Section 4.8: Undesirable effects

Deletion of:

“Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V”.

Addition of:

“Healthcare professionals are asked to report any suspected adverse reactions via the national reporting (see details below):

 

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

 

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie ”.

Section 6.5 : Nature and contents of the container

Addition of:

“PVC-PVDC-Aluminium blister of 1 tablet”.

“Not all pack sizes may be marketed”.

 

Section 8: Marketing Authorization Number

Addition of:

EU/1/09/522/002

 

Section 10: Date of revision of text

30/01/2017

 

 



Changes to ellaOne SmPC :

Section 4.4 : Special Precautions for Use

Addition of:

“barbiturates (including primidone and phenobarbital), phenytoin, fosphenytoin, carbamazepine, oxcarbazepine, herbal medicines containing Hypericum perforatum (St. John’s wort), rifampicin, rifabutin, griseofulvin, efavirenz, nevirapine and long term use of ritonavir”.

Deletion of:

“rifampicin, phenytoin, phenobarbital, carbamazepine, efavirenz, fosphenytoine, nevirapine, oxcarbazepine, primidone, rifabutine, St John’s wort/Hypericum perforatum. 

 

Section 4.5 Inreraction with other medicinal products and other forms of interaction

-          CYP3A4 inducers

Addition of:

“barbiturates (including primidone and phenobarbital), phenytoin, fosphenytoin, carbamazepine, oxcarbazepine, herbal medicines containing Hypericum perforatum (St. John’s wort), rifampicin, rifabutin, griseofulvin, efavirenz and nevirapine”.

“For women who have used enzyme-inducing drugs in the past 4 weeks, ellaOne is not recommended (see section 4.4 ) and non-hormonal emergency contraception (i.e. a copper intrauterine device (Cu-IUD)) should be considered”.

 

Deletion of:

 “rifampicin, phenytoin, phenobarbital, carbamazepine, efavirenz, fosphenytoine, nevirapine, oxcarbazepine, primidone, rifabutine, St John’s wort/Hypericum perforatum”

-          CYP3A4 inhibitors

Change of :

 

“within the last 2‑3 weeks” to ““in the past 4 weeks” in the sentence: “Enzyme induction wears off slowly and effects on the plasma concentrations of ulipristal acetate may occur even if a woman has stopped taking an enzyme inducer…”

 

Precision of the appearance of the pill: White to marble creamy, round curved tablet engraved with code “еllа” on both faces

 

Change of legal status form POM to P, following EC decision on 07 Jan 2015, to give women direct access to ellaOne
update date of revision of the text

These changes have been evaluated during the renewal of the MA.

 

The new SmPC introduce the PV contact in section 4.8 of SmPC, according to QRD template V.9.

It has also been the opportunity to update and clarify some sections, especially the Section 4.8 “undesirable effects” in order to provide only the most relevant and helpful information on the drug’s adverse reactions.

 

Section 2. Qualitative and quantitative composition

-          Presentation of the information for the excipient has been adapted for clarity. Was  previously “Excipients with known effect: each tablet contains 237 mg lactose monohydrate.” and is now:” Each tablet contains 237 mg lactose (as monohydrate).”

Section 4.2 Posology and method of administration: 

-          Introduction of subtitles, i.e. Posology, Special populations, Method of administration. Oral use.

Section 4.4 Special warning and precaution for use: 

-          Precision added on concomitant use to include Concomitant use “of ulipristal acetate”.

-          Remove the same information that was in double on the last paragraph of the section.

Section 4.5. interaction with other medicinal products and other forms of interaction:

-          tmax was changed to Tmax

-          P-glycoprotein wording was added after the abbreviation P-gp

 

Section 4.7: Effects om ability to drive and use machines:

-          Removal of the text: “No studies on the effect on the ability to drive and use machine have been performed”

-          Addition of the text: “The patient should be informed not to drive or use machines if they are experiencing such symptoms (see section Error! Reference source not found.).”

Section 4.8 undesirable effects:

-          Addition of a subtitle: “Summary of the safety profile”

-          Addition of a subtitle: “Tabulated list of adverse reactions”. Within the same paragraph, removal of the following text: “The vast majority of adverse reