GONAL-f 300IU (22 mcg) pen

1. Name Of The Medicinal Product

GONAL-f 300 IU/0.5 ml (22 micrograms/0.5 ml) solution for injection in pre-filled pen.

2. Qualitative And Quantitative Composition

Each ml of the solution contains 600 IU of follitropin alfa*, (equivalent to 44 micrograms).

Each pre-filled multidose pen delivers 300 IU (equivalent to 22 micrograms) in 0.5 ml.

* recombinant human follicle stimulating hormone (r-hFSH) produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection in a pre-filled pen.

Clear colourless solution.

The pH of the solution is 6.7-7.3.

4. Clinical Particulars

4.1 Therapeutic Indications

In adult women

• Anovulation (including polycystic ovarian syndrome) in women who have been unresponsive to treatment with clomiphene citrate.

• Stimulation of multifollicular development in women undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilisation (IVF), gamete intra-fallopian transfer and zygote intra-fallopian transfer.

• GONAL-f in association with a luteinising hormone (LH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level < 1.2 IU/l.

In adult men

• GONAL-f is indicated for the stimulation of spermatogenesis in men who have congenital or acquired hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotropin (hCG) therapy.

4.2 Posology And Method Of Administration

Treatment with GONAL-f should be initiated under the supervision of a physician experienced in the treatment of fertility disorders.

Posology

The dose recommendations given for GONAL-f are those in use for urinary FSH. Clinical assessment of GONAL-f indicates that its daily doses, regimens of administration, and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing medicinal products. It is advised to adhere to the recommended starting doses indicated below.

Comparative clinical studies have shown that on average patients require a lower cumulative dose and shorter treatment duration with GONAL-f compared with urinary FSH. Therefore, it is considered appropriate to give a lower total dose of GONAL-f than generally used for urinary FSH, not only in order to optimise follicular development but also to minimise the risk of unwanted ovarian hyperstimulation. See section 5.1.

Bioequivalence has been demonstrated between equivalent doses of the monodose presentation and the multidose presentation of GONAL-f.

Women with anovulation (including polycystic ovarian syndrome)

GONAL-f may be given as a course of daily injections. In menstruating women treatment should commence within the first 7 days of the menstrual cycle.

A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14 day intervals if necessary, to obtain an adequate, but not excessive, response. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and/or oestrogen secretion. The maximal daily dose is usually not higher than 225 IU FSH. If a patient fails to respond adequately after 4 weeks of treatment, that cycle should be abandoned and the patient should undergo further evaluation after which she may recommence treatment at a higher starting dose than in the abandoned cycle.

When an optimal response is obtained, a single injection of 250 micrograms recombinant human choriogonadotropin alfa (r-hCG) or 5,000 IU, up to 10,000 IU hCG should be administered 24-48 hours after the last GONAL-f injection. The patient is recommended to have coitus on the day of, and the day following, hCG administration. Alternatively intrauterine insemination (IUI) may be performed.

If an excessive response is obtained, treatment should be stopped and hCG withheld (see section 4.4). Treatment should recommence in the next cycle at a dose lower than that of the previous cycle.

Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other assisted reproductive technologies.

A commonly used regimen for superovulation involves the administration of 150-225 IU of GONAL-f daily, commencing on days 2 or 3 of the cycle. Treatment is continued until adequate follicular development has been achieved (as assessed by monitoring of serum oestrogen concentrations and/or ultrasound examination), with the dose adjusted according to the patient's response, to usually not higher than 450 IU daily. In general adequate follicular development is achieved on average by the tenth day of treatment (range 5 to 20 days).

A single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG is administered 24-48 hours after the last GONAL-f injection to induce final follicular maturation.

Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is now commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. In a commonly used protocol, GONAL-f is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. For example, following two weeks of treatment with an agonist, 150-225 IU GONAL-f are administered for the first 7 days. The dose is then adjusted according to the ovarian response.

Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter.

Women with anovulation resulting from severe LH and FSH deficiency.

In LH and FSH deficient women (hypogonadotrophic hypogonadism), the objective of GONAL-f therapy in association with lutropin alfa is to develop a single mature Graafian follicle from which the oocyte will be liberated after the administration of human chorionic gonadotropin (hCG). GONAL-f should be given as a course of daily injections simultaneously with lutropin alfa. Since these patients are amenorrhoeic and have low endogenous oestrogen secretion, treatment can commence at any time.

A recommended regimen commences at 75 IU of lutropin alfa daily with 75-150 IU FSH. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and oestrogen response.

If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5-75 IU increments. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks.

When an optimal response is obtained, a single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last GONAL-f and lutropin alfa injections. The patient is recommended to have coitus on the day of, and on the day following, hCG administration.

Alternatively, IUI may be performed.

Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum.

If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle.

Men with hypogonadotrophic hypogonadism

GONAL-f should be given at a dose of 150 IU three times a week, concomitantly with hCG, for a minimum of 4 months. If after this period, the patient has not responded, the combination treatment may be continued; current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis.

Special population

Elderly population

There is no relevant use of GONAL-f in the elderly population. Safety and effectiveness of GONAL-f in elderly patients have not been established.

Renal or hepatic impairment

Safety, efficacy and pharmacokinetics of GONAL-f in patients with renal or hepatic impairment have not been established.

Paediatric population

There is no relevant use of GONAL-f in the paediatric population.

Method of administration

GONAL-f is intended for subcutaneous administration. The first injection of GONAL--f should be performed under direct medical supervision.. Self-administration of GONAL-f should only be performed by patients who are well motivated, adequately trained and have access to expert advice.

As GONAL-f pre-filled pen with multidose cartridge is intended for several injections, clear instructions should be provided to the patients to avoid misuse of the multidose presentation.

For instructions on the administration with the pre-filled pen, see section 6.6 and the package leaflet.

4.3 Contraindications

• hypersensitivity to the active substance follitropin alfa, FSH or to any of the excipients

• tumours of the hypothalamus or pituitary gland

• ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome

• gynaecological haemorrhages of unknown aetiology

• ovarian, uterine or mammary carcinoma

GONAL-f must not be used when an effective response cannot be obtained, such as:

• primary ovarian failure

• malformations of sexual organs incompatible with pregnancy

• fibroid tumours of the uterus incompatible with pregnancy

• primary testicular insufficiency

4.4 Special Warnings And Precautions For Use

GONAL-f is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management.

Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of GONAL-f calls for monitoring of ovarian response with ultrasound, alone or preferably in combination with measurement of serum oestradiol levels, on a regular basis. There may be a degree of interpatient variability in response to FSH administration, with a poor response to FSH in some patients and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used in both men and women.

Porphyria

Patients with porphyria or a family history of porphyria should be closely monitored during treatment with GONAL-f. Deterioration or a first appearance of this condition may require cessation of treatment.

Treatment in women

Before starting treatment, the couple's infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia and appropriate specific treatment given.

Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to recommended GONAL-f dose and regimen of administration, and careful monitoring of therapy will minimise the incidence of such events. For accurate interpretation of the indices of follicle development and maturation, the physician should be experienced in the interpretation of the relevant tests.

In clinical trials, an increase of the ovarian sensitivity to GONAL-f was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with 37.5-75 IU increments.

No direct comparison of GONAL-f/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with GONAL-f/LH is similar to that obtained with hMG.

Ovarian Hyperstimulation Syndrome (OHSS)

A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women with polycystic ovarian syndrome and usually regresses without treatment.

In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities.

The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemic stroke or myocardial infarction.

Independent risk factors for developing OHSS include polycystic ovarian syndrome high absolute or rapidly rising serum oestradiol levels (e.g.> 900 pg/ml or> 3,300 pmol/l in anovulation;> 3,000 pg/ml or> 11,000 pmol/l in ART) and large number of developing ovarian follicles (e.g.> 3 follicles of

Adherence to recommended GONAL-f dose and regimen of administration can minimise the risk of ovarian hyperstimulation (see sections 4.2 and 4.8). Monitoring of stimulation cycles by ultrasound scans as well as oestradiol measurements are recommended to early identify risk factors.

There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur such as serum oestradiol level> 5,500 pg/ml or> 20,200 pmol/l and/or

In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation.

Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy be started.

Multiple pregnancy

In patients undergoing ovulation induction, the incidence of multiple pregnancy is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially of high order, carries an increased risk of adverse maternal and perinatal outcomes.

To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.

In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age.

The patients should be advised of the potential risk of multiple births before starting treatment.

Pregnancy loss

The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction or ART than following natural conception.

Ectopic pregnancy

Women with a history of tubal disease are at risk of ectopic pregnancy, whether the pregnancy is obtained by spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancy after ART, was reported to be higher than in the general population.

Reproductive system neoplasms

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women.

Congenital malformation

The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies.

Thromboembolic events

In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thrombo-embolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however that pregnancy itself as well as OHSS also carry an increased risk of thrombo-embolic events.

Treatment in men

Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to GONAL-f/hCG therapy. GONAL-f should not be used when an effective response cannot be obtained.

Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response.

Sodium content

GONAL-f contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of GONAL-f with other medicinal products used to stimulate ovulation (e.g. hCG, clomiphene citrate) may potentiate the follicular response, whereas concurrent use of a GnRH agonist or antagonist to induce pituitary desensitisation may increase the dose of GONAL-f needed to elicit an adequate ovarian response. No other clinically significant medicinal product interaction has been reported during GONAL-f therapy.

4.6 Pregnancy And Lactation

Pregnancy

There is no indication for use of GONAL-f during pregnancy. Data on a limited number of exposed pregnancies (less than 300 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of follitropin alfa.

No teratogenic effect has been observed in animal studies (see section 5.3).

In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of GONAL-f.

Breastfeeding

GONAL-f is not indicated during breastfeeding.

Fertility

GONAL-f is indicated for use in infertility (see section 4.1).

4.7 Effects On Ability To Drive And Use Machines

GONAL-f is expected to have no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

The most commonly reported adverse reactions are headache, ovarian cysts and local injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection).

Mild or moderate ovarian hyperstimulation syndrome (OHSS) have been commonly reported and should be considered as an intrinsic risk of the stimulation procedure. Severe OHSS is uncommon (see section 4.4).

Thromboembolism may occur very rarely, usually associated with severe OHSS (see section 4.4).

The following definitions apply to the frequency terminology used hereafter:

Very common (

Common (

Uncommon (

Rare (

Very rare (< 1/10,000)

Treatment in women

Immune system disorders
Very rare:	Mild to severe hypersensitivity reactions including anaphylactic reactions and shock
Nervous system disorders
Very common:	Headache
Vascular disorders
Very rare:	Thromboembolism, usually associated with severe OHSS (see section 4.4)
Respiratory, thoracic and mediastinal disorders
Very rare:	Exacerbation or aggravation of asthma
Gastrointestinal disorders
Common:	Abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhoea
Reproductive system and breast disorders
Very common:	Ovarian cysts
Common:	Mild or moderate OHSS (including associated symptomatology)
Uncommon:	Severe OHSS (including associated symptomatology) (see section 4.4)
Rare:	Complication of severe OHSS
General disorders and administration site conditions
Very common:	Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection)

Treatment in men

Immune system disorders
Very rare:	Mild to severe hypersensitivity reactions including anaphylactic reactions and shock
Respiratory, thoracic and mediastinal disorders
Very rare:	Exacerbation or aggravation of asthma
Skin and subcutaneous tissue disorders
Common:	Acne
Reproductive system and breast disorders
Common:	Gynaecomastia, Varicocele
General disorders and administration site conditions
Very common:	Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection)
Investigations
Common:	Weight gain

4.9 Overdose

The effects of an overdose of GONAL-f are unknown, nevertheless, there is a possibility that OHSS may occur (see section 4.4).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05.

In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the object of GONAL-f therapy is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG.

Clinical efficacy and safety in women

In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/l as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories.

In clinical studies comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table below) and in ovulation induction, GONAL-f was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.

In ART, GONAL-f at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH.

Table: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of GONAL-f with urinary FSH in assisted reproduction technologies)

	GONAL-f (n = 130)	urinary FSH (n = 116)
Number of oocytes retrieved	11.0 ± 5.9	8.8 ± 4.8
Days of FSH stimulation required	11.7 ± 1.9	14.5 ± 3.3
Total dose of FSH required (number of FSH 75 IU ampoules)	27.6 ± 10.2	40.7 ± 13.6
Need to increase the dose (%)	56.2	85.3

Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed.

Clinical efficacy and safety in men

In men deficient in FSH, GONAL-f administered concomitantly with hCG for at least 4 months induces spermatogenesis.

5.2 Pharmacokinetic Properties

Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 l and 0.6 l/h, respectively. One-eighth of the follitropin alfa dose is excreted in the urine.

Following subcutaneous administration, the absolute bioavailability is about 70 %. Following repeated administration, follitropin alfa accumulates 3-fold achieving a steady-state within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity additional to that already stated in other sections of this SmPC.

Impaired fertility has been reported in rats exposed to pharmacological doses of follitropin alfa (

Given in high doses (

6. Pharmaceutical Particulars

6.1 List Of Excipients

Poloxamer 188

Sucrose

Methionine

Sodium dihydrogen phosphate monohydrate

Disodium phosphate dihydrate

m-Cresol

Phosphoric acid, concentrated

Sodium hydroxide

Water for injections

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

Once opened, the medicinal product may be stored for a maximum of 28 days at or below 25°C. The patient should write on the GONAL-f pre-filled pen the day of the first use.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C-8°C). Do not freeze.

Before opening and within its shelf life, the medicinal product may be removed from the refrigerator, without being refrigerated again, for up to 3 months at or below 25°C. The product must be discarded if it has not been used after 3 months.

