylcysteine is most effective up to 8 hours after ingestion but may be used up to 24 hours after overdose. Antidote effectiveness declines sharply after 8 hours. If required, administer N-acetylcysteine intravenously, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction more than 24h after ingestion should be discussed with the NPIS or a liver unit.

Codeine

Simultaneous ingestion of alcohol and psychotropic drugs will potentiate the effects of overdosage.

Symptoms of codeine overdose may include:

• Central nervous system depression (including respiratory depression) but this is unlikely to be severe unless the overdose is large, or there is co-ingestion with other sedative agents or alcohol;

• pinpoint sized pupils;

• nausea and vomiting;

• hypotension and tachycardia are possible but unlikely.

Management

General symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal if an adult presents within 1 hour after ingesting more than 350 mg or a child more than 5 mg/kg. Give naloxone if coma or respiratory depression is present. Naloxone is a competitive antagonist with a short half-life, so large and repeated doses may be required in a seriously poisoned patient. Observe patients for at least 4 hours after ingestion.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Paracetamol has analgesic and antipyretic actions similar to those of aspirin with weak anti-inflammatory effects. Paracetamol is only a weak inhibitor of prostaglandin biosynthesis, although there is some evidence to suggest that it may be more effective against enzymes in the CNS than those in the periphery. This fact may partly account for its well documented ability to reduce fever and to induce analgesia, effects that involve actions on neural tissues. Single or repeated therapeutic doses of paracetamol have no effect on the cardiovascular and respiratory systems. Acid-based changes do not occur and gastric irritation, erosion or bleeding is not produced as may occur after salicylates. There is only a weak effect upon platelets and no effect on bleeding time or the excretion of uric acid.

Codeine is an analgesic with uses similar to those of morphine but has only mild sedative effects. The major effect is on the CNS and the bowel. The effects are remarkably diverse and include analgesia, drowsiness, changes in mood, respiratory depression, decreased gastrointestinal motility, nausea, vomiting and alterations of the endocrine and autonomic nervous systems. The relief of pain is relatively selective, in that other sensory modalities, (touch, vibration, vision, hearing etc) are not obtunded.

5.2 Pharmacokinetic Properties

Paracetamol is readily absorbed from the gastro-intestinal tract with peak plasma

concentration occurring about 30 minutes to 2 hours after ingestion. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about 1 to 4 hours. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.

A minor hydroylated metabolite which is usually produced in very small amounts by mixedfunction oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following paracetamol overdosage and cause liver damage.

Codeine and its salts are absorbed from the gastro intestinal tract. Ingestion of codeine phosphate produces peak plasma codeine concentrations in about one hour. Codeine is metabolised by O- & N-demethylation in the liver to morphine and norcodeine. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid.

The plasma half-life has been reported to be between 3 and 4 hours after administration by mouth or intravascular injection.

5.3 Preclinical Safety Data

None stated

6. Pharmaceutical Particulars

6.1 List Of Excipients

Citric Acid Anhydrous

Sodium Bicarbonate

Sodium Carbonate Anhydrous

Aspartame

Polyethylene Glycol 6000

Magnesium Stearate

Ethanol 96 % (not detected in the finished product)

6.2 Incompatibilities

None pertinent

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Store at room temperature (at or below 25°C) in a dry place. Protect from light

6.5 Nature And Contents Of Container

Paper/aluminium laminate blister strips packed in cardboard cartons.

Pack sizes: 1, 6, 8, 24, 30, 36, 42, 48, 90, 100 and 102 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

UCB Pharma Limited

208 Bath Road

Slough

Berkshire

SL1 3WE

United Kingdom

8. Marketing Authorisation Number(S)

PL 00039/750

9. Date Of First Authorisation/Renewal Of The Authorisation

05/11/2009

10. Date Of Revision Of The Text

Tyverb

1. Name Of The Medicinal Product

Tyverb

2. Qualitative And Quantitative Composition

Each film-coated tablet contains lapatinib ditosylate monohydrate, equivalent to 250 mg lapatinib.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet (tablet).

