AVONEX 30 micrograms powder and solvent for solution for injection

1. Name Of The Medicinal Product

AVONEX 30 micrograms powder and solvent for solution for injection

2. Qualitative And Quantitative Composition

Each BIO-SET vial contains 30 micrograms (6 million IU) of interferon beta-1a.

Following reconstitution with the solvent (water for injections) the vial contains 1.0 ml of solution. The concentration is 30 micrograms per ml.

Using the World Health Organisation (WHO) International Standard for Interferon, 30 micrograms of AVONEX contains 6 million IU of antiviral activity. The activity against other standards is not known.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection.

The vial contains a white to off-white cake.

4. Clinical Particulars

4.1 Therapeutic Indications

AVONEX is indicated for the treatment of

• Patients diagnosed with relapsing multiple sclerosis (MS). In clinical trials, this was characterised by two or more acute exacerbations (relapses) in the previous three years without evidence of continuous progression between relapses; AVONEX slows the progression of disability and decreases the frequency of relapses.

• Patients with a single demyelinating event with an active inflammatory process, if it is severe enough to warrant treatment with intravenous corticosteroids, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis (see section 5.1).

AVONEX should be discontinued in patients who develop progressive MS.

4.2 Posology And Method Of Administration

Treatment should be initiated under supervision of a physician experienced in the treatment of the disease.

Adults: The recommended dosage for the treatment of relapsing MS is 30 micrograms (1 ml solution), administered by intramuscular (IM) injection once a week (see section 6.6). No additional benefit has been shown by administering a higher dose (60 micrograms) once a week.

Titration: To help patients reduce the incidence and severity of flu-like symptoms (see section 4.8), titration can be performed at the initiation of treatment. Titration using the BIOSET or pre-filled syringe can be achieved by initiating therapy on ¼ dose increments per week reaching the full dose (30 micrograms/week) by the fourth week.

An alternative titration schedule can be achieved by initiating therapy on approximately a ½ dose of AVONEX once a week before increasing to the full dose. In order to obtain adequate efficacy, a dose of 30mcg once a week should be reached and maintained after the initial titration period.

Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised to decrease flu-like symptoms associated with AVONEX administration. These symptoms are usually present during the first few months of treatment.

Paediatric population: The safety and efficacy of AVONEX in adolescents aged 12 to 16 years have not yet been established. Currently available data are described in section 4.8 and 5.1 but no recommendation on a posology can be made.

The safety and efficacy of AVONEX in children below 12 years of age have not yet been established.

No data are available

Elderly: Clinical studies did not include a sufficient number of patients aged 65 and over to determine whether they respond differently than younger patients. However, based on the mode of clearance of the active substance there are no theoretical reasons for any requirement for dose adjustments in the elderly.

The intramuscular injection site should be varied each week (see section 5.3).

Doctors may prescribe a 25 mm, 25 gauge needle to patients for whom such a needle is appropriate to administer an intramuscular injection.

At the present time, it is not known for how long patients should be treated. Patients should be clinically evaluated after two years of treatment and longer-term treatment should be decided on an individual basis by the treating physician. Treatment should be discontinued if the patient develops chronic progressive MS.

4.3 Contraindications

- Initiation of treatment in pregnancy (see section 4.6).

- Patients with a history of hypersensitivity to natural or recombinant interferon -ß, human albumin or to any excipients.

- Patients with current severe depression and/or suicidal ideation (see sections 4.4 and 4.8).

4.4 Special Warnings And Precautions For Use

AVONEX should be administered with caution to patients with previous or current depressive disorders, in particular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidal ideation are known to occur in increased frequency in the multiple sclerosis population and in association with interferon use. Patients should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician.

Patients exhibiting depression should be monitored closely during therapy and treated appropriately. Cessation of therapy with AVONEX should be considered (see also sections 4.3 and 4.8).

AVONEX should be administered with caution to patients with a history of seizures, to those receiving treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with anti-epileptics (see sections 4.5 and 4.8).

Caution should be used and close monitoring considered when administering AVONEX to patients with severe renal and hepatic failure and to patients with severe myelosuppression.

Hepatic injury including elevated serum hepatic enzyme levels, hepatitis, autoimmune hepatitis and hepatic failure has been reported with interferon beta in post-marketing (see section 4.8). In some cases, these reactions have occurred in the presence of other medicinal products that have been associated with hepatic injury. The potential of additive effects from multiple medicinal products or other hepatotoxic agents (e.g. alcohol) has not been determined. Patients should be monitored for signs of hepatic injury and caution exercised when interferons are used concomitantly with other medicinal products associated with hepatic injury.

Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely monitored for worsening of their clinical condition during treatment with AVONEX. Flu-like symptoms associated with AVONEX therapy may prove stressful to patients with underlying cardiac conditions.

Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those laboratory tests normally required for monitoring patients with MS, complete and differential white blood cell counts, platelet counts, and blood chemistry, including liver function tests, are recommended during AVONEX therapy. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.

Patients may develop antibodies to AVONEX. The antibodies of some of those patients reduce the activity of interferon beta-1a in vitro (neutralising antibodies). Neutralising antibodies are associated with a reduction in the in vivo biological effects of AVONEX and may potentially be associated with a reduction of clinical efficacy. It is estimated that the plateau for the incidence of neutralising antibody formation is reached after 12 months of treatment. Data from patients treated up to two years with AVONEX suggests that approximately 8% develop neutralising antibodies.

The use of various assays to detect serum antibodies to interferons limits the ability to compare antigenicity among different products.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No formal interaction studies have been performed in humans.

The interaction of AVONEX with corticosteroids or adrenocorticotropic hormone (ACTH) has not been studied systematically. The clinical studies indicate that MS patients can receive AVONEX and corticosteroids or ACTH during relapses.

Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. The effect of high-dose AVONEX administration on P450-dependent metabolism in monkeys was evaluated and no changes in liver metabolising capabilities were observed. Caution should be exercised when AVONEX is administered in combination with medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome P450 system for clearance, e.g. antiepileptics and some classes of antidepressants.

4.6 Pregnancy And Lactation

Pregnancy

There is limited information on the use of AVONEX in pregnancy. Available data indicates that there may be an increased risk of spontaneous abortion. Initiation of treatment is contraindicated during pregnancy (see section 4.3).

Women of child-bearing potential

Women of child-bearing potential have to take appropriate contraceptive measures. If the patient becomes pregnant or plans to become pregnant while taking AVONEX she should be informed of the potential hazards and discontinuation of therapy should be considered (see section 5.3). In patients with a high relapse rate before treatment started, the risk of a severe relapse following discontinuation of AVONEX in the event of pregnancy should be weighed against a possible increased risk of spontaneous abortion.

Lactation

It is not known whether AVONEX is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made either to discontinue breast-feeding or AVONEX therapy.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects of AVONEX on the ability to drive and use machines have been performed. Central nervous system-related adverse reactions may have a minor influence on the ability to drive and use machines in susceptible patients (see section 4.8).

4.8 Undesirable Effects

The highest incidence of adverse reactions associated with AVONEX therapy is related to flu-like symptoms. The most commonly reported flu-like symptoms are myalgia, fever, chills, sweating, asthenia, headache and nausea. Titrating AVONEX at the initiation of therapy has demonstrated a reduction in the severity and incidence of flu-like symptoms. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in frequency with continued treatment.

Transient neurological symptoms that may mimic MS exacerbations may occur following injections. Transient episodes of hypertonia and/or severe muscular weakness that prevent voluntary movements may occur at any time during treatment. These episodes are of limited duration, temporally related to the injections and may recur after subsequent injections. In some cases these symptoms are associated with flu-like symptoms.

The frequencies of adverse reactions are expressed in patient-years, according to the following categories:

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000 patient-years);

Not known (cannot be estimated from the available data).

Patient-time is the sum of individual units of time that the patient in the study has been exposed to AVONEX before experiencing the adverse reaction. For example, 100 person-years could be observed in 100 patients who were on treatment for one year or in 200 patients who were on treatment for half a year.

Adverse reactions identified from studies (clinical trials and observational studies, with a period of follow-up ranging from two years to six years) and other adverse reactions identified through spontaneous reporting from the market, with unknown frequency, are provided in the table below.

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

Investigations
common	lymphocyte count decreased, white blood cell count decreased, neutrophil count decreased, hematocrit decreased, blood potassium increased, blood urea nitrogen increased
uncommon	platelet count decreased
not known	weight decreased, weight increased, liver function tests abnormal
Cardiac disorders
not known	cardiomyopathy, congestive heart failure (see section 4.4), palpitations, arrhythmia, tachycardia
Blood and lymphatic system disorders
not known	pancytopenia, thrombocytopenia
Nervous system disorders
very common	headache2
common	muscle spasticity, hypoesthesia
not known	neurological symptoms, syncope3, hypertonia, dizziness, paraesthesia, seizures, migraine
Respiratory, thoracic and mediastinal disorders
common	rhinorrhoea
rare	dyspnoea
Gastrointestinal disorders
common	vomiting, diarrhoea, nausea2
Skin and subcutaneous tissue disorders
common	rash, sweating increased, contusion
uncommon	alopecia
not known	angioneurotic oedema, pruritus, rash vesicular, urticaria, aggravation of psoriasis
Musculoskeletal and connective tissue disorders
common	muscle cramp, neck pain, myalgia2, arthralgia, pain in extremity, back pain, muscle stiffness, musculoskeletal stiffness
not known	systemic lupus erythematosus, muscle weakness, arthritis
Endocrine disorders
not known	hypothyroidism, hyperthyroidism
Metabolism and nutrition disorders
common	anorexia
Infections and infestations
not known	injection site abscess1
Vascular disorders
common	flushing
not known	vasodilatation
General disorders and administration site conditions
very common	flu-like symptoms, pyrexia2, chills2, sweating2
common	injection site pain, injection site erythema, injection site bruising, asthenia2, pain, fatigue2, malaise, night sweats
uncommon	injection site burning
not known	injection site reaction, injection site inflammation, injection site cellulitis1, injection site necrosis, injection site bleeding, chest pain
Immune system disorders
not known	anaphylactic reaction, anaphylactic shock, hypersensitivity reactions (angioedema, dyspnoea, urticaria, rash, pruritic rash)
Hepatobiliary disorders
not known	hepatic failure (see section 4.4), hepatitis, autoimmune hepatitis
Reproductive system and breast disorders
uncommon	metrorrhagia, menorrhagia
Psychiatric disorders
common	depression (see section 4.4), insomnia
not known	suicide, psychosis, anxiety, confusion, emotional lability

¹Injection site reactions including pain, inflammation and very rare cases of abscess or cellulitis that may require surgical intervention have been reported.

²The frequency of occurrence is higher at the beginning of treatment.

³A syncope episode may occur after AVONEX injection, it is normally a single episode that usually appears at the beginning of the treatment and does not recur with subsequent injections.

Paediatric population: Limited published data suggest that the safety profile in adolescents from 12 to 16 years of age receiving AVONEX 30 micrograms IM once per week is similar to that seen in adults.

4.9 Overdose

No case of overdose has been reported. However, in case of overdose, patients should be hospitalised for observation and appropriate supportive treatment given.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Interferons, ATC code: L03 AB07.

Interferons are a family of naturally occurring proteins that are produced by eukaryotic cells in response to viral infection and other biological inducers. Interferons are cytokines that mediate antiviral, antiproliferative and immunomodulatory activities. Three major forms of interferons have been distinguished: alpha, beta and gamma. Interferons alpha and beta are classified as Type I interferons and interferon gamma is a Type II interferon. These interferons have overlapping but clearly distinguishable biological activities. They can also differ with respect to their cellular sites of synthesis.

Interferon beta is produced by various cell types including fibroblasts and macrophages. Natural interferon beta and AVONEX (interferon beta-1a) are glycosylated and have a single N-linked complex carbohydrate moiety. Glycosylation of other proteins is known to affect their stability, activity, biodistribution, and half-life in blood. However, the effects of interferon beta that are dependent on glycosylation are not fully defined.

AVONEX exerts its biological effects by binding to specific receptors on the surface of human cells. This binding initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers. These include MHC Class I, Mx protein, 2' / 5'-oligoadenylate synthetase, β₂-microglobulin, and neopterin. Some of these products have been measured in the serum and cellular fractions of blood collected from patients treated with AVONEX. After a single intramuscular dose of AVONEX, serum levels of these products remain elevated for at least four days and up to one week.

Whether the mechanism of action of AVONEX in MS is mediated by the same pathway as the biological effects described above is not known because the pathophysiology of MS is not well established.

The effects of lyophilised AVONEX in the treatment of MS were demonstrated in a placebo-controlled study of 301 patients (AVONEX n=158, placebo n=143) with relapsing MS characterised by at least 2 exacerbations in the previous 3 years or at least one exacerbation per year prior to entry when the duration of the disease was less than 3 years. Patients with an EDSS of 1.0 to 3.5 at entry were included in the clinical trial. Due to the design of the study, patients were followed for variable lengths of time. 150 AVONEX-treated patients completed one year on study and 85 completed two years on study. In the study, the cumulative percentage of patients who developed disability progression (by Kaplan-Meier life table analysis) by the end of two years was 35% for placebo-treated patients and 22% for AVONEX-treated patients. Disability progression was measured as an increase in the Expanded Disability Status Scale (EDSS) of 1.0 point, sustained for at least six months. It was also shown that there was a one-third reduction in annual relapse rate. This latter clinical effect was observed after more than one year of treatment.

A double-blind randomised dose comparison study of 802 relapsing MS patients (AVONEX 30 micrograms n=402, AVONEX 60 micrograms n=400) has shown no statistically significant differences or trends between the 30 micrograms and the 60 micrograms doses of AVONEX in clinical and general MRI parameters.

The effects of AVONEX in the treatment of MS were also demonstrated in a randomised double-blind study performed with 383 patients (AVONEX n=193, placebo n=190) with a single demyelinating event associated with at least two compatible brain MRI lesions. A reduction of the risk of experiencing a second event was noted in the AVONEX treatment group. An effect on MRI parameters was also seen. The estimated risk of a second event was 50% in three years and 39% in two years in the placebo group and 35% (three years) and 21% (two years) in the AVONEX group. In a post-hoc analysis, those patients with a baseline MRI with at least one Gd-enhancing lesion and nine T2 lesions had a two-year risk of suffering a second event of 56% in the placebo group and 21% in the AVONEX treatment group. However, the impact of early treatment with AVONEX is unknown even in this high-risk subgroup as the study was mainly designed to assess the time to the second event rather than the long term evolution of the disease. Furthermore, for the time-being there is no well established definition of a high risk patient although a more conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least three months after the initial scan. In any case, treatment should only be considered for patients classified at high risk.

Paediatric population: Limited data of the efficacy/safety of AVONEX 15 micrograms IM once per week (n=8) as compared to no treatment (n=8) with follow up for 4 years showed results in line to those seen in adults, although the EDSS scores increased in the treated group over the 4 year follow-up thus indicating disease progression. No direct comparison with the dose currently recommended in adults is available.

5.2 Pharmacokinetic Properties

The pharmacokinetic profile of AVONEX has been investigated indirectly with an assay that measures interferon antiviral activity. This assay is limited in that it is sensitive for interferon but lacks specificity for interferon beta. Alternative assay techniques are not sufficiently sensitive.

Following intramuscular administration of AVONEX, serum antiviral activity levels peak between 5 and 15 hours post-dose and decline with a half-life of approximately 10 hours. With appropriate adjustment for the rate of absorption from the injection site, the calculated bioavailability is approximately 40%. The calculated bioavailability is greater without such adjustments. Intramuscular bioavailability is three-fold higher than subcutaneous bioavailability. Subcutaneous administration cannot be substituted for intramuscular administration.

5.3 Preclinical Safety Data

Carcinogenesis: No carcinogenicity data for interferon beta-1a are available in animals or humans.

Chronic Toxicity: In a 26-week, repeated-dose toxicity study in rhesus monkeys by intramuscular route once per week, administered in combination with another immunomodulating agent, an anti CD40 ligand monoclonal antibody, no immune response toward interferon beta-1a and no signs of toxicity were demonstrated.

Local Tolerance: Intramuscular irritation has not been evaluated in animals following repeated administration to the same injection site.

Mutagenesis: Limited but relevant mutagenesis tests have been carried out. The results have been negative.

Impairment of Fertility: Fertility and developmental studies in rhesus monkeys have been carried out with a related form of interferon beta-1a. At very high doses, anovulatory and abortifacient effects in test animals were observed. Similar reproductive dose-related effects have also been observed with other forms of alpha and beta interferons. No teratogenic effects or effects on foetal development have been observed, but the available information on the effects of interferon beta-1a in the peri- and postnatal periods is limited.

No information is available on the effects of interferon beta-1a on male fertility.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Human serum albumin,

Dibasic sodium phosphate,

Monobasic sodium phosphate,

Sodium chloride.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

AVONEX should be administered as soon as possible after reconstitution. However, the reconstituted solution can be stored at 2 °C-8 °C for up to six hours, prior to injection.

6.4 Special Precautions For Storage

Store below 25 °C.

DO NOT FREEZE the powder or the reconstituted product.

For storage conditions of the reconstituted medicinal product see section 6.3.

6.5 Nature And Contents Of Container

AVONEX is available as a package of four individual doses. Each dose is supplied in a 3 ml clear glass vial with BIO-SET device and a 13 mm bromobutyl rubber stopper. It is provided with a 1 ml pre-filled glass syringe of solvent for reconstitution (water for injections) and one needle.

6.6 Special Precautions For Disposal And Other Handling

Use the supplied pre-filled syringe of solvent to reconstitute AVONEX for injection. Do not use any other solvent. Inject the content of the syringe into the vial of AVONEX by connecting the pre-filled syringe to the BIO-SET device. Gently swirl the contents in the vial until all materials are dissolved; DO NOT SHAKE. Inspect the reconstituted product: If it contains particulate matter or is other than colourless to slightly yellow in colour, the vial must not be used. After reconstitution, draw all the liquid (1 ml) from the vial back into the syringe for the administration of 30 micrograms AVONEX. The needle for intramuscular injection is provided. The formulation does not contain a preservative. Each vial of AVONEX contains a single dose only. Discard the unused portion of any vial.

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

7. Marketing Authorisation Holder

BIOGEN IDEC LIMITED

Innovation House

70 Norden Road

Maidenhead

Berkshire

SL6 4AY

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/97/033/002

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 13 March 1997

Date of latest renewal: 13 March 2007

10. Date Of Revision Of The Text

10/2011

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

Alphagan

1. Name Of The Medicinal Product

Alphagan 0.2% w/v (2 mg/ml) eye drops, solution

2. Qualitative And Quantitative Composition

One ml solution contains 2.0 mg brimonidine tartrate, equivalent to 1.3 mg of brimonidine.

Excipient(s): Contains benzalkonium chloride 0.05 mg/ml. For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Eye drops, solution.

Clear, greenish-yellow to light greenish-yellow solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Reduction of elevated intraocular pressure (IOP) in patients with open angle glaucoma or ocular hypertension.

− As monotherapy in patients in whom topical beta-blocker therapy is contraindicated.

− As adjunctive therapy to other intraocular pressure lowering medications when the target IOP is not achieved with a single agent (see Section 5.1).

4.2 Posology And Method Of Administration

Recommended dosage in adults (including the elderly)

The recommended dose is one drop of Alphagan in the affected eye(s) twice daily, approximately 12 hours apart. No dosage adjustment is required for the use in elderly patients.

As with any eye drops, to reduce possible systemic absorption, it is recommended that the lachrymal sac be compressed at the medial canthus (punctal occlusion) for one minute. This should be performed immediately following the instillation of each drop.

If more than one topical ophthalmic drug is to be used, the different drugs should be instilled 5-15 minutes apart.

Use in renal and hepatic impairment

Alphagan has not been studied in patients with hepatic or renal impairment (see section 4.4).

Use in paediatric subjects

No clinical studies have been performed in adolescents (12 to 17 years).

Alphagan is not recommended for use in children below 12 years and is contraindicated in neonates and infants (less than 2 years of age) (see sections 4.3, 4.4 and 4.9). It is known that severe adverse reactions can occur in neonates. The safety and efficacy of Alphagan have not been established in children.

4.3 Contraindications

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

− Neonates and infants (see section 4.8).

− Patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants and mianserin).

4.4 Special Warnings And Precautions For Use

Children of 2 years of age and above, especially those in the 2-7 age range and/or weighing < 20 Kg, should be treated with caution and closely monitored due to the high incidence of somnolence (see section 4.8).

Caution should be exercised in treating patients with severe or unstable and uncontrolled cardiovascular disease.

Some (12.7%)patients in clinical trials experienced an ocular allergic type reaction with Alphagan (see section 4.8 for details). If allergic reactions are observed, treatment with Alphagan should be discontinued.

Alphagan should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension or thromboangiitis obliterans.

Alphagan has not been studied in patients with hepatic or renal impairment; caution should be used in treating such patients.

The preservative in Alphagan, benzalkonium chloride, may cause eye irritation. Avoid contact with soft contact lenses. Remove contact lenses prior to application and wait at least 15 minutes before reinsertion. Known to discolour soft contact lenses.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Although specific drug interactions studies have not been conducted with Alphagan, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered.

No data on the level of circulating catecholamines after Alphagan administration are available. Caution, however, is advised in patients taking medications which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine.

After the application of Alphagan, clinically insignificant decreases in blood pressure were noted in some patients. Caution is advised when using drugs such as antihypertensives and/or cardiac glycosides concomitantly with Alphagan.

Caution is advised when initiating (or changing the dose of) a concomitant systemic agent (irrespective of pharmaceutical form) which may interact with α-adrenergic agonists or interfere with their activity i.e. agonists or antagonists of the adrenergic receptor e.g. (isoprenaline, prazosin).

4.6 Pregnancy And Lactation

The safety of use during human pregnancy has not been established. In animal studies, brimonidine tartrate did not cause any teratogenic effects. In rabbits, brimonidine tartrate, at plasma levels higher than are achieved during therapy in humans, has been shown to cause increased preimplantation loss and postnatal growth reduction. Alphagan should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the foetus.

It is not known if brimonidine is excreted in human milk. The compound is excreted in the milk of the lactating rat. Alphagan should not be used by women nursing infants.

4.7 Effects On Ability To Drive And Use Machines

Alphagan may cause fatigue and/or drowsiness, which may impair the ability to drive or operate machinery. Alphagan may cause blurred and/or abnormal vision, which may impair the ability to drive or to use machinery, especially at night or in reduced lighting. The patient should wait until these symptoms have cleared before driving or using machinery.

4.8 Undesirable Effects

The most commonly reported ADRs are oral dryness, ocular hyperaemia and burning/stinging, all occurring in 22 to 25% of patients. They are usually transient and not commonly of a severity requiring discontinuation of treatment.

Symptoms of ocular allergic reactions occurred in 12.7% of subjects (causing withdrawal in 11.5% of subjects) in clinical trials with the onset between 3 and 9 months in the majority of patients.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The following terminologies have been used in order to classify the occurrence of undesirable effects: Very Common (

Cardiac disorders

Uncommon: palpitations/arrhythmias (including bradycardia and tachycardia)

Nervous system disorders

Very common: headache, drowsiness

Common: dizziness, abnormal taste

Very rare: syncope

Eye disorders

Very common:

− ocular irritation including allergic reactions (hyperaemia, burning and stinging, pruritus, foreign body sensation, conjunctival follicles)

− blurred vision

Common:

− local irritation (eyelid hyperaemia and oedema, blepharitis, conjunctival oedema and discharge, ocular pain and tearing)

− photophobia

− corneal erosion and staining

− ocular dryness

− conjunctival blanching

− abnormal vision

− conjunctivitis

Very rare:

− iritis (anterior uveitis)

− miosis

Respiratory, thoracic and mediastinal disorders

Common: upper respiratory symptoms

Uncommon: nasal dryness

Rare: dyspnoea

Gastrointestinal disorders

Very common: oral dryness

Common: gastrointestinal symptoms

Vascular disorders

Very rare: hypertension, hypotension

General disorders and administration site conditions

Very common: fatigue

Common: asthenia

Immune system disorders

Uncommon: systemic allergic reactions

Psychiatric disorders

Uncommon: depression

Very rare: insomnia

In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, hypotension, hypotonia, bradycardia, hypothermia, cyanosis and apnoea have been reported in neonates and infants receiving brimonidine (see section 4.3).

In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing

4.9 Overdose

Ophthalmic overdose:

There is no experience in adults with the unlikely case of an overdosage via the ophthalmic route. However, symptoms of brimonidine overdose (including loss of consciousness, hypotension, hypotonia, bradycardia, hypothermia, cyanosis and apnoea) have been reported in neonates and infants receiving Alphagan as part of medical treatment of congenital glaucoma.

Systemic overdose resulting from accidental ingestion:

Two cases of adverse effects following inadvertent ingestion of 9-10 drops of Alphagan by adult subjects have been received. The subjects experienced a hypotensive episode, followed in one instance by rebound hypertension approximately 8 hours after ingestion. Both subjects were reported to have made a full recovery within 24 hours. No adverse effects were noted in a third subject who also ingested an unknown amount of Alphagan orally.

Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, hypotonia, bradycardia, hypothermia and apnoea, and required admission to intensive care with intubation if indicated. All subjects were reported to have made a full recovery, usually within 6-24 hours.

Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Sympathomimetics in glaucoma therapy, ATC code = S01EA 05.

Brimonidine is an alpha-2 adrenergic receptor agonist that is 1000-fold more selective for the alpha-2 adrenoceptor than the alpha-1 adrenoreceptor.

This selectivity results in no mydriasis and the absence of vasoconstriction in microvessels associated with human retinal xenografts.

Topical administration of brimonidine tartrate decreases intraocular pressure (IOP) in humans with minimal effect on cardiovascular or pulmonary parameters.

Limited data are available for patients with bronchial asthma showing no adverse effects.

Alphagan has a rapid onset of action, with peak ocular hypotensive effect seen at two hours post-dosing. In two 1 year studies, Alphagan lowered IOP by mean values of approximately 4-6 mmHg.

Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of action. It is thought that Alphagan may lower IOP by reducing aqueous humour formation and enhancing uveoscleral outflow.

Clinical trials show that Alphagan is effective in combination with topical beta-blockers. Shorter term studies also suggest that Alphagan has a clinically relevant additive effect in combination with travoprost (6 weeks) and latanoprost (3 months).