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

For in-use storage conditions, see section 6.3.

6.5 Nature And Contents Of Container

0.5 ml of solution for injection in 3 ml cartridge (Type I glass), with a plunger stopper (halobutyl rubber) and an aluminium crimp cap with a black rubber inlay.

Pack of one pre-filled pen and 5 needles to be used with the pen for administration.

6.6 Special Precautions For Disposal And Other Handling

See section “How to use the GONAL-f pre-filled pen" in the package leaflet.

The solution should not be administered if it contains particles or is not clear.

Any unused solution must be discarded not later than 28 days after first opening.

GONAL-f 300 IU/0.5 ml (22 micrograms/0.5 ml) is not designed to allow the cartridge to be removed.

Discard used needles immediately after injection.

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

7. Marketing Authorisation Holder

Merck Serono Europe Ltd.

56 Marsh Wall

London E14 9TP

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/95/001/033

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 20 October 1995.

Date of last renewal: 20 October 2010.

10. Date Of Revision Of The Text

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

Ventavis

1. Name Of The Medicinal Product

Ventavis 10 microgram/ml nebuliser solution

2. Qualitative And Quantitative Composition

1 ml solution contains 10 micrograms iloprost (as iloprost trometamol).

Each ampoule with 1 ml solution contains 10 micrograms iloprost.

Each ampoule with 2 ml solution contains 20 micrograms iloprost.

Excipient: Ethanol 96% 0,81 mg per ml.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Nebuliser solution.

Clear, colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of patients with primary pulmonary hypertension, classified as NYHA functional class III, to improve exercise capacity and symptoms.

4.2 Posology And Method Of Administration

Ventavis should only be initiated and monitored by a physician experienced in the treatment of pulmonary hypertension.

Ventavis is intended for inhalation use by nebulisation (see section 6.6).

Concomitant therapy should be adjusted to individual needs (see section 4.5 Interaction with other medicaments and other forms of interaction).

Adults

• Dose per inhalation session:

The recommended dose is 2.5 micrograms or 5.0 micrograms of inhaled iloprost (as delivered at the mouthpiece of the nebuliser) , starting with the low dose of 2.5 microgram for the first inhalation, followed by 5.0 micrograms for the second inhalation. In case of poor tolerability of the 5.0 microgram dose, the dose should be reduced to 2.5 micrograms.

Two compressed air nebuliser systems, HaloLite and Prodose, have been shown to be suitable nebulisers for the administration of Ventavis. With both systems the mass median aerodynamic diameter of the aerosol droplet (MMAD) with iloprost was between 2.6 and 2.7 micrometres. For each inhalation session the content of one ampoule containing 2 ml of Ventavis nebuliser solution will be transferred into the nebuliser medication chamber immediately before use. HaloLite and Prodose are dosimetric systems. They stop automatically after the pre-set dose has been delivered. The inhalation time depends on the patient's breathing pattern.

Device	Dose of iloprost at mouthpiece	Estimated inhalation time (frequency of 15 breaths per minute)
HaloLite	2.5 micrograms 5 micrograms	4 to 5 min 8 to 10 min
Prodose	2.5 micrograms 5 micrograms	4 to 5 min 8 to 10 min

For a dose of 5 micrograms iloprost at mouthpiece it is recommended to complete two inhalation cycles with 2.5 micrograms pre-set dose program with a filling of one ampoule containing 2 ml Ventavis nebuliser solution, which shows two coloured rings (white – pink).

Venta-Neb, a portable ultrasonic battery-powered nebuliser, has also been shown to be suitable for the administration of Ventavis. The measured MMAD of the aerosol droplets was 2.6 micrometres.

For each inhalation session, the content of one ampoule containing 2 ml Ventavis nebuliser solution and showing two coloured rings (white – pink) will be transferred into the nebuliser medication chamber immediately before use.

Two programs can be operated:

P1 Program 1: 5.0 micrograms active substance on the mouth piece 25 inhalation cycles.

P2 Program 2: 2.5 micrograms active substance on the mouth piece 10 inhalation cycles.

The selection of the pre set program is made by the physician.

Venta-Neb prompts the patient to inhale by an optical and an acoustic signal. It stops after the pre-set dose has been administered.

To obtain the optimal droplet size for the administration of Ventavis the green baffle plate should be used. For details refer to the instruction manual of the Venta-Neb nebuliser.

Device	Dose of iloprost at mouthpiece	Estimated Inhalation time
Venta-Neb	2.5 micrograms 5 micrograms	4 min 8 min

The I-Neb AAD System is a portable, hand-held, vibrating mesh technology nebuliser system. This system generates droplets by ultrasound, which is forcing the solution through a mesh. The I-Neb AAD nebuliser has also been shown to be suitable for the administration of Ventavis. The measured MMAD of the aerosol droplets was 2.1 micrometres.

This nebuliser monitors the breathing pattern to determine the aerosol pulse time required to deliver the pre-set dose of 2.5 or 5 micrograms iloprost.

The pre-set dose provided by the I-Neb AAD system is controlled by the medication chamber in combination with a control disc. There are two different colour coded medication chambers. For each medication chamber there is a corresponding colour coded control disc:

For the 2.5 micrograms dose the medication chamber (350 microlitre) with the red latch is used together with the red control disc.

For the 5 micrograms dose the medication chamber (650 microlitre) with the purple coloured latch is used together with the purple control disc.

For each inhalation session with the I-Neb AAD, the content of one 1-ml ampoule of Ventavis, showing two coloured rings (white-yellow), will be transferred into the appropriate nebuliser medication chamber immediately before use.

Device	Dose of iloprost at mouthpiece	Estimated Inhalation time
I-Neb AAD	2.5 micrograms 5 micrograms	3.2 min 6.5 min

Since the I-Neb nebuliser has been shown to produce an aerosol with slightly different physical characteristics to those of HaloLite, Prodose and VentaNeb devices and a faster delivery of the solution (see section 5.2), patients stabilized on one nebuliser should not switch to another nebuliser without supervision by the treating physician.

The efficacy and tolerability of inhaled iloprost when administered with other nebulising systems, which provide different nebulisation characteristics of iloprost solution, have not been established.

• Daily dose:

The dose per inhalation session should be administered 6 to 9 times per day according to the individual need and tolerability.

• Duration of treatment:

The duration of treatment depends on clinical status and is left to the physician's discretion. Should patients deteriorate on this treatment intravenous prostacyclin treatment should be considered.

Patients with hepatic impairment

Iloprost elimination is reduced in patients with hepatic dysfunction (see section 5.2).

To avoid undesired accumulation over the day, special caution has to be exercised with these patients during initial dose titration. Initially, doses of 2.5 micrograms should be administered with dosing intervals of at least 3 hours (corresponds to administration of max. 6 times per day). Thereafter, dosing intervals may be shortened cautiously based on individual tolerability. If a further increase in the dose up to 5.0 micrograms is indicated, again dosing intervals of at least 3 hours should be chosen initially and shortened according to individual tolerability. A further undesired accumulation of the medicinal product following treatment over several days is not likely due to the overnight break in administration of the medicinal product.