Oval, biconvex, yellow film-coated tablets, with “GS XJG” debossed on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Tyverb is indicated for the treatment of patients with breast cancer, whose tumours overexpress HER2 (ErbB2);

• in combination with capecitabine for patients with advanced or metastatic disease with progression following prior therapy, which must have included anthracyclines and taxanes and therapy with trastuzumab in the metastatic setting (see section 5.1).

• in combination with an aromatase inhibitor for postmenopausal women with hormone receptor positive metastatic disease, not currently intended for chemotherapy. The patients in the registration study were not previously treated with trastuzumab or an aromatase inhibitor (See section 5.1).

4.2 Posology And Method Of Administration

Tyverb treatment should only be initiated by a physician experienced in the administration of anti-cancer agents.

HER2 (ErbB2) overexpressing tumours are defined by IHC3+, or IHC2+ with gene amplification or gene amplification alone. HER2 status should be determined using accurate and validated methods.

The daily dose of Tyverb should not be divided. Tyverb should be taken either at least one hour before, or at least one hour after food. To minimise variability in the individual patient, administration of Tyverb should be standardised in relation to food intake, for example always to be taken one hour before a meal (see sections 4.5 and 5.2 for information on absorption).

Missed doses should not be replaced and the dosing should resume with the next scheduled daily dose (see section 4.9).

Consult the full prescribing information of the co-administered medicinal product for relevant details of their posology including any dose reductions, contraindications and safety information.

Tyverb / capecitabine combination posology

The recommended dose of Tyverb is 1250 mg (i.e. five tablets) once daily continuously.

The recommended dose of capecitabine is 2000 mg/m²/day taken in 2 doses 12 hours apart on days 1-14 in a 21 day cycle (see section 5.1). Capecitabine should be taken with food or within 30 minutes after food. Please refer to the full prescribing information of capecitabine.

Tyverb / aromatase inhibitor combination posology

The recommended dose of Tyverb is 1500 mg (i.e. six tablets) once daily continuously.

Please refer to the full prescribing information of the co-administered aromatase inhibitor for dosing details.

Dose delay and dose reduction

Cardiac events

Tyverb should be discontinued in patients with symptoms associated with decreased left ventricular ejection fraction (LVEF) that are National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade 3 or greater or if their LVEF drops below the institutions lower limit of normal (see section 4.4). Tyverb may be restarted at a reduced dose (1000 mg/day when administered with capecitabine or 1250 mg/day when administered with an aromatase inhibitor) after a minimum of 2 weeks and if the LVEF recovers to normal and the patient is asymptomatic.

Interstitial lung disease / pneumonitis

Tyverb should be discontinued in patients who experience pulmonary symptoms which are NCI CTCAE grade 3 or greater (see section 4.4).

Other toxicities

Discontinuation or interruption of dosing with Tyverb may be considered when a patient develops toxicity greater than or equal to grade 2 on the NCI CTCAE. Dosing can be restarted, when the toxicity improves to grade 1 or less, at either 1250 mg/day when administered with capecitabine or 1500 mg/day when administered with an aromatase inhibitor. If the toxicity recurs, then Tyverb should be restarted at a lower dose (1000 mg/day when administered with capecitabine or 1250 mg/day when administered with an aromatase inhibitor).

Renal impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment. Caution is advised in patients with severe renal impairment as there is no experience of Tyverb in this population (see section 5.2).

Hepatic impairment

Tyverb should be discontinued if changes in liver function are severe and patients should not be retreated (see section 4.4).

Administration of Tyverb to patients with moderate to severe hepatic impairment should be undertaken with caution due to increased exposure to the medicinal product. Insufficient data are available in patients with hepatic impairment to provide a dose adjustment recommendation (see section 5.2).

Paediatric Population

Tyverb is not recommended for use in the paediatric population due to insufficient data on safety and efficacy.