5.2 Pharmacokinetic Properties

a) General characteristics

After ocular administration of a 0.2% solution twice daily for 10 days, plasma concentrations were low (mean Cmax was 0.06 ng/ml). There was a slight accumulation in the blood after multiple (2 times daily for 10 days) instillations. The area under the plasma concentration-time curve over 12 hours at steady state (AUC_0-12h) was 0.31 ng·hr/ml, as compared to 0.23 ng·hr/ml after the first dose. The mean apparent half-life in the systemic circulation was approximately 3 hours in humans after topical dosing.

The plasma protein binding of brimonidine after topical dosing in humans is approximately 29%.

Brimonidine binds reversibly to melanin in ocular tissues, in vitro and in vivo. Following 2 weeks of ocular instillation, the concentrations of brimonidine in iris, ciliary body and choroid-retina were 3- to 17-fold higher than those after a single dose. Accumulation does not occur in the absence of melanin.

The significance of melanin binding in humans is unclear. However, no significant ocular adverse reaction was found during biomicroscopic examination of eyes in patients treated with Alphagan for up to one year, nor was significant ocular toxicity found during a one year ocular safety study in monkeys given approximately four times the recommended dose of brimonidine tartrate.

Following oral administration to man, brimonidine is well absorbed and rapidly eliminated. The major part of the dose (around 75% of the dose) was excreted as metabolites in urine within five days; no unchanged drug was detected in urine. In vitro studies, using animal and human liver, indicate that the metabolism is mediated largely by aldehyde oxidase and cytochrome P450. Hence, the systemic elimination seems to be primarily hepatic metabolism.

Kinetics profile:

No great deviation from dose proportionality for plasma Cmax and AUC was observed following a single topical dose of 0.08%, 0.2% and 0.5%.

b) Characteristics in patients

Characteristics in elderly patients:

The C_max, AUC, and apparent half-life of brimonidine are similar in the elderly (subjects 65 years or older)after a single dose compared with young adults, indicating that its systemic absorption and elimination are not affected by age.

Based on data from a 3 month clinical study, which included elderly patients, systemic exposure to brimonidine was very low.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Benzalkonium Chloride

Poly(vinyl alcohol)

Sodium chloride

Sodium citrate

Citric acid monohydrate

Purified water

Hydrochloric acid (for pH-adjustment) or

Sodium hydroxide (for pH-adjustment)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Before first opening:	2 years for the 2.5 ml container.
	3 years for the 5 ml and 10 ml containers.
After first opening:	28 days.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

White low density polyethylene dropper bottles with a 35 microlitre tip. The cap is either a conventional polystyrene screw cap or a Compliance Cap (C-Cap).

2.5 ml, 5 ml and 10 ml bottles in packs of 1, 3 or 6.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Allergan Ltd

1^st Floor Marlow International

The Parkway

Marlow

Buckinghamshire SL7 1YL

UK

8. Marketing Authorisation Number(S)

PL 00426/0088

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 18 March 1997

Date of last renewal: 17 September 2006

10. Date Of Revision Of The Text

8^th February 2008

Grisactin Ultra

Generic Name: griseofulvin (GRIS ee oh FUL vin)

Brand Names: Fulvicin P/G, Fulvicin U/F, Grifulvin V, Gris-PEG

What is Grisactin Ultra (griseofulvin)?

Griseofulvin is an antifungal antibiotic that fights infections caused by fungus.

Griseofulvin is used to treat infections such as ringworm, athlete's foot, jock itch, and fungal infections of the scalp, fingernails, or toenails.

Griseofulvin may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Grisactin Ultra (griseofulvin)?

You should not use griseofulvin if you are allergic to it, or if you have liver failure, porphyria, or if you are pregnant.

Before you take griseofulvin, tell your doctor if you have liver disease, heart disease, lupus, or an allergy to penicillin.

Avoid exposure to sunlight or tanning beds. Griseofulvin can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors. Drinking alcohol can increase certain side effects of griseofulvin. Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Griseofulvin will not treat a viral infection such as the common cold or flu.

What should I discuss with my healthcare provider before taking Grisactin Ultra (griseofulvin)?

You should not use griseofulvin if you are allergic to it, or if you have:

• 
  

  liver failure;

  
  


• 
  

  porphyria (a genetic enzyme disorder that causes symptoms affecting the skin or nervous system); or

  
  


• 
  

  if you are pregnant.

  
  

To make sure you can safely take griseofulvin, tell your doctor if you have any of the following conditions:

• 
  

  liver disease;

  
  


• 
  

  heart disease;

  
  


• 
  

  lupus; or

  
  


• 
  

  an allergy to penicillin.

  
  

FDA pregnancy category C. It is not known whether griseofulvin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether griseofulvin passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Grisactin Ultra (griseofulvin)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Griseofulvin works best if you take it with foods that are high in fat. Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Griseofulvin will not treat a viral infection such as the common cold or flu. Shake the oral suspension (liquid) well just before you measure a dose. Measure the liquid with a special dose-measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one. If you use this medication long-term, your blood will need to be tested often. Visit your doctor regularly. Store at room temperature away from moisture, heat, and light.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking Grisactin Ultra (griseofulvin)?

Avoid exposure to sunlight or tanning beds. Griseofulvin can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors. Drinking alcohol can increase certain side effects of griseofulvin.

Grisactin Ultra (griseofulvin) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

• 
  

  fever, chills, flu symptoms;

  
  


• 
  

  white patches or sores inside your mouth or on your lips;

  
  


• 
  

  confusion, trouble with daily activities;

  
  


• 
  

  nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

  
  


• 
  

  severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling;

  
  

Less serious side effects may include:

• 
  

  flushing (warmth, redness, or tingly feeling);

  
  


• 
  

  nausea, vomiting, or diarrhea;

  
  


• 
  

  headache, dizziness, feeling tired;;

  
  


• 
  

  sleep problems (insomnia);

  
  


• 
  

  confusion;

  
  


• 
  

  numbness or tingling in your hands or feet; or

  
  


• menstrual irregularities.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Grisactin Ultra (griseofulvin)?

Tell your doctor about all other medicines you use, especially:

• 
  

  birth control pills;

  
  


• 
  

  a blood thinner such as warfarin (Coumadin, Jantoven);

  
  

This list is not complete and other drugs may interact with griseofulvin. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Grisactin Ultra resources

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

• Griseofulvin Prescribing Information (FDA)


• Griseofulvin Professional Patient Advice (Wolters Kluwer)


• Griseofulvin Monograph (AHFS DI)


• Fulvicin P/G Advanced Consumer (Micromedex) - Includes Dosage Information


• Grifulvin V Microsize MedFacts Consumer Leaflet (Wolters Kluwer)


• Gris-PEG Ultramicrosize Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Gris-PEG Prescribing Information (FDA)

Compare Grisactin Ultra with other medications

• Dermatophytosis
• Onychomycosis, Fingernail
• Onychomycosis, Toenail
• Tinea Barbae
• Tinea Capitis
• Tinea Corporis
• Tinea Cruris
• Tinea Pedis

Where can I get more information?

• Your pharmacist can provide more information about griseofulvin.

See also: Grisactin Ultra side effects (in more detail)

Zantryl

Generic Name: phentermine (FEN ter meen)

Brand Names: Adipex-P, Oby-Cap, T-Diet, Zantryl

What is Zantryl (phentermine)?

Phentermine is a stimulant that is similar to an amphetamine. Phentermine is an appetite suppressant that affects the central nervous system.

Phentermine is used together with diet and exercise to treat obesity (overweight) in people with risk factors such as high blood pressure, high cholesterol, or diabetes.

Phentermine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Zantryl (phentermine)?

Do not use phentermine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects. Taking phentermine together with other diet medications such as fenfluramine (Phen-Fen) or dexfenfluramine (Redux) can cause a rare fatal lung disorder called pulmonary hypertension. Do not take phentermine with any other diet medications without your doctor's advice. Phentermine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Drinking alcohol can increase certain side effects of phentermine.

Phentermine is only part of a complete program of treatment that may also include diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely.

Phentermine may be habit-forming and should be used only by the person it was prescribed for. Never share phentermine with another person, especially someone with a history of drug abuse or addiction. Keep track of the amount of medicine used from each new bottle. Phentermine is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription. Do not stop using phentermine suddenly, or you could have unpleasant withdrawal symptoms. Ask your doctor how to avoid withdrawal symptoms when you stop using phentermine.

What should I discuss with my healthcare provider before taking Zantryl (phentermine)?

Do not use phentermine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Taking phentermine together with other diet medications such as fenfluramine (Phen-Fen) or dexfenfluramine (Redux) can cause a rare fatal lung disorder called pulmonary hypertension. Do not take phentermine with any other diet medications without your doctor's advice.

You should not take phentermine if you are allergic to it, or if you have:

• 
  

  coronary artery disease (hardening of the arteries);

  
  


• 
  

  heart disease;

  
  


• 
  

  severe or uncontrolled high blood pressure;

  
  


• 
  

  overactive thyroid;

  
  


• 
  

  glaucoma;

  
  


• 
  

  if you have a history of drug or alcohol abuse; or

  
  


• 
  

  if you are allergic to other diet pills, amphetamines, stimulants, or cold medications.

  
  

To make sure you can safely take phentermine, tell your doctor if you have any of these other conditions:

• 
  

  high blood pressure;

  
  


• 
  

  diabetes; or

  
  


• 
  

  a thyroid disorder.

  
  

FDA pregnancy category C. It is not known whether phentermine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Phentermine can pass into breast milk and may harm a nursing baby. You should not breast-feed while taking phentermine. Do not give this medication to a child younger than 16 years old. Phentermine may be habit-forming and should be used only by the person it was prescribed for. Never share phentermine with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it.

How should I take Zantryl (phentermine)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

It is best to take phentermine on an empty stomach before breakfast or within 2 hours after breakfast.

To prevent sleep problems, take this medication early in the day, no later than 6:00 pm.

Talk with your doctor if you have increased hunger or if you otherwise think the medication is not working properly. Taking more of this medication will not make it more effective and can cause serious, life-threatening side effects.

Phentermine should be taken only for a short time, such as a few weeks.

Do not stop taking phentermine suddenly, or you could have unpleasant withdrawal symptoms. Ask your doctor how to avoid withdrawal symptoms when you stop using phentermine. Store at room temperature away from moisture and heat. Keep track of the amount of medicine used from each new bottle. Phentermine is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of phentermine can be fatal.

Overdose symptoms may include confusion, hallucinations, panic, feeling hostile or aggressive, nausea, vomiting, diarrhea, stomach cramps, irregular heartbeat, rapid breathing, overactive reflexes, confusion, hallucinations, seizure (convulsions), feeling light-headed, or fainting.

What should I avoid while taking Zantryl (phentermine)?

Drinking alcohol can increase certain side effects of phentermine. Phentermine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Zantryl (phentermine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

• 
  

  feeling short of breath, even with mild exertion;

  
  


• 
  

  chest pain, feeling like you might pass out;

  
  


• 
  

  swelling in your ankles or feet;

  
  


• 
  

  pounding heartbeats or fluttering in your chest;

  
  


• 
  

  confusion or irritability, unusual thoughts or behavior;

  
  


• 
  

  feelings of extreme happiness or sadness; or

  
  


• 
  

  dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, confusion, chest pain, shortness of breath, uneven heartbeats, seizure).

  
  

Less serious side effects may include:

• 
  

  feeling restless or hyperactive;

  
  


• 
  

  headache, dizziness, tremors;

  
  


• 
  

  sleep problems (insomnia);

  
  


• 
  

  dry mouth or an unpleasant taste in your mouth;

  
  


• 
  

  diarrhea or constipation, upset stomach; or

  
  


• 
  

  increased or decreased interest in sex, impotence.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Zantryl (phentermine)?

Tell your doctor about all other medicines you use, especially:

• 
  

  blood pressure medications;

  
  


• 
  

  insulin or oral diabetes medication; or

  
  


• 
  

  an antidepressant such as citalopram (Celexa), fluoxetine (Prozac, Sarafem, Symbyax), paroxetine (Paxil), sertraline (Zoloft), and others.

  
  

This list is not complete and other drugs may interact with phentermine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Zantryl resources

• Zantryl Side Effects (in more detail)
• Zantryl Use in Pregnancy & Breastfeeding
• Zantryl Drug Interactions
• Zantryl Support Group
• 1 Review for Zantryl - Add your own review/rating

• Phentermine Prescribing Information (FDA)


• Phentermine Monograph (AHFS DI)


• Adipex-P MedFacts Consumer Leaflet (Wolters Kluwer)


• Adipex-P Prescribing Information (FDA)


• Fastin Advanced Consumer (Micromedex) - Includes Dosage Information


• Ionamin MedFacts Consumer Leaflet (Wolters Kluwer)


• Ionamin Prescribing Information (FDA)

Compare Zantryl with other medications

• Obesity
• Weight Loss

Where can I get more information?

• Your pharmacist can provide more information about phentermine.

See also: Zantryl side effects (in more detail)

Arpicolin Procyclidine Hydrochloride Syrup 2.5mg / 5ml

1. Name Of The Medicinal Product

Arpicolin 2.5mg/5ml Oral Syrup

2. Qualitative And Quantitative Composition

Procyclidine Hydrochloride BP 2.5mg/5ml

3. Pharmaceutical Form

Syrup for oral administration

4. Clinical Particulars

4.1 Therapeutic Indications

Procyclidine is indicated in all forms of Parkinson's disease: idiopathic (paralysis agitans), postencephalitic and arteriosclerotic.

Symptoms often responding well to Procyclidine include: rigidity, akinesia, tremor, speech and writing difficulties, gait, sialorrhoea and drooling, sweating, oculogyric crises and depressed mood.

Procyclidine is also used to control troublesome extrapyramidal symptoms induced by neuroleptic drugs including pseudo-parkinsonism, acute dystonic reactions and akathisia.

4.2 Posology And Method Of Administration

For oral administration only.

Adults:

The variation in optimum dosage from one patient to another should be taken into consideration by the physician. Treatment is usually started at 2.5mg three times a day, increasing by 2.5 – 5mg daily at intervals of two to three days until the optimum clinical response is achieved. The usual maximum total daily dose is 30mg. However, at the discretion of the attending physician where appropriate this total may be as high as 60mg.

The daily dosage used in the control of neuroleptic-induced extrapyramidal symptoms is usually not more than 20mg daily. After a period of 3-4 months 'Arpicolin' should be stopped and the patient observed to see if the neuroleptic-induced extrapyramidal symptoms recur. Cessation of treatment periodically is to be recommended even in patients who appear to require the drug for longer periods.

Avoid abrupt discontinuation of treatment.

'Arpicolin' may be combined with levodopa or amantadine in patients who are inadequately controlled on a single agent.

Children:

Not recommended for use in children.

Use in the Elderly:

Elderly patients are more sensitive to anticholinergics, and a reduced dose may be required.

4.3 Contraindications

Procyclidine is contra-indicated in individuals with known hypersensitivity to any component of the preparation, untreated urinary retention, closed angle glaucoma and gastro-intestinal obstruction.

4.4 Special Warnings And Precautions For Use

As with all anticholinergics such as 'Arpicolin', cautious prescribing is indicated in patients pre-disposed to glaucoma or with existing angle-closure (narrow angle) glaucoma, obstructive disease of the gastro-intestinal tract and those with urinary symptoms associated with prostatic hypertrophy.

In a proportion of patients undergoing neuroleptic treatment, tardive dyskinesias will occur. While anticholinergic agents do not cause this syndrome, when given in combination with neuroleptics they may reduce the threshold at which the dyskinesias appear in patients pre-disposed to the abnormality. In such individuals, subsequent adjustment of neuroleptic therapy or reduction in anti-cholinergic treatment should be considered.

Patients with mental disorders occasionally experience a precipitation of a psychotic episode when procyclidine is administered for the treatment of the extrapyramidal side effects of neuroleptics.

Elderly patients especially those on high doses of anticholinergics may be more susceptible to the adverse events associated with such therapy (see Undesirable Effects). Specifically the elderly patient may be particularly vunerable to central nervous system disturbances such as confusion, impairment of cognitive function and memory, disorientation and hallucinations. These effects are usually reversible on reduction or discontinuation of anticholinergic therapy.

There is no specific information available concerning the use of procyclidine hydrochloride in patients with impairment of renal or hepatic function. However, since procyclidine is metabolised in the liver and excreted via the urine care should be exercised when administering procyclidine to patients with impairment of renal or hepatic function

Procyclidine should not be withdrawn abruptly as rebound parkinsonian symptoms may occur.

Abuse

Procyclidine, along with other anticholinergic drugs, has the potential to be abused. Although the cases of abuse are rare, physicians should exercise caution in prescribing Procyclidine to patients with symptoms that may not be genuine.

Excipient Warnings

This product also contains liquid maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Methyl and propyl hydroxybenzoates are contained in this product which may cause allergic reactions (possibly delayed).

The product contains a flavouring agent which contains ethanol, less than 100mg/5ml.

It is recommended that if high dosages are required that the 5mg/5ml product should be used.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Monoamine oxidase inhibitors or drugs with anticholinergic properties, such as amantadine, memantine, antihistamines, phenothiazines, and tricyclic antidepressants and related antidepressants, clozapine, disopyramide and nefopam, may increase the anticholinergic action of procyclidine.

The use of drugs with cholinergic properties, such as tacrine, may reduce the therapeutic response to procyclidine. Furthermore, drugs with anticholinergic properties may antagonise the effect of parasympathetic agents.

The concomitant use of procyclidine with some neuroleptics for the treatment of extrapyramidal symptoms has been associated with a reduction in neuroleptic plasma concentrations. However, this reduction is unlikely to be associated with a significant reduction in clinical effect.

Drugs with anticholinergic properties may decrease salivation causing dry mouth and, in theory, may reduce the absorption and therefore the therapeutic effect of sublingual or buccal nitrate tablets.

Anticholinergics, including procyclidine may reduce the efficacy of levodopa by increasing gastric emptying time, resulting in enhanced gastric degradation.

The effect of anticholinergics such as procyclidine may antagonise the gastrointestinal effects of domperidone and metoclopramide.

Procyclidine may potentiate the vagolytic effects of quinidine.

Anticholinergics may reduce the absorption of ketoconazole.

Exposure to high environmental temperature and humidity in association with a phenothiazine/anticholinergic drug regimen has rarely resulted in hyperpyrexia.

Daily administration of paroxetine increases significantly the plasma levels of procyclidine. If anticholinergic effects are seen, the dose of procyclidine should be reduced.

4.6 Pregnancy And Lactation

The safety of using 'Arpicolin' during pregnancy has not been established. However, extensive clinical use has not given any evidence that it in any way compromises the normal course of pregnancy. Nevertheless, as with all drugs, use should be considered only when the expected clinical benefit of treatment for the mother outweighs any possible risk to the developing foetus. No data are available on the excretion of this drug in breast milk.

4.7 Effects On Ability To Drive And Use Machines

Adverse events of a neurological character such as blurred vision, dizziness, confusion and disorientation have been reported with procyclidine. Therefore, if affected patients should be advised not to drive or operate machinery.

4.8 Undesirable Effects

The main side effects are those to be expected from any anticholinergic agent. Dry mouth, blurring of vision, urinary retention and constipation are most commonly recorded. Nausea, vomiting, gingivitis, nervousness and rash have been reported occasionally. The unwanted anticholinergic effects are easily reversed by reducing the dosage.

At higher doses, dizziness, mental confusion, impaired cognition and memory, disorientation, anxiety, agitation and hallucinations may occur.

Rarely the development of psychotic-like symptoms have been reported in association with procyclidine.

4.9 Overdose

Reports of overdosage are relatively rare. Symptoms of overdosage are agitation, restlessness and confusion with severe sleeplessness lasting up to 24 hours or more. Visual and occasionally auditory hallucinations are likely. Most subjects are euphoric but the occasional patient may be anxious and aggressive. The pupils are widely dilated and unreactive to light. In recorded cases, the disorientation has lasted 1 to 4 days and ended in recuperative sleep.

Tachycardia has also been reported in association with cases of procyclidine overdose.

If procyclidine has been ingested within the previous hour or two (or possibly longer in view of its likely effects on gastric motility) then gastric lavage is probably indicated. Other active measures such as the use of cholinergic agents or haemodialysis are extremely unlikely to be of clinical value, although if convulsions occur they should be controlled by injections of diazepam.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Procyclidine is a synthetic anticholinergic agent, which blocks the excitatory effects of acetyl choline at the muscarinic receptor.

Idiopathic Parkinson's disease is now thought to result from degeneration of neurones in the substantia nigra whose axons project and inhibit cells in the corpus striatum. Blockade by neuroleptic drugs of the dopamine released by these terminals produce a similar clinical picture. The cell bodies in the corpus striatum also receive cholinergic innervation which is excitatory. Relief of the Parkinsonian syndrome can be achieved either by potentiation of the dopaminergic system or blockade of the cholinergic input by anticholinergics. It is by a central action of this latter type that procyclidine exerts its effect.

5.2 Pharmacokinetic Properties

Procyclidine is adequately absorbed from the gastro-intestinal tract and disappears rapidly from the tissues. After both oral and IV dosing the mean values for volume of distribution, total body clearance and plasma elimination half-life of procyclidine were of the order of 1 litre/Kg, 68ml/min and 12 hours respectively.

5.3 Preclinical Safety Data

None known.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Citric acid monohydrate, sodium citrate, methyl hydroxybenzoate, propyl hydroxybenzoate, propylene glycol, liquid maltitol, grape flavour 545419E, blackcurrant flavour 512903E and purified water.

6.2 Incompatibilities

None known

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Store at or below 25°C

6.5 Nature And Contents Of Container

Bottles: Amber (Type III) glass

Closures:

a) Aluminium, EPE wadded, roll-on pilfer proof

b) HDPE, EPE wadded, tamper evident, child resistant.

c) HDPE, EPE wadded, tamper evident.

Capacity: 150ml, 200ml or 500ml

6.6 Special Precautions For Disposal And Other Handling

Keep out of the reach and sight of children

7. Marketing Authorisation Holder

Rosemont Pharmaceuticals Ltd, Rosemont House, Yorkdale Industrial Park, Braithwaite Street, Leeds, LS11 9XE, UK

8. Marketing Authorisation Number(S)

PL 0427/0082

9. Date Of First Authorisation/Renewal Of The Authorisation

4.10.91/1.11.96

10. Date Of Revision Of The Text

October 2006

Eporatio 30,000 IU

1. Name Of The Medicinal Product

Eporatio 30,000 IU/1 ml solution for injection in pre

2. Qualitative And Quantitative Composition

One pre-filled syringe contains 30,000 international units (IU) (250 µg) epoetin theta in 1 ml solution for injection corresponding to 30,000 IU (250 µg) epoetin theta per ml.

Epoetin theta (recombinant human erythropoietin) is produced in Chinese Hamster Ovary Cells (CHO

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection (injection) in pre

The solution is clear and colourless.

4. Clinical Particulars

4.1 Therapeutic Indications

- Treatment of symptomatic anaemia associated with chronic renal failure in adult patients.

- Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving chemotherapy.

4.2 Posology And Method Of Administration

Special requirements

Epoetin theta treatment should be initiated by physicians experienced in the above-mentioned indications.

Routes of administration

The solution can be administered subcutaneously (SC) or intravenously (IV). Subcutaneous use is preferable in patients who are not undergoing haemodialysis, in order to avoid puncturing peripheral veins. If epoetin theta is substituted for another epoetin, the same route of administration should be used. Epoetin theta should be administered by the subcutaneous route to cancer patients with non

Posology

Symptomatic anaemia associated with chronic renal failure

Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician's evaluation of the individual patient's clinical course and condition is necessary. Epoetin theta should be administered either subcutaneously or intravenously in order to increase haemoglobin level to not greater than 12 g/dl (7.45 mmol/l).

Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the haemoglobin target range of 10 g/dl (6.21 mmol/l) to 12 g/dl (7.45 mmol/l). A sustained haemoglobin level of greater than 12 g/dl (7.45 mmol/l) should be avoided; guidance for appropriate dose adjustment if haemoglobin values exceeding 12 g/dl (7.45 mmol/l) are observed are described below.

A rise in haemoglobin of greater than 2 g/dl (1.24 mmol/l) over a four week period should be avoided. If the rise in haemoglobin is greater than 2 g/dl (1.24 mmol/l) in 4 weeks or the haemoglobin value exceeds 12 g/dl (7.45 mmol/l), the dose should be reduced by 25 to 50%. It is recommended that haemoglobin be monitored every two weeks until levels have stabilised and periodically thereafter. If the haemoglobin level continues to increase, therapy should be interrupted until the haemoglobin level begins to decrease, at which point therapy should be restarted at a dose approximately 25% below the previously administered dose.

In the presence of hypertension or existing cardiovascular, cerebrovascular or peripheral vascular diseases, the increase in haemoglobin and the target haemoglobin value should be determined individually taking into account the clinical picture.

Treatment with epoetin theta is divided into two stages.

Correction phase

Subcutaneous administration: The initial posology is 20 IU/kg body weight 3 times per week. The dose may be increased after 4 weeks to 40 IU/kg, 3 times per week, if the increase in haemoglobin is not adequate (< 1 g/dl [0.62 mmol/l] within 4 weeks). Further increases of 25% of the previous dose may be made at monthly intervals until the individual target haemoglobin level is obtained.

Intravenous administration: The initial posology is 40 IU/kg body weight 3 times per week. The dose may be increased after 4 weeks to 80 IU/kg, 3 times per week, and by further increases of 25% of the previous dose at monthly intervals, if needed.

For both routes of administration, the maximum dose should not exceed 700 IU/kg body weight per week.

Maintenance phase

The dose should be adjusted as necessary to maintain the individual target haemoglobin level between 10 g/dl (6.21 mmol/l) to 12 g/dl (7.45 mmol/l), whereby a haemoglobin level of 12 g/dl (7.45 mmol/l) should not be exceeded. If a dose adjustment is required to maintain the desired haemoglobin level, it is recommended that the dose be adjusted by approximately 25%.

Subcutaneous administration: The weekly dose can be given as one injection per week or three times per week.

Intravenous administration: Patients who are stable on a three times weekly dosing regimen may be switched to twice-weekly administration.

If the frequency of administration is changed, haemoglobin level should be monitored closely and dose adjustments may be necessary.

The maximum dose should not exceed 700 IU/kg body weight per week.

If epoetin theta is substituted for another epoetin, haemoglobin level should be monitored closely and the same route of administration should be used.

Patients should be monitored closely to ensure that the lowest approved dose of epoetin theta is used to provide adequate control of the symptoms of anaemia.