Patients with renal impairment

There is no need for dose adaptation in patients with a creatinine clearance > 30 ml/min (as determined from serum creatinine using the Cockroft and Gault formula). Patients with a creatinine clearance of

Paediatric population

There is no experience with Ventavis in children or adolescents.

4.3 Contraindications

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

− Pregnancy and lactation (see section 4.6).

− Conditions where the effects of Ventavis on platelets might increase the risk of haemorrhage (e.g. active peptic ulcers, trauma, intracranial haemorrhage).

− Severe coronary heart disease or unstable angina;

− Myocardial infarction within the last six months;

− Decompensated cardiac failure if not under close medical supervision;

− Severe arrhythmias;

− Cerebrovascular events (e.g. transient ischaemic attack, stroke) within the last 3 months.

− Pulmonary hypertension due to venous occlusive disease.

− Congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension.

4.4 Special Warnings And Precautions For Use

The use of Ventavis is not recommended in patients with unstable pulmonary hypertension, with advanced right heart failure. In case of deterioration or worsening of right heart failure transfer to other medicinal products should be considered.

Blood pressure should be checked while initiating Ventavis. In patients with low systemic blood pressure and in patients with postural hypotension or receiving drugs known to reduce blood pressure levels, care should be taken to avoid further hypotension. Ventavis should not be initiated in patients with systolic blood pressure less than 85 mmHg.

Physicians should be alert to the presence of concomitant conditions or drugs that might increase the risk of hypotension and syncope (see section 4.5).

The pulmonary vasodilatory effect of inhaled iloprost is of short duration (one to two hours).

Syncope is a common symptom of the disease itself and can also occur under therapy. Patients who experience syncope in association with pulmonary hypertension should avoid any exceptional straining, for example during physical exertion. Before physical exertion it might be useful to inhale. The increased occurrence of syncopes can reflect therapeutic gaps, insufficient effectiveness and/or deterioration of the disease. The need to adapt and/or change the therapy should be considered (see section 4.8).

Ventavis inhalation might entail the risk of inducing bronchospasm, especially in patients with bronchial hyperactivity (see section 4.8 Undesirable effects). Moreover, the benefit of Ventavis has not been established in patients with concomitant Chronic Obstructive Pulmonary Disease (COPD) and severe asthma. Patients with concomitant acute pulmonary infections, COPD and severe asthma should be carefully monitored.

Should signs of pulmonary oedema occur when inhaled iloprost is administered in patients with pulmonary hypertension, the possibility of associated pulmonary veno-occlusive disease should be considered. The treatment should be stopped.

In case of interruption of Ventavis therapy, the risk of rebound effect is not formally excluded. Careful monitoring of the patient should be performed, when inhaled iloprost therapy is stopped and an alternative treatment should be considered in critically ill patients.

Data with intravenously admninistered iloprost indicated that the elimination is reduced in patients with hepatic dysfunction and in patients with renal failure requiring dialysis (see section 5.2). A cautious initial dose titration using dosing intervals of at least 3 hours is recommended (see section 4.2).

Prolonged oral treatment with iloprost clathrate in dogs up to one year was associated with slightly increased fasted serum glucose levels. It cannot be excluded that this is also relevant to man on prolonged Ventavis therapy.

To minimise accidental exposure, it is recommended to use Ventavis with nebulisers with inhalation-triggered systems (such as HaloLite/Prodose, I-Neb), and to keep the room well ventilated.

Ventavis nebuliser solution should not come into contact with skin and eyes; oral ingestion of Ventavis solution should be avoided. During nebulisation sessions a facial mask must be avoided and only a mouthpiece should be used.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Iloprost may increase the effects of vasodilatators and antihypertensive agents and then favour the risk of hypotension (see section 4.4). Should significant hypotension occur this can be corrected by dose reduction of iloprost.

Since iloprost inhibits platelet function its use with anticoagulants (such as heparin, coumarin-type anticoagulants) or other inhibitors of platelet aggregation (such as acetylsalicylic acid, non-steroidal anti-inflammatory medicinal products, ticlopidine, clopidogrel, glycoprotein IIb/IIIa antagonists: abciximab, eptifibatide and tirofiban) may increase the risk of bleeding. A careful monitoring of the patients taking anticoagulants according to common medical practice is recommended.

Intravenous infusion of iloprost has no effect either on the pharmacokinetics of multiple oral doses of digoxin or on the pharmacokinetics of co-administered tissue plasminogen activator (t-PA) in patients.

Although, clinical studies have not been conducted, in vitro studies investigating the inhibitory potential of iloprost on the activity of cytochrome P450 enzymes revealed that no relevant inhibition of drug metabolism via these enzymes by iloprost have to be expected.

4.6 Pregnancy And Lactation

Women of child-bearing potential

The potential risk for humans is unknown. Therefore, women of child-bearing potential should use effective contraceptive measures during treatment.

Pregnancy

There are no adequate data from the use of Ventavis in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Iloprost must not be administered to pregnant women (see section 4.3 Contraindications).

Breast-feeding

It is not known whether iloprost/metabolites are excreted in human breast milk. The medicinal product must not be administered to breast feeding mothers (see section 4.3 Contraindications).

4.7 Effects On Ability To Drive And Use Machines

Care should be exercised during initiation of therapy until any effects on the individual have been determined. In patients experiencing hypotensive symptoms such as dizziness, the ability to drive or operate machines may be seriously affected.

4.8 Undesirable Effects

In addition to local effects resulting from administration of iloprost by inhalation such as increased cough, adverse reactions with iloprost are related to the pharmacological properties of prostacyclins.

The most common adverse reactions seen in clinical trials include vasodilatation (including hypotension), headache and increased cough.

The adverse reactions reported below are based on pooled clinical trial data from phase II and III clinical trials involving 131 patients taking the medication. The frequencies of ADRs are defined as very common (

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

System organ class	Very common (	Common (	Frequency not known
Immune system disorders			Hypersensitivity
Nervous system disorders	Headache	Dizziness
Vascular disorders	Vasodilatation	Syncope (see section 4.4), Hypotension
Blood and lymphatic system disorders	Bleeding events*
Respiratory, thoracic and mediastinal disorders	Chest discomfort / chest pain Cough increased	Dyspnoea Pharyngolaryngeal pain and throat irritation	Bronchospasm (see section 4.4) / Wheezing
Gastrointestinal disorder	Nausea	Diarrhoea Vomiting Mouth and tongue irritation	Dysgueusia
Musculoskeletal and connective tissue disorders	Pain in jaw/trismus
Skin and subcutaneous skin disorders		Rash

* Bleeding events were very common as expected in this patient population with a high proportion of patients taking anticoagulant co-medication (see section 4.5).

Syncope is a common symptom of the disease itself, but can also occur under therapy. The increased occurrence of syncopes can be related to the deterioration of the disease or insufficient effectiveness of the product (see section 4.4).