Elderly

There are limited data of the use of Tyverb and capecitabine in patients aged

In the phase III clinical study of Tyverb in combination with letrozole, of the total number of hormone receptor positive metastatic breast cancer patients (Intent to treat population N=642), 44 % were

4.3 Contraindications

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

4.4 Special Warnings And Precautions For Use

Lapatinib has been associated with reports of decreases in left ventricular ejection fraction (LVEF) (see section 4.8). Lapatinib has not been evaluated in patients with symptomatic cardiac failure. Caution should be taken if Tyverb is to be administered to patients with conditions that could impair left ventricular function (including coadministration with potentially cardiotoxic agents). Evaluation of cardiac function, including LVEF determination, should be conducted for all patients prior to initiation of treatment with Tyverb to ensure that the patient has a baseline LVEF that is within the institutions normal limits. LVEF should continue to be evaluated during treatment with Tyverb to ensure that LVEF does not decline to an unacceptable level (see section 4.2). In some cases, LVEF decrease may be severe and lead to cardiac failure. Fatal cases have been reported, causality of the deaths is uncertain.

There has been no dedicated study to assess the potential for lapatinib to prolong the QT interval. A small, concentration dependent increase in QTc interval was observed in an uncontrolled, open-label dose-escalation study of lapatinib in advanced cancer patients, such that an effect on QT interval cannot be ruled out. Caution should be taken if Tyverb is administered to patients with conditions that could result in prolongation of QTc (including hypokalemia, hypomagnesemia, congenital long QT syndrome, or coadministration of other medicines known to cause QT prolongation). Hypokalemia or hypomagnesemia should be corrected prior to treatment. Electrocardiograms with QT measurement should be considered prior to administration of Tyverb and throughout treatment.

Lapatinib has been associated with reports of pulmonary toxicity including interstitial lung disease and pneumonitis (see section 4.8). Patients should be monitored for symptoms of pulmonary toxicity (dyspnoea, cough, fever) and treatment discontinued in patients who experience symptoms which are NCI CTCAE grade 3 or greater. Pulmonary toxicity may be severe and lead to respiratory failure. Fatal cases have been reported, causality of the deaths is uncertain.

Hepatotoxicity has occurred with Tyverb use and may in rare cases be fatal. At the initiation of treatment patients should be advised of the potential for hepatotoxicity. Liver function (transaminases, bilirubin and alkaline phosphatase) should be monitored before the initiation of treatment and monthly thereafter, or as clinically indicated. Tyverb dosing should be discontinued if changes in liver function are severe and patients should not be retreated.

Caution is warranted if Tyverb is prescribed to patients with moderate or severe hepatic impairment (see sections 4.2 and 5.2).

Caution is advised if Tyverb is prescribed to patients with severe renal impairment (see sections 4.2 and 5.2).

Diarrhoea, including severe diarrhoea, has been reported with Tyverb treatment (see section 4.8). At the start of therapy, the patients bowel pattern and any other symptoms (e.g. fever, cramping pain, nausea, vomiting, dizziness and thirst) should be determined, to allow identification of changes during treatment and to help identify patients at greater risk of diarrhoea. Patients should be instructed to promptly report any change in bowel patterns. Proactive management of diarrhoea with anti-diarrhoeal agents is important. Severe cases of diarrhoea may require administration of oral or intravenous electrolytes and fluids, and interruption or discontinuation of Tyverb therapy (see section 4.2 – dose delay and dose reduction – other toxicities).

Concomitant treatment with inducers of CYP3A4 should be avoided due to risk of decreased exposure to lapatinib (see section 4.5).

Concomitant treatment with strong inhibitors of CYP3A4 should be avoided due to risk of increased exposure to lapatinib (see section 4.5).

Grapefruit juice should be avoided during treatment with Tyverb (see section 4.5).

Coadministration of Tyverb with orally administered medicinal products with narrow therapeutic windows that are substrates of CYP3A4 should be avoided (see section 4.5).