Symptomatic anaemia in cancer patients with non-myeloid malignancies receiving chemotherapy

Epoetin theta should be administered by the subcutaneous route to patients with anaemia (e.g. haemoglobin concentration

Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the haemoglobin target range of 10 g/dl (6.21 mmol/l) to 12 g/dl (7.45 mmol/l). A sustained haemoglobin level of greater than 12 g/dl (7.45 mmol/l) should be avoided; guidance for appropriate dose adjustment if haemoglobin values exceeding 12 g/dl (7.45 mmol/l) are observed are described below.

The recommended initial dose is 20,000 IU, independent of bodyweight, given once-weekly. If, after 4 weeks of therapy, the haemoglobin value has increased by at least 1 g/dl (0.62 mmol/l), the current dose should be continued. If the haemoglobin value has not increased by at least 1 g/dl (0.62 mmol/l) a doubling of the weekly dose to 40,000 IU should be considered. If, after an additional 4 weeks of therapy, the haemoglobin increase is still insufficient an increase of the weekly dose to 60,000 IU should be considered.

The maximum dose should not exceed 60,000 IU per week.

If, after 12 weeks of therapy, the haemoglobin value has not increased by at least 1 g/dl (0.62 mmol/l), response is unlikely and treatment should be discontinued.

If the rise in haemoglobin is greater than 2 g/dl (1.24 mmol/l) in 4 weeks or the haemoglobin level exceeds 12 g/dl (7.45 mmol/l), the dose should be reduced by 25 to 50%. Treatment with epoetin theta should be temporarily discontinued if haemoglobin levels exceed 13 g/dl (8.07 mmol/l). Therapy should be reinitiated at approximately 25% lower than the previous dose after haemoglobin levels fall to 12 g/dl (7.45 mmol/l) or below.

Therapy should be continued up to 4 weeks after the end of chemotherapy.

Patients should be monitored closely to ensure that the lowest approved dose of epoetin theta is used to provide adequate control of the symptoms of anaemia.

Special populations

Paediatric patients

There is no experience in children and adolescents.

Method of administration

The solution can be administered subcutaneously or intravenously. Subcutaneous use is preferable in patients who are not undergoing haemodialysis, in order to avoid puncturing peripheral veins. If epoetin theta is substituted for another epoetin, the same route of administration should be used. In cancer patients with non

Subcutaneous injections should be given into the abdomen, arm or thigh.

Eporatio is supplied in a single use pre-filled syringe. The solution should be visually inspected prior to use. Only clear, colourless solutions without particles should be used. The solution for injection should not be shaken. It should be allowed to reach a comfortable temperature (15 °C

Eporatio must not be mixed with other medicinal products (see section 6.2).

The injection sites should be rotated and the injection performed slowly to avoid discomfort at the site of injection.

4.3 Contraindications

- Hypersensitivity to the active substance, other epoetins and derivatives or to any of the excipients.

- Uncontrolled hypertension.

4.4 Special Warnings And Precautions For Use

General

Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l or with transferrin saturation below 20%. To ensure effective erythropoiesis, iron status has to be evaluated for all patients prior to and during treatment.

Non-response to therapy with epoetin theta should prompt a search for causative factors. Deficiencies of iron, folic acid or vitamin B₁₂ reduce the effectiveness of epoetins and should therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, haemolysis, aluminium intoxication, underlying haematological diseases or bone marrow fibrosis may also compromise the erythropoietic response. A reticulocyte count should be considered as part of the evaluation.

Pure red cell aplasia (PRCA)

If typical causes of non-response are excluded, and the patient has a sudden drop in haemoglobin associated with reticulocytopenia, an examination of anti-erythropoietin antibodies and the bone marrow for diagnosis of pure red cell aplasia should be considered. Discontinuation of treatment with epoetin theta should be taken into account.

PRCA caused by neutralising anti-erythropoietin antibodies has been reported in association with erythropoietin therapy. These antibodies have been shown to cross-react with all epoetins, and patients suspected or confirmed to have neutralising antibodies to erythropoietin should not be switched to epoetin theta (see section 4.8).

Hypertension

Patients on epoetin theta therapy can experience an increase in blood pressure or aggravation of existing hypertension particularly during the initial treatment phase.

Therefore, in patients treated with epoetin theta, special care should be taken to monitor closely and control blood pressure. Blood pressure should be controlled adequately before initiation and during therapy to avoid acute complications, such as hypertensive crisis with encephalopathy-like symptoms (e.g. headaches, confused state, speech disturbances, impaired gait) and related complications (seizures, stroke), which may also occur in individual patients with otherwise normal or low blood pressure. If these reactions occur, they require the immediate attention of a physician and intensive medical care. Particular attention should be paid to sudden sharp migraine-like headaches as a possible warning signal.

Increases in blood pressure may require treatment with antihypertensive medicinal products or a dose increase of existing antihypertensive medicinal products. In addition, a reduction of the administered dose of epoetin theta needs to be considered. If blood pressure values remain high, temporary interruption of epoetin theta therapy may be required. Once hypertension has been controlled with more intensified therapy, epoetin theta therapy should be re-started at a reduced dose.

Misuse

Misuse of epoetin theta by healthy persons may lead to an excessive increase in haemoglobin and haematocrit. This may be associated with life-threatening cardiovascular complications.

Special populations

Due to limited experience, the efficacy and safety of epoetin theta could not be assessed in patients with impaired liver function or homozygous sickle cell anaemia.

In clinical trials, patients over 75 years of age had a higher incidence of serious and severe adverse events irrespective of a causal relationship to treatment with epoetin theta. Furthermore, deaths were more frequent in this patient group compared to younger patients.

Laboratory monitoring

It is recommended that haemoglobin measurement, a complete blood count and platelet count be performed regularly.

Symptomatic anaemia associated with chronic renal failure

The use of epoetin theta in nephrosclerotic patients not yet undergoing dialysis should be defined individually, as a possible accelerated progression of renal failure cannot be ruled out with certainty.

During haemodialysis, patients treated with epoetin theta may require increased anticoagulation treatment to prevent clotting of the arterio-venous shunt.

In patients with chronic renal failure, the maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical trials, an increased risk of death and serious cardiovascular events was observed when epoetins were administered to target a haemoglobin level in excess of 12 g/dl (7.45 mmol/l). Controlled clinical trials have not shown significant benefits attributable to the administration of epoetins when the haemoglobin concentration is increased beyond the level necessary to control symptoms of anaemia and to avoid blood transfusion.

Symptomatic anaemia in cancer patients with non-myeloid malignancies receiving chemotherapy

Effect on tumour growth

Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that epoetins could stimulate the growth of any type of malignancy (see section 5.1).

In several controlled studies, epoetins have not been shown to improve overall survival or decrease the risk of tumour progression in patients with anaemia associated with cancer. In controlled clinical studies, use of epoetins has shown:

	- shortened time to tumour progression in patients with advanced head and neck cancer receiving radiation therapy when administered to target a haemoglobin level in excess of 14 g/dl (8.69 mmol/l),
	- shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a haemoglobin value of 12
	- increased risk of death when administered to target a haemoglobin value of 12 g/dl (7.45 mmol/l) in patients with active malignant disease receiving neither chemotherapy nor radiation therapy.

Epoetins are not indicated for use in this patient population.

In view of the above, in some clinical situations blood transfusion should be the preferred treatment for the management of anaemia in patients with cancer. The decision to administer recombinant erythropoietins should be based on a benefit-risk assessment with the participation of the individual patient, which should take into account the specific clinical context. Factors that should be considered in this assessment should include the type of tumour and its stage, the degree of anaemia, life

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, i.e. essentially 'sodium-free'.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

4.6 Pregnancy And Lactation

For epoetin theta no clinical data on exposed pregnancies are available. Animal studies with other epoetins do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.

It is unknown whether epoetin theta is excreted in human breast milk, but data in neonates show no absorption or pharmacological activity of erythropoietin when given together with breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with epoetin theta should be made taking into account the benefit of breast-feeding to the child and the benefit of epoetin theta therapy for the woman.

4.7 Effects On Ability To Drive And Use Machines

Epoetin theta has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

The safety of epoetin theta has been evaluated based on results from clinical studies including 972 patients.

Approximately 9% of patients can be expected to experience an adverse reaction. The most frequent undesirable effects are hypertension, influenza-like illness and headache.

Adverse reactions listed below are classified according to System Organ Class. Frequency groupings are defined according to the following convention:

Very common:
Common:
Uncommon:
Rare:
Very rare:	< 1/10,000;
Not known:	cannot be estimated from the available data.

System organ class	Adverse reaction	Frequency
Symptomatic anaemia associated with chronic renal failure	Symptomatic anaemia in cancer patients with non-myeloid malignancies receiving chemotherapy
Blood and lymphatic system disorders	Thromboembolic events	—	Not known
Shunt thrombosis	Common	—
Immune system disorders	Hypersensitivity reactions	Not known
Nervous system disorders	Headache	Common
Vascular disorders	Hypertension	Common
Hypertensive crisis	Common	—
Skin and subcutaneous tissue disorders	Skin reactions	Common
Musculoskeletal and connective tissue disorders	Arthralgia	—	Common
General disorders and administration site conditions	Influenza-like illness	Common

Shunt thrombosis may occur, especially in patients who have a tendency to hypotension or whose arterio-venous fistulae exhibit complications (e.g. stenoses, aneurisms) (see section 4.4).