Peripheral oedema is a very common symptom of the disease itself, but can also occur under therapy. The occurrence of peripheral oedema can be related to the deterioration of the disease or insufficient effectiveness of the product.

4.9 Overdose

• Symptoms

No case of overdose has been reported. In the case of an overdose hypotensive/vasovagal reaction might be anticipated as well as headache, flushing, nausea, vomiting, and diarrhoea. An increase of blood pressure, bradycardia or tachycardia and limb or back pain might be possible.

• Therapy

A specific antidote is not known. Interruption of the inhalation session, monitoring and symptomatic measures are recommended.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin, ATC code: B01AC11

This medicinal product has been authorised under “Exceptional Circumstances”.

This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.

The European Medicines Agency (EMA) will review any new information which may become available every year and this SPC will be updated as necessary.

Iloprost, the active substance of Ventavis, is a synthetic prostacyclin analogue. The following pharmacological effects have been observed in vitro:

• Inhibition of platelet aggregation, platelet adhesion and release reaction

• Dilatation of arterioles and venules

• Increase of capillary density and reduction of increased vascular permeability caused by mediators such as serotonin or histamine in the microcirculation

• Stimulation of endogenous fibrinolytic potential

The pharmacological effects after inhalation of Ventavis are:

Direct vasodilatation of the pulmonary arterial bed occur with consecutive significant improvement of pulmonary artery pressure, pulmonary vascular resistance and cardiac output as well as mixed venous oxygen saturation.

In a small, randomized, 12-week double-blinded phase, placebo-controlled study (the STEP trial), 34 patients treated with bosentan 125 mg twice per day for at least 16 weeks who were in stable haemodynamic conditions before enrolment, tolerated the addition of inhaled iloprost (up to 5 microgram 6 to 9 times per day during waking hours). The mean daily inhaled dose was 27 microgram and the mean number of inhalations per day was 5.6. The acute adverse effects in patients receiving concomitant bosentan and iloprost were consistent with those observed in the larger experience of the phase 3 study in patients receiving only iloprost. No reliable conclusion could be drawn on efficacy of the association as the sample size was limited and the study was of short duration.

No clinical trial data are available comparing directly in intra-patient observations the acute haemodynamic response after intravenous to that after inhaled iloprost. The haemodynamics observed suggest an acute response with preferential effect of inhaled treatment on the pulmonary vessels. The pulmonary vasodilatory effect of each single inhalation levels off within one to two hours.

However, the predictive value of these acute haemodynamic data are considered to be of limited value as acute response does not in all cases correlate with long-term benefit of treatment with inhaled iloprost.

• Efficacy in adult patients with pulmonary hypertension

A randomised, double-blind, multi-centre, placebo-controlled phase III trial (study RRA02997) has been conducted in 203 adult patients (inhaled iloprost: N=101; placebo n=102) with stable pulmonary hypertension. Inhaled iloprost (or placebo) was added to patients' current therapy, which could include a combination of anticoagulants, vasodilators (e.g. calcium channel blockers), diuretics, oxygen, and digitalis, but not PGI2 (prostacyclin or its analogues). 108 of the patients included were diagnosed with primary pulmonary hypertension, 95 were diagnosed with secondary pulmonary hypertension of which 56 were associated with chronic thromboembolic disease, 34 with connective tissue disease (including CREST and scleroderma) and 4 were considered appetite suppressant drug related. The baseline 6-minute walk test values reflected a moderate exercise limitation: in the iloprost group the mean was 332 metres (median value: 340 metres) and in the placebo group the mean was 315 metres (median value: 321 metres). In the iloprost group, the median daily inhaled dose was 30 micrograms (range 12.5 to 45 micrograms/day). The primary efficacy endpoint defined for this study, was a combined response criterion consisting of improvement in exercise capacity (6 minute walk test) at 12 weeks by at least 10% versus baseline, and improvement by at least one NYHA class at 12 weeks versus baseline, and no deterioration of pulmonary hypertension or death at any time before 12 weeks. The rate of responders to iloprost was 16.8% (17/101) and the rate of responders in the placebo group was 4.9% (5/102) (p=0.007).

In the iloprost group, the mean change from baseline after 12 weeks of treatment in the 6 minute walking distance was an increase of 22 metres (-3.3 metres in the placebo group, no data imputation for death or missing values).

In the iloprost group the NYHA class was improved in 26% of patients (placebo: 15%) (p = 0.032), unchanged in 67.7% of patients (placebo: 76%) and deteriorated in 6.3% of patients (placebo: 9%). Invasive haemodynamic parameters were assessed at baseline and after 12 weeks treatment.

A subgroup analysis showed that no treatment effect was observed as compared to placebo on the 6-minute walk test in the subgroup of patients with secondary pulmonary hypertension.

A mean increase in the 6-minute walk test of 44.7 metres from a baseline mean value of 329 metres vs. a change of -7.4 metres from a baseline mean value of 324 metres in the placebo group (no data imputation for death or missing values) was observed in the subgroup of 49 patients with primary pulmonary hypertension receiving treatment of inhaled iloprost for 12 weeks (46 patients in the placebo group).

No study has been performed with Ventavis in children with pulmonary hypertension.

5.2 Pharmacokinetic Properties

• Absorption

When iloprost is administered via inhalation in patients with pulmonary hypertension (iloprost dose at the mouthpiece: 5 micrograms), peak serum levels of 100 to 200 picograms/ml were observed at the end of inhalation session. These levels decline with half-lives between approximately 5 and 25 minutes. Within 30 minutes to 1 hour after the end of inhalation, iloprost is not detectable in the central compartment (limit of quantification 25 picograms/ml).

• Distribution

No studies performed following inhalation.

Following intravenous infusion, the apparent steady-state volume of distribution was 0.6 to 0.8 l/kg in healthy subjects. Total plasma protein binding of iloprost is concentration-independent in the range of 30 to 3000 picograms/ml and amounts to approximately 60 %, of which 75 % is due to albumin binding.

• Metabolism

No studies performed following inhalation.

Iloprost is extensively metabolised principally via β-oxidation of the carboxyl side chain. No unchanged substance is eliminated. The main metabolite is tetranor-iloprost, which is found in the urine in free and conjugated form in 4 diastereoisomers. Tetranor-iloprost is pharmacologically inactive as shown in animal experiments. Results of in vitro studies reveal that CYP 450-dependent metabolism plays only a minor role in the biotransformation of iloprost. Further in vitro studies suggest that metabolism of iloprost in the lungs is similar after intravenous administration or inhalation.

• Elimination

No studies performed following inhalation.

In subjects with normal renal and hepatic function, the disposition of iloprost following intravenous infusion is characterised in most cases by a two-phase profile with mean half-lives of 3 to 5 minutes and 15 to 30 minutes. The total clearance of iloprost is about 20 ml/kg/min, which indicates extrahepatic contribution to the metabolism of iloprost.