Coadministration of Tyverb with medicinal products with narrow therapeutic windows that are substrates of CYP2C8 should be avoided (see section 4.5).

Concomitant treatment with substances that increase gastric pH should be avoided, as lapatinib solubility and absorption may decrease (see section 4.5).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of other medicinal products on lapatinib

Lapatinib is predominantly metabolised by CYP3A (see section 5.2).

In healthy volunteers receiving ketoconazole, a strong CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure to lapatinib (100 mg daily) was increased approximately 3.6–fold, and half-life increased 1.7–fold. Coadministration of Tyverb with strong inhibitors of CYP3A4 (e.g. ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone) should be avoided. Coadministration of Tyverb with moderate inhibitors of CYP3A4 should proceed with caution and clinical adverse reactions should be carefully monitored.

In healthy volunteers receiving carbamazepine, a CYP3A4 inducer, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure to lapatinib was decreased approximately 72%. Coadministration of Tyverb with known inducers of CYP3A4 (e.g. rifampicin, rifabutin, carbamazepine, phenytoin or Hypericum perforatum [St John's Wort]) should be avoided.

Lapatinib is a substrate for the transport proteins Pgp and BCRP. Inhibitors (ketoconazole, itraconazole, quinidine, verapamil, cyclosporine, erythromycin) and inducers (rifampicin, St John's Wort) of these proteins may alter the exposure and/or distribution of lapatinib (see section 5.2).

The solubility of lapatinib is pH-dependent. Concomitant treatment with substances that increase gastric pH should be avoided, as lapatinib solubility and absorption may decrease. Pre-treatment with a proton pump inhibitor (esomeprazole) decreased lapatinib exposure by an average of 27% (range: 6% to 49%). This effect decreases with increasing age from approximately 40 to 60 years.

Effects of lapatinib on other medicinal products

Lapatinib inhibits CYP3A4 in vitro at clinically relevant concentrations. Coadministration of Tyverb with orally administered midazolam resulted in an approximate 45% increase in the AUC of midazolam. There was no clinically meaningful increase in AUC when midazolam was dosed intravenously. Coadministration of Tyverb with orally administered medicines with narrow therapeutic windows that are substrates of CYP3A4 (e.g. cisapride, pimozide and quinidine) should be avoided (see sections 4.4 and 5.2).

Lapatinib inhibits CYP2C8 in vitro at clinically relevant concentrations. Coadministration of Tyverb with medicines with narrow therapeutic windows that are substrates of CYP2C8 (e.g. repaglinide) should be avoided (see sections 4.4 and 5.2).

Coadministration of lapatinib with intravenous paclitaxel increased the exposure of paclitaxel by 23%, due to lapatinib inhibition of CYP2C8 and/or Pgp. An increase in the incidence and severity of diarrhoea and neutropenia has been observed with this combination in clinical trials. Caution is advised if lapatinib is coadministered with paclitaxel.

Coadministration of lapatinib with intravenously administered docetaxel did not significantly affect the AUC or Cmax of either active substance. However, the occurrence of docetaxel-induced neutropenia was increased.

Coadministration of Tyverb with irinotecan (when administered as part of the FOLFIRI regimen) resulted in an approximate 40% increase in the AUC of SN-38, the active metabolite of irinotecan. The precise mechanism of this interaction is unknown, but it is assumed to be due to inhibition of one or more transport proteins by lapatinib. Adverse reactions should be carefully monitored if Tyverb is coadministered with irinotecan, and a reduction in the dose of irinotecan should be considered.

Lapatinib inhibits the transport protein Pgp in vitro at clinically relevant concentrations. Coadministration of lapatinib with orally administered digoxin resulted in an approximate 80% increase in the AUC of digoxin. Caution should be exercised when dosing lapatinib concurrently with medications with narrow therapeutic windows that are substrates of Pgp, and a reduction in the dose of the Pgp substrate should be considered.