One of the most frequent adverse reactions during treatment with epoetin theta is an increase in blood pressure or aggravation of existing hypertension particularly during the initial treatment phase. Hypertension occurs in chronic renal failure patients more often during the correction phase than during the maintenance phase. Hypertension can be treated with appropriate medicinal products (see section 4.4).

Hypertensive crisis with encephalopathy-like symptoms (e.g. headaches, confused state, speech disturbances, impaired gait) and related complications (seizures, stroke) may also occur in individual patients with otherwise normal or low blood pressure (see section 4.4).

Skin reactions such as rash, pruritus or injection site reactions may occur.

Symptoms of influenza-like illness such as fever, chills and asthenic conditions have been reported.

Certain adverse reactions have not yet been observed with epoetin theta, but are generally accepted as being attributable to epoetins:

In isolated cases in patients with chronic renal failure, neutralising anti-erythropoietin antibody-mediated PRCA associated with therapy with other epoetins has been reported. If PRCA is diagnosed, therapy with epoetin theta must be discontinued and patients should not be switched to another recombinant epoetin (see section 4.4).

4.9 Overdose

The therapeutic margin of epoetin theta is very wide. In the case of overdose, polycythaemia can occur. In the event of polycythaemia, epoetin theta should be temporarily withheld.

If severe polycythaemia occurs, conventional methods (phlebotomy) may be indicated to reduce the haemoglobin level.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other anti-anaemic preparations, ATC code: B03XA01

Mechanism of action

Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor cells in the bone marrow. It acts as a mitosis-stimulating factor and differentiation hormone. The production of erythropoietin primarily occurs in and is regulated by the kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is impaired in patients with chronic renal failure and the primary cause of their anaemia is erythropoietin deficiency. In patients with cancer receiving chemotherapy the aetiology of anaemia is multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid progenitor cells to endogenous erythropoietin both contribute significantly towards their anaemia.

Epoetin theta is identical in its amino acid sequence and similar in its carbohydrate composition (glycosylation) to endogenous human erythropoietin.

Preclinical efficacy

The biological efficacy of epoetin theta has been demonstrated after intravenous and subcutaneous administration in various animal models in vivo (mice, rats, dogs). After administration of epoetin theta, the number of erythrocytes, the haematocrit values and reticulocyte counts increase.

Clinical efficacy and safety

Symptomatic anaemia associated chronic renal failure

Data from correction phase studies in 284 chronic renal failure patients show that the haemoglobin response rates (defined as haemoglobin levels above 11 g/dl at two consecutive measurements) in the epoetin theta group (88.4% and 89.4% in studies in patients on dialysis and not yet undergoing dialysis, respectively) were comparable to epoetin beta (86.2% and 81.0%, respectively). The median time to response was similar in the treatment groups with 56 days in haemodialysis patients and 49 days in patients not yet undergoing dialysis.

Two randomised controlled studies were conducted in 270 haemodialysis patients and 288 patients not yet undergoing dialysis, who were on stable treatment with epoetin beta. Patients were randomised to continue their current treatment or to be converted to epoetin theta (same dose as epoetin beta) in order to maintain their haemoglobin levels. During the evaluation period (weeks 15 to 26), the mean and median level of haemoglobin in patients treated with epoetin theta was virtually identical to their baseline haemoglobin level. In these two studies, 180 haemodialysis patients and 193 patients not undergoing dialysis were switched from maintenance phase treatment with epoetin beta to treatment with epoetin theta for a period of six months showing stable haemoglobin values and a similar safety profile as epoetin beta. In the clinical studies, patients not yet undergoing dialysis (subcutaneous administration) discontinued the study more frequently than haemodialysis patients (intravenous administration) as they had to terminate the study when starting dialysis.

In two long-term studies, the efficacy of epoetin theta was evaluated in 124 haemodialysis patients and 289 patients not yet undergoing dialysis. The haemoglobin levels remained within the desired target range and epoetin theta was well tolerated over a period of up to 15 months.

In the clinical studies, pre-dialysis patients were treated once-weekly with epoetin theta, 174 patients in the maintenance phase study and 111 patients in the long-term study.

Symptomatic anaemia in cancer patients with non-myeloid malignancies receiving chemotherapy

409 cancer patients receiving chemotherapy were included in two prospective, randomised double

Effect on tumour growth

Erythropoietin is a growth factor that primarily stimulates red cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells.

Survival and tumour progression have been examined in five large controlled studies involving a total of 2,833 patients, of which four were double-blind placebo-controlled studies and one was an open-label study. Two of the studies recruited patients who were being treated with chemotherapy. The target haemoglobin concentration in two studies was> 13 g/dl; in the remaining three studies it was 12

Data from three placebo-controlled clinical studies in 586 anaemic cancer patients conducted with epoetin theta, showed no negative effect of epoetin theta on survival. During the studies, mortality was lower in the epoetin theta group (6.9%) compared to placebo (10.3%).

A systematic review has also been performed involving more than 9,000 cancer patients participating in 57 clinical trials. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.08 in favour of controls (95% CI: 0.99, 1.18; 42 trials and 8,167 patients). An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and 6,769 patients) was observed in patients treated with recombinant human erythropoietin. There is therefore consistent evidence to suggest that there may be significant harm to patients with cancer who are treated with recombinant human erythropoietin. The extent to which these outcomes might apply to the administration of recombinant human erythropoietin to patients with cancer, treated with chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients with these characteristics were included in the data reviewed.

5.2 Pharmacokinetic Properties

General

The pharmacokinetics of epoetin theta have been examined in healthy volunteers, in patients with chronic renal failure and in cancer patients receiving chemotherapy. The pharmacokinetics of epoetin theta are independent of age or gender.

Subcutaneous administration

Following subcutaneous injection of 40 IU/kg body weight epoetin theta at three different sites (upper arm, abdomen, thigh) in healthy volunteers, similar plasma level profiles were observed. The extent of absorption (AUC) was slightly greater after injection in the abdomen in comparison to the other sites. The maximum concentration is reached after an average of 10 to 14 hours and the average terminal half-life ranges from approximately 22 to 41 hours.

Average bioavailability of epoetin theta after subcutaneous administration is approximately 31% compared with intravenous administration.

In pre-dialysis patients with chronic renal failure following subcutaneous injection of 40 IU/kg body weight, the protracted absorption results in a concentration plateau, whereby the maximum concentration is reached after an average of approximately 14 hours. The terminal half-life is higher than after intravenous administration, with an average of 25 hours after single dosing and 34 hours in steady state after repeated dosing three times weekly, without leading to an accumulation of epoetin theta.

In cancer patients receiving chemotherapy, after repeated subcutaneous administration of 20,000 IU epoetin theta once-weekly, the terminal half-life is 29 hours after the first dose and 28 hours in steady state. No accumulation of epoetin theta was observed.

Intravenous administration

In patients with chronic renal failure undergoing haemodialysis, the elimination half-life of epoetin theta is 6 hours after single dosing and 4 hours in steady state after repeated intravenous administration of 40 IU/kg body weight epoetin theta three times weekly. No accumulation of epoetin theta was observed. Following intravenous administration, the volume of distribution approximates to total blood volume.

5.3 Preclinical Safety Data

Non-clinical data with epoetin theta reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated-dose toxicity.

Non-clinical data with other epoetins reveal no special hazard for humans based on conventional studies of genotoxicity and toxicity to reproduction.

In reproductive toxicity studies performed with other epoetins, effects interpreted as being secondary to decreased maternal body weight were observed at doses sufficiently in excess to the recommended human dose.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium dihydrogen phosphate dihydrate

Sodium chloride

Polysorbate 20

Trometamol

Hydrochloric acid (6 M) (for pH adjustment)

Water for injections

6.2 Incompatibilities

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

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Store in a refrigerator (2 °C – 8 °C).

Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

For the purpose of ambulatory use, the patient may remove the product from the refrigerator and store it at a temperature not above 25 °C for a single period of up to 7 days without exceeding the expiry date. Once removed from the refrigerator, the medicinal product must be used within this period or disposed of.

6.5 Nature And Contents Of Container

1 ml of solution in a pre-filled syringe (type I glass) with a tip cap (bromobutyl rubber), a plunger stopper (teflonised chlorobutyl rubber), an injection needle (stainless steel) and with or without a pre

Pack sizes of 1, 4 and 6 pre-filled syringes with or without safety device.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The pre

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

7. Marketing Authorisation Holder

ratiopharm GmbH

Graf-Arco-Straße 3

89079 Ulm

Germany

info@ratiopharm.de

8. Marketing Authorisation Number(S)

EMEA/H/C/0010350000/25

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 29 October 2009

10. Date Of Revision Of The Text

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