A mass-balance study was done using ³H-iloprost in healthy subjects. Following intravenous infusion, the recovery of total radioactivity is 81 %, and the respective recoveries in urine and faeces are 68 % and 12 %. The metabolites are eliminated from plasma and urine in 2 phases, for which half-lives of about 2 and 5 hours (plasma) and 2 and 18 hours (urine) have been calculated.

• Pharmacokinetics after use with different nebulisers

In a randomized, crossover study with 20 healthy adult men, pharmacokinetics was investigated following inhalation of Ventavis (5 mcg iloprost) by the I-Neb AAD in comparison to the ProDose (5 mcg disk).

Higher maximum serum level (Cmax) and systemic exposure (AUC(0-tlast)) as well as a shorter time to reach maximum serum concentration (tmax) were found following Ventavis inhalation via the I-Neb AAD in comparison to the ProDose nebulizer. The pharmacokinetic results reflect the slightly different in vitro characteristics of these nebulizers (see Section 4.2).

Pharmacokinetic parameters of iloprost after inhalation of 5 mcg iloprost by I-Neb AAD vs. ProDose

	Cmax (pg/mL) geometric mean (CV%)	t max (h), median (range)	AUC(0-tlast) (pg•h/mL) geometric mean (CV%)
I-Neb	119 (41.2%)	0.147 (0.086 – 0.268)	28.9 (47.4%)
ProDose	80.0 (46.7%)	0.183 (0.133 – 0.279)	18.7 (50.5%)

AUC(0-tlast) = Area under the concentration time curve from 0h data point up to last measurable serum level

CV = coefficient of variation

• Characteristics in patients

Renal dysfunction:

In a study with intravenous infusion of iloprost, patients with end-stage renal failure undergoing intermittent dialysis treatment are shown to have a significantly lower clearance (mean CL = 5 ± 2 ml/minute/kg) than that observed in patients with renal failure not undergoing intermittent dialysis treatment (mean CL = 18 ± 2 ml/minute/kg).

Hepatic dysfunction:

Because iloprost is extensively metabolised by the liver, the plasma levels of the active substance are influenced by changes in hepatic function. In an intravenous study, results were obtained involving 8 patients suffering from liver cirrhosis. The mean clearance of iloprost is estimated to be 10 ml/minute/kg.

Age and gender:

Age and gender are not of clinical relevance to the pharmacokinetics of iloprost.

5.3 Preclinical Safety Data

• Systemic toxicity

In acute toxicity studies, single intravenous and oral doses of iloprost caused severe symptoms of intoxication or death (IV) at doses about two orders of magnitude above the intravenous therapeutic dose. Considering the high pharmacological potency of iloprost and the absolute doses required for therapeutic purposes the results obtained in acute toxicity studies do not indicate a risk of acute adverse effects in humans. As expected for a prostacyclin, iloprost produced haemodynamic effects (vasodilatation, reddening of skin, hypotension, inhibition of platelet function, respiratory distress) and general signs of intoxication such as apathy, gait disturbances, and postural changes.

Continuous IV/SC infusion of iloprost up to 26 weeks in rodents and non-rodents did not cause any organ toxicity at dose levels which exceeded the human therapeutic systemic exposure between 14 and 47 times (based on plasma levels). Only expected pharmacological effects like hypotension, reddening of skin, dyspnoea, increased intestinal motility were observed.

Based on Cmax values in rats the systemic exposure in these parenteral studies was approximately 3.5 times higher than the maximum achievable exposure after inhalation. This highest achievable dose of 48.7 micrograms/kg/day was also the “no observed adverse effect level” (NOAEL) as evaluated in inhalation toxicity studies in rats up to 26 weeks. Following inhalation the systemic exposure based on AUC values in rats exceeded the corresponding therapeutic exposure in human patients by approximately 13 times.

• Genotoxic potential, tumorigenicity

In vitro (bacterial, mammalian cells, human lymphocytes) and in vivo studies (micronucleus test) for genotoxic effects have not produced any evidence for a mutagenic potential.

No tumorigenic potential of iloprost was observed in tumorigenicity studies in rats and mice.

• Reproduction toxicology

In embryo- and foetotoxicity studies in rats continuous intravenous administration of iloprost led to anomalies of single phalanges of the forepaws in a few foetuses/pups without dose dependence.

These alterations are not considered as true teratogenic effects, but are most likely related to iloprost induced growth retardation in late organogenesis due to haemodynamic alterations in the foetoplacental unit. In comparable embryotoxicity studies in rabbits and monkeys no such digit anomalies or other gross-structural abnormalities were observed.

In rats, passage of extremely low levels of iloprost into the milk was observed.

• Local tolerance, contact sensitising and antigenicity potential

In inhalation studies in rats, the administration of an iloprost formulation with a concentration of 20 micrograms/ml up to 26 weeks did not cause any local irritation of the upper and lower respiratory tract.

A dermal sensitisation (maximisation test) and an antigenicity study in guinea pigs showed no sensitising potential.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Trometamol,

Ethanol 96 %,

Sodium chloride,

Hydrochloric acid (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

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

1-ml ampoules, colourless, glass type I, containing 1 ml nebuliser solution, ring coded with two coloured rings (white - yellow).

3-ml ampoules, colourless, glass type I, containing 2 ml nebuliser solution, ring coded with two coloured rings (white – pink).

1 ml nebuliser solution:

Packages containing 30 or 168 ampoules.

2 ml nebuliser solution:

Packages containing 30, 90, 100 or 300 ampoules.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

For each inhalation session the contents of one opened ampoule of Ventavis has to be transferred completely into the nebuliser medication chamber immediately before use.

After each inhalation session, any solution remaining in the nebuliser should be discarded.

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

7. Marketing Authorisation Holder

Bayer Pharma AG

D-13342 Berlin

Germany

8. Marketing Authorisation Number(S)

EU/1/03/255/001

EU/1/03/255/002

EU/1/03/255/003

EU/1/03/255/004

EU/1/03/255/005

EU/1/03/255/006

EU/1/03/255/007

EU/1/03/255/008

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 16 September 2003

Date of last renewal: 16 September 2008

10. Date Of Revision Of The Text

07/2011

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

Distributed in the United Kingdom by:

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire

RG14 1JA

Colestid

Generic Name: colestipol (koe LES ti pol)

Brand Names: Colestid, Colestid Flavored

What is Colestid (colestipol)?

Colestipol is a cholesterol-lowering drug.

Colestipol lowers "bad" cholesterol in the blood, which is also called LDL (low-density lipoprotein) cholesterol. Lowering your LDL cholesterol may reduce your risk of hardened arteries, which can lead to heart attacks, stroke, and circulation problems.

Lowering high cholesterol levels is an important part of preventing heart disease and arteriosclerosis (hardening of the arteries).

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

What is the most important information I should know about Colestid (colestipol)?

You should not take this medication if you are allergic to colestipol, or if you have a blockage in your intestines.