Lapatinib inhibits the transport proteins BCRP and OATP1B1 in vitro. The clinical relevance of this effect has not been evaluated. It cannot be excluded that lapatinib will affect the pharmacokinetics of substrates of BCRP (e.g. topotecan) and OATP1B1 (e.g. rosuvastatin) (see section 5.2).

Concomitant administration of Tyverb with capecitabine, letrozole or trastuzumab did not meaningfully alter the pharmacokinetics of these agents (or the metabolites of capecitabine) or lapatinib.

Interactions with food and drink

The bioavailability of lapatinib is increased up to about 4 times by food, depending on e.g. the fat content in the meal (see sections 4.2 and 5.2).

Grapefruit juice may inhibit CYP3A4 in the gut wall and increase the bioavailability of lapatinib and should therefore be avoided during treatment with Tyverb.

4.6 Pregnancy And Lactation

There are no adequate data from the use of Tyverb in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is not known.

Tyverb should not be used during pregnancy unless clearly necessary. Women of childbearing potential should be advised to use adequate contraception and avoid becoming pregnant while receiving treatment with Tyverb.

The safe use of Tyverb during breast-feeding has not been established. It is not known whether lapatinib is excreted in human milk. In rats, growth retardation was observed in pups which were exposed to lapatinib via breast milk. Breast-feeding must be discontinued in women who are receiving therapy with Tyverb.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects of lapatinib on the ability to drive and use machines have been performed. A detrimental effect on such activities cannot be predicted from the pharmacology of lapatinib. The clinical status of the patient and the adverse event profile of lapatinib should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills.

4.8 Undesirable Effects

The safety of lapatinib has been evaluated as monotherapy or in combination with other chemotherapies for various cancers in more than 11,000 patients, including 198 patients who received lapatinib in combination with capecitabine and 654 patients who received lapatinib in combination with letrozole (see section 5.1).

The most common adverse reactions (>25%) during therapy with lapatinib were gastrointestinal events (such as diarrhoea, nausea, and vomiting) and rash. Palmar-plantar erythrodysesthesia [PPE] was also common (>25%) when lapatinib was administered in combination with capecitabine. The incidence of PPE was similar in the lapatinib plus capecitabine and capecitabine alone treatment arms. Diarrhoea was the most common adverse reaction resulting in discontinuation of treatment when lapatinib was administered in combination with capecitabine, or with letrozole.

The following convention has been utilised for the classification of frequency: Very common ((

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

The following adverse reactions have been reported to have a causal association with lapatinib alone or lapatinib in combination with capecitabine or letrozole.

Immune system disorders
Rare	Hypersensitivity reactions including anaphylaxis (see section 4.3)
Metabolism and nutrition disorders
Very common	Anorexia
Psychiatric disorders
Very common	Insomnia*
Nervous system disorders
Very common	Headache†
Common	Headache*
Cardiac disorders
Common	Decreased left ventricular ejection fraction (see section 4.2 - dose reduction – cardiac events and section 4.4).
Vascular disorders
Very common	Hot flush†
Respiratory, thoracic and mediastinal disorders
Very common	Epistaxis† , cough† , dyspnoea†.
Uncommon	Interstitial lung disease/pneumonitis.
Gastrointestinal disorders
Very common	Diarrhoea, which may lead to dehydration (see section 4.2 - dose delay and dose reduction – other toxicities and section 4.4), nausea, vomiting, dyspepsia*, stomatitis*, constipation*, abdominal pain*.
Common	Constipation†
Hepatobiliary disorders
Common	Hyperbilirubinaemia, hepatotoxicity (see section 4.4).
Skin and subcutaneous tissue disorders
Very common	Rash (including dermatitis acneiform) (see section 4.2 - dose delay and dose reduction – other toxicities), dry skin*†, palmar-plantar erythrodysaesthesia*, alopecia†, pruritus†.
Common	Nail disorders including paronychia.
Musculoskeletal and connective tissue disorders
Very common	Pain in extremity*†, back pain*†, arthralgia†.
General disorders and administration site conditions
Very common	Fatigue, mucosal inflammation*, asthenia†.

*These adverse reactions were observed when lapatinib was administered in combination with capecitabine.

^†These adverse reactions were observed when lapatinib was administered in combination with letrozole.

Decreased left ventricular ejection fraction and QT interval prolongation

Left ventricular ejection fraction (LVEF) decreases have been reported in approximately 1% of patients receiving lapatinib and were asymptomatic in more than 90% of cases. LVEF decreases resolved or improved in more than 70 % of cases, in 60 % of these on discontinuation of treatment with lapatinib, and in 40 % of cases lapatinib was continued. Symptomatic LVEF decreases were observed in approximately 0.2% of patients who received lapatinib monotherapy or in combination with other anti-cancer agents. Observed symptoms included dyspnoea, cardiac failure and palpitations. Overall 58 % of these symptomatic subjects recovered. LVEF decreases were reported in 2.5 % of patients who received lapatinib in combination with capecitabine, as compared to 1.0 % with capecitabine alone. LVEF decreases were reported in 3.1 % of patients who received lapatinib in combination with letrozole as compared to 1.3 % of patients receiving letrozole plus placebo.

A small, concentration dependent increase in QTc interval was observed in a phase I uncontrolled study. The potential for lapatinib to prolong the QTc interval has not been ruled out (see section 4.4).

Diarrhoea

Diarrhoea occurred in approximately 65 % of patients who received lapatinib in combination with capecitabine and in 64 % of patients who received lapatinib in combination with letrozole. Most cases of diarrhoea were grade 1 or 2 and did not result in discontinuation of treatment with lapatinib. Diarrhoea responds well to proactive management (see section 4.4). However, a few cases of acute renal failure have been reported secondary to severe dehydration due to diarrhoea.

Rash

Rash occurred in approximately 28 % of patients who received lapatinib in combination with capecitabine and in 45 % of patients who received lapatinib in combination with letrozole. Rash was generally low grade and did not result in discontinuation of treatment with lapatinib. Prescribing physicians are advised to perform a skin examination prior to treatment and regularly during treatment. Patients experiencing skin reactions should be encouraged to avoid exposure to sunlight and apply broad spectrum sunscreens with a Sun Protection Factor (SPF)

4.9 Overdose

There is no specific antidote for the inhibition of EGFR (ErbB1) and/or HER2 (ErbB2) tyrosine phosphorylation. The maximum oral dose of lapatinib that has been administered in clinical trials is 1800 mg once daily.

Asymptomatic and symptomatic cases of overdose have been reported in patients being treated with Tyverb. In patients who took up to 5000 mg of lapatinib, symptoms observed include known lapatinib associated events (see Section 4.8) and in some cases sore scalp and/or mucosal inflammation. In a single case of a patient who took 9000 mg of Tyverb, sinus tachycardia (with otherwise normal ECG) was also observed.

Lapatinib is not significantly renally excreted and is highly bound to plasma proteins, therefore haemodialysis would not be expected to be an effective method to enhance the elimination of lapatinib.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Protein kinase inhibitor, ATC code: L01XE07

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

This means that further evidence on this medicinal product is awaited.

The European Medicines Agency (EMA) will review new information on the product every year and this SPC will be updated as necessary.

The European Medicines Agency has waived the obligation to submit the results of studies with Tyverb in all subsets of the paediatric population in the treatment of breast carcinoma (see section 4.2 for information on paediatric use).

Mechanism of action

Lapatinib, a 4-anilinoquinazoline, is an inhibitor of the intracellular tyrosine kinase domains of both EGFR (ErbB1) and of HER2 (ErbB2) receptors (estimated Ki^app values of 3nM and 13nM, respectively) with a slow off-rate from these receptors (half-life greater than or equal to 300 minutes). Lapatinib inhibits ErbB-driven tumour cell growth in vitro and in various animal models.

The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro.