Before taking colestipol, tell your doctor if have trouble swallowing, constipation or hemorrhoids, a stomach or intestinal disorder, liver disease, a thyroid disorder, a bleeding disorder, a history of major stomach or bowel surgery, or if you have a vitamin A, D, E, or K deficiency.

Before taking colestipol, tell your doctor if you are pregnant or breast-feeding a baby.

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

Do not take other medications at the same time you take colestipol. Taking colestipol can make it harder for your body to absorb certain drugs, making them less effective. Take your other medications at least 1 hour before or 4 hours after you take colestipol. Avoid constipation by drinking 8 to 12 full glasses (8 ounces each) every day while taking this medication. Ask your doctor before using a laxative or stool softener. Call your doctor at once if you have severe constipation or stomach pain.

To be sure colestipol is helping your condition, your blood will need to be tested often. This will help your doctor determine how long to treat you with colestipol. Do not miss any scheduled appointments.

What should I discuss with my healthcare provider before taking Colestid (colestipol)?

You should not take this medication if you are allergic to colestipol, or if you have a blockage in your intestines.

Before taking colestipol, tell your doctor if you are allergic to any drugs, or if you have:

• 
  

  trouble swallowing;

  
  


• 
  

  constipation or hemorrhoids;

  
  


• 
  

  a stomach, intestinal, or digestive disorder;

  
  


• 
  

  liver disease;

  
  


• 
  

  a thyroid disorder;

  
  


• 
  

  a bleeding disorder;

  
  


• 
  

  a history of major stomach or bowel surgery; or

  
  


• 
  

  if you have a vitamin A, D, E, or K deficiency.

  
  

If you have any of these conditions, you may need a dose adjustment or special tests to safely take colestipol.

This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Taking colestipol can make it harder for your body to absorb certain vitamins. These vitamins are important if you are nursing a baby. Do not take colestipol without telling your doctor if you are breast-feeding a baby.

Some forms of this medication may contain phenylalanine. Talk to your doctor before using colestipol if you have phenylketonuria (PKU).

How should I take Colestid (colestipol)?

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

Colestipol is usually taken 1 or 2 times per day with meals. Follow your doctor's instructions.

Your doctor may occasionally change your dose to make sure you get the best results from this medication.

Dissolve the colestipol granules in a small amount of water, broth soup, applesauce, crushed pineapple, or hot or cold cereal. Stir this mixture and drink or eat all of it right away. Swallow the mixture without chewing or holding it in your mouth. Colestipol can damage your teeth if left in contact with them for too long.

If you mix colestipol granules with a liquid, after drinking the mixture add a little more water to the same glass, swirl gently and drink right away. This will assure that you get the entire dose.

To be sure this medication is helping your condition, your blood will need to be tested often. This will help your doctor determine how long to treat you with colestipol. Do not miss any scheduled appointments.

It may take 2 weeks to several months of using this medicine before your cholesterol levels improve. For best results, keep using the medication as directed.

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

Store colestipol at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include severe stomach pain or constipation.

What should I avoid while taking Colestid (colestipol)?

Avoid taking other medications at the same time you take colestipol. Taking colestipol can make it harder for your body to absorb certain drugs, making them less effective. Take your other medications at least 1 hour before or 4 hours after you take colestipol. Avoid constipation by drinking 8 to 12 full glasses (8 ounces each) every day while taking this medication. Ask your doctor before using a laxative or stool softener.

Colestid (colestipol) 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:

• 
  

  trouble swallowing;

  
  


• 
  

  severe constipation or stomach pain;

  
  


• 
  

  black, bloody, or tarry stools; or

  
  


• 
  

  easy bruising or bleeding, muscle or joint pain, loss of appetite.

  
  

Less serious side effects may include:

• 
  

  mild or occasional constipation;

  
  


• 
  

  gas, indigestion, heartburn;

  
  


• 
  

  diarrhea; or

  
  


• 
  

  hemorrhoids or rectal irritation.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Colestid (colestipol)?

Taking colestipol can make it harder for your body to absorb many other medications. Below is just a partial list of these medications. Tell your doctor if you are using:

• 
  

  steroid drugs such as hydrocortisone (Cortef, Hydrocortone);

  
  


• 
  

  heart medication such as digoxin (Lanoxin, Lanoxicaps), propranolol (Inderal), furosemide (Lasix), hydrochlorothiazide (HCTZ, HydroDiuril), chlorothiazide (Diuril);

  
  


• 
  

  a diuretic (water pill) such as furosemide (Lasix), hydrochlorothiazide (HCTZ, HydroDiuril), or chlorothiazide (Diuril);

  
  


• 
  

  an antibiotic such as demeclocycline (Declomycin), doxycycline (Adoxa, Doryx, Oracea, Vibramycin), minocycline (Dynacin, Minocin, Solodyn, Vectrin), or tetracycline (Brodspec, Panmycin, Sumycin, Tetracap); or

  
  


• 
  

  other cholesterol-lowering medications such as atorvastatin (Caduet, Lipitor), lovastatin (Altocor, Mevacor, Advicor), ezetimibe (Zetia, Vytorin), fenofibrate (Antara, Lipofen, Lofibra, TriCor, Triglide), gemfibrozil (Lopid), clofibrate (Atromid-S), nicotinic acid (niacin), or ursodiol (Actigall, Urso, Urso Forte).

  
  

This list is not complete and there may be other drugs that can interact with colestipol. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Colestid resources

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

• Colestid Prescribing Information (FDA)


• Colestid MedFacts Consumer Leaflet (Wolters Kluwer)


• Colestid Monograph (AHFS DI)


• Colestid Advanced Consumer (Micromedex) - Includes Dosage Information


• Colestipol Prescribing Information (FDA)

Compare Colestid with other medications

• Hyperlipoproteinemia
• Hyperlipoproteinemia Type IIa, Elevated LDL
• Hyperlipoproteinemia Type IIb, Elevated LDL VLDL

Where can I get more information?

• Your pharmacist can provide more information about colestipol.

See also: Colestid side effects (in more detail)

Sustiva

Pronunciation: EF-a-VIR-enz
Generic Name: Efavirenz
Brand Name: Sustiva

Sustiva is used for:

Treating HIV infection in combination with other medicines. If Sustiva is taken alone to treat HIV, it may stop working.

Sustiva is a nonnucleoside reverse transcriptase inhibitor (NNRTI). It works by blocking the growth of HIV.

Do NOT use Sustiva if:

• you are allergic to any ingredient in Sustiva or have developed red, swollen, blistered, or peeling skin after taking any ingredient in Sustiva


• you have moderate to severe liver problems


• you are taking astemizole, bepridil, cabazitaxel, cisapride, an ergot medicine (eg, dihydroergotamine, ergotamine, methylergonovine), lurasidone, midazolam, nevirapine, pimozide, St. John's wort, terfenadine, ticagrelor, triazolam, or vandetanib.