Clinical studies

Combination treatment with Tyverb and capecitabine

The efficacy and safety of Tyverb in combination with capecitabine in breast cancer patients with good performance status was evaluated in a randomised, phase III trial. Patients eligible for enrolment had HER2-overexpressing, locally advanced or metastatic breast cancer, progressing after prior treatment that included taxanes, anthracyclines and trastuzumab. LVEF was evaluated in all patients (using echocardiogram or MUGA) prior to initiation of treatment with Tyverb to ensure baseline LVEF was within the institutions normal limits. In the clinical trial LVEF was monitored at approximately eight week intervals during treatment with Tyverb to ensure it did not decline to below the institutions lower limit of normal. The majority of LVEF decreases (greater than 60 %) were observed during the first nine weeks of treatment, however limited data was available for long term exposure.

Patients were randomised to receive either Tyverb 1250 mg once daily (continuously) plus capecitabine (2000 mg/m²/day on days 1-14 every 21 days), or to receive capecitabine alone (2500 mg/m²/day on days 1-14 every 21 days). The primary endpoint was time to progression (TTP). Assessments were undertaken by the study investigators and by an independent review panel, blinded to treatment. The study was halted based on the results of a pre-specified interim analysis that showed an improvement in TTP for patients receiving Tyverb plus capecitabine. An additional 75 patients were enrolled in the study between the time of the interim analysis and the end of the enrolment. Investigator analysis on data at the end of enrolment is presented in Table 1.

Table 1 Time to Progression data from Study EGF100151 (Tyverb / capecitabine)

	Investigator assessment
Tyverb (1,250 mg/day)+ capecitabine (2,000 mg/m2/day)	Capecitabine (2,500 mg/m2/day)
(N = 198)	(N = 201)
Number of TTP events	121	126
Median TTP, weeks	23.9	18.3
Hazard Ratio	0.72
(95% CI)	(0.56, 0.92)
p value	0.008

The independent assessment of the data also demonstrated that Tyverb when given in combination with capecitabine significantly increased time to progression (Hazard Ratio 0.57 [95 % Cl 0.43, 0.77] p=0.0001) compared to capecitabine alone.

Results of an updated analysis of the overall survival data to 28 September 2007 are presented in Table 2.

Table 2 Overall survival data from Study EGF100151 (Tyverb / capecitabine)

	Tyverb (1,250 mg/day)+ capecitabine (2,000 mg/m2/day)	Capecitabine (2,500 mg/m2/day)
	(N = 207)	(N = 201)
Number of subjects who died	148	154
Median overall survival, weeks	74.0	65.9
Hazard Ratio	0.9
(95% CI)	(0.71, 1.12)
p value	0.3

On the combination arm, there were 4 (2%) progressions in the central nervous system as compared with the 13 (6%) progressions on the capecitabine alone arm.

Combination treatment with Tyverb and letrozole

Tyverb has been studied in combination with letrozole for the treatment of postmenopausal women with hormone receptor-positive (oestrogen receptor [ER] positive and / or progesterone receptor [PgR] positive) advanced or metastatic breast cancer.

The Phase III study (EGF30008) was randomised, double-blind, and placebo controlled. The study enrolled patients who had not received prior therapy for their metastatic disease. The period of enrolment to the trial (December 2003 – December 2006) preceded the adoption of trastuzumab in combination with an aromatase inhibitor. A comparative study between lapatinib and trastuzumab in this patient population has not been conducted.

In the HER2-overexpressing population, only 2 patients were enrolled who had received prior trastuzumab, 2 patients had received prior aromatase inhibitor therapy, and approximately half had received tamoxifen.

Patients were randomised to letrozole 2.5 mg once daily plus Tyverb 1500 mg once daily or letrozole with placebo. Randomisation was stratified by sites of disease and by time from discontinuation of prior adjuvant anti-oestrogen therapy. HER2 receptor status was retrospectively determined by central laboratory testing. Of all patients randomised to treatment, 219 patients had tumours overexpressing the HER2 receptor, and this was the pre-specified primary population for the analysis of efficacy. There were 952 patients with HER2-negative tumours, and a total of 115 patients whose tumour HER2 status was unconfirmed (no tumour sample, no assay result, or other reason).

In patients with HER2-overexpressing MBC, investigator-determined progression-free survival (PFS) was significantly greater with letrozole plus Tyverb compared with letrozole plus placebo. In the HER2-negative population, there was no benefit in PFS when letrozole plus Tyverb was compared with letrozole plus placebo (see Table 3).

Table 3 Progression Free Survival data from Study EGF30008 (Tyverb / letrozole)

	HER2-Overexpressing Population	HER2-Negative Population
N = 111	N = 108	N = 478	N = 474
Tyverb 1500 mg / day + Letrozole 2.5 mg /day	Letrozole 2.5 mg /day + placebo	Tyverb 1500 mg / day + Letrozole 2.5 mg /day	Letrozole 2.5 mg /day + placebo
Median PFS, weeks (95% CI)	35.4 (24.1, 39.4)	13.0 (12.0, 23.7)	59.7 (48.6, 69.7)	58.3 (47.9, 62.0)
Hazard Ratio	0.71 (0.53, 0.96)	0.90 (0.77, 1.05)
P-value	0.019	0.188
Objective Response Rate (ORR)	27.9%	14.8%	32.6%	31.6%
Odds Ratio	0.4 (0.2, 0.9)	0.9 (0.7, 1.3)
P-value	0.021	0.26
Clinical Benefit Rate (CBR)	47.7%	28.7%	58.2%	31.6%
Odds Ratio	0.4 (0.2, 0.8)	1.0 (0.7, 1.2)
P-value	0.003	0.199

CI= confidence interval

HER2 overexpression = IHC 3+ and/or FISH positive; HER2 negative = IHC 0, 1+ or 2+ and/or FISH negative

Clinical Benefit Rate was defined as complete plus partial response plus stable disease for

At the time of analysis, the overall survival data were not mature and there was no significant difference between treatment groups (Tyverb + letrozole combination HR= 0.77 [95 %CI 0.52-1.14] p=0.185). However, no negative effect on overall survival was apparent.

5.2 Pharmacokinetic Properties

The absolute bioavailability following oral administration of lapatinib is unknown, but it is incomplete and variable (approximately 70% coefficient of variation in AUC). Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 1.5 hours). Peak plasma concentrations (C_max) of lapatinib are achieved approximately 4 hours after administration. Daily dosing of 1250 mg produces steady state geometric mean (coefficient of variation) C_max values of 2.43 (76%) µg/ml and AUC values of 36.2 (79%) µg*hr/ml.

Systemic exposure to lapatinib is increased when administered with food. Lapatinib AUC values were approximately 3- and 4-fold higher (C_max approximately 2.5 and 3–fold higher) when administered with a low fat (5% fat [500 calories]) or with a high fat (50% fat [1,000 calories]) meal, respectively.

Lapatinib is highly bound (greater than 99%) to albumin and alpha-1 acid glycoprotein. In vitro studies indicate that lapatinib is a substrate for the transporters BCRP (ABCG1) and p-glycoprotein (ABCB1). Lapatinib has also been shown in vitro to inhibit these efflux transporters, as well as the hepatic uptake transporter OATP 1B1, at clinically relevant concentrations (IC₅₀ values were equal to 2.3 µg/ml). The clinical significance of these effects on the pharmacokinetics of other medicinal products or the pharmacological activity of other anti-cancer agents is not known.

Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which account for more than 14% of the dose recovered in the faeces or 10% of lapatinib concentration in plasma.

Lapatinib inhibits CYP3A (Ki 0.6 to 2.3 µg/ml) and CYP2C8 (0.3 µg/ml) in vitro at clinically relevant concentrations. Lapatinib did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT enzymes (in vitro IC₅₀ values were greater than or equal to 6.9 µg/ml).