• you are taking another medicine that contains efavirenz

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

Before using Sustiva:

Some medical conditions may interact with Sustiva. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are of childbearing age


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have high cholesterol, kidney problems, or a history of liver problems (eg, hepatitis, abnormal liver function tests)


• if you have a history of seizures, mental or mood problems (eg, depression), or suicidal thoughts or actions


• if you drink alcohol or have a history of alcohol or other substance abuse or dependence

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

• Astemizole, bepridil, cisapride, pimozide, or terfenadine because serious heart problems (eg, irregular heartbeat) may occur


• Midazolam or triazolam because serious side effects, such as prolonged sedation or breathing problems, may occur


• Ergot medicines (eg, dihydroergotamine, ergotamine, methylergonovine) because serious blood flow problems may occur


• Nevirapine, rifamycins (eg, rifampin), or St. John's wort because they may decrease Sustiva's effectiveness


• HIV protease inhibitors (eg, amprenavir, atazanavir, ritonavir) or warfarin because their effectiveness may be decreased or the risk of their side effects may be increased by Sustiva


• Azole antifungals (eg, itraconazole, posaconazole, voriconazole), bupropion, cabazitaxel, calcium channel blockers (eg, diltiazem, nifedipine, verapamil), carbamazepine, cyclosporine, hepatitis C virus (HCV) protease inhibitors (eg, boceprevir), HMG-CoA reductase inhibitors (eg, atorvastatin), hormonal contraceptives (eg, birth control pills, etonogestrel), ixabepilone, lurasidone, certain macrolide antibiotics (eg, clarithromycin), maraviroc, methadone, phenobarbital, phenytoin, rifabutin, sertraline, sirolimus, tacrolimus, ticagrelor, ulipristal, or vandetanib because their effectiveness may be decreased by Sustiva


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

This may not be a complete list of all interactions that may occur. Ask your health care provider if Sustiva may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Sustiva:

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

• An extra patient leaflet is available with Sustiva. Talk to your pharmacist if you have questions about this information.


• Take Sustiva by mouth on an empty stomach at least 1 hour before or 2 hours after eating. Taking Sustiva with food, especially with a high-fat meal, may lead to increased blood levels of Sustiva. This may increase your risk of side effects.


• Take Sustiva with a full glass of water (8 oz/240 mL).


• Take Sustiva at the same time(s) every day, preferably at bedtime unless otherwise directed by your doctor.


• Continue to use Sustiva even if you feel well. Do not miss any doses.


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

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

Important safety information:

• Sustiva may cause drowsiness, dizziness, or trouble concentrating. These effects may be worse if you take it with alcohol or certain medicines. Use Sustiva with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do not drink alcohol or use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Sustiva; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.


• Sustiva may cause dizziness, drowsiness, trouble sleeping, trouble concentrating, or unusual dreams. These effects usually go away after you have taken Sustiva for about 2 to 4 weeks. Taking it at bedtime may help to decrease these effects. Check with your doctor if they continue or are severe.


• Do NOT take more than the recommended dose, change your dose, or stop taking Sustiva without checking with your doctor. Taking more than the recommended dose may not provide additional benefits and may increase the risk of side effects.


• Sustiva may improve immune system function. This may reveal hidden infections in some patients. Tell your doctor right away if you notice symptoms of infection (eg, fever, sore throat, weakness, cough, shortness of breath) after you start Sustiva.


• Changes in body fat (eg, an increased amount of fat in the upper back, neck, breast, and trunk, and loss of fat from the legs, arms, and face) may occur in some patients taking Sustiva. The cause and long-term effects of these changes are unknown. Discuss any concerns with your doctor.


• Sustiva is not a cure for HIV infection. Patients may still get illnesses and infections associated with HIV. Remain under the care of your doctor.


• Sustiva does not stop the spread of HIV to others through blood or sexual contact. Use barrier methods of birth control (eg, condoms) if you have HIV infection. Do not share needles, injection supplies, or items like toothbrushes or razors.


• Sustiva will not prevent you from getting sexually transmitted diseases (STDs). Always use a condom during sexual intercourse.


• If your health changes, check with your doctor.


• When your medicine supply is low, get more from your doctor or pharmacist as soon as you can. Do not stop taking Sustiva, even for a short period of time. If you do, the virus may grow resistant to the medicine and become harder to treat.


• Sustiva may interfere with certain lab tests, including cannabinoids/marijuana false-positive result. Be sure your doctor and lab personnel know you are taking Sustiva.


• Talk to your doctor about whether you should have a pregnancy test before you begin taking Sustiva.


• If you may become pregnant, you must use an effective form of birth control while you take Sustiva and for 12 weeks after you stop taking it. Hormonal birth control (eg, birth control pills) may not work as well while you are using Sustiva. You should always use a barrier form of birth control (eg, condoms), even if you already use a hormonal birth control method. If you have questions about effective birth control, talk with your doctor.


• Lab tests, including liver function and cholesterol and triglyceride levels, may be performed while you use Sustiva. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Sustiva with caution in the ELDERLY; they may be more sensitive to its effects.


• Sustiva should be used with extreme caution in CHILDREN younger than 3 years old and in children who weigh less than 13 kg (28.6 lb); safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Sustiva may cause harm to the fetus. Do not become pregnant while you are taking it or for 12 weeks after you stop taking it. If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of using Sustiva while you are pregnant. It is not known if Sustiva is found in breast milk. Mothers infected with HIV should not breast-feed. There is a risk of passing the HIV infection or Sustiva to the baby.

Possible side effects of Sustiva:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Abnormal dreams; diarrhea; dizziness; drowsiness; headache; nausea; tiredness; trouble concentrating; trouble sleeping; upset stomach; vomiting.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); burning, numbness, or tingling; change in personality; confusion; cough; delusions; fainting; fever, chills, or persistent sore throat; hallucinations; irregular heartbeat; memory loss; mental, mood, or behavior changes (eg, abnormal thoughts, agitation, aggression, anxiety, depression, nervousness, paranoia); mouth sores; rash with or without fever; red, swollen, blistered, or peeling skin; seizures; severe or persistent tiredness or weakness; severe stomach pain; shortness of breath; suicidal thoughts or behaviors; symptoms of liver problems (eg, dark urine, loss of appetite, pale stools, yellowing of the skin or eyes); vision changes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Sustiva side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include hallucinations; muscle twitching; severe dizziness, drowsiness, or coordination problems; trouble concentrating; trouble sleeping.

Proper storage of Sustiva:

Store Sustiva at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store in a tightly closed container away from heat, moisture, and light. Do not store in the bathroom. Keep Sustiva out of the reach of children and away from pets.

General information:

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


• Sustiva is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Sustiva. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Sustiva resources

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

• Sustiva Prescribing Information (FDA)


• Sustiva Consumer Overview


• Sustiva Monograph (AHFS DI)


• Sustiva Advanced Consumer (Micromedex) - Includes Dosage Information


• Efavirenz Professional Patient Advice (Wolters Kluwer)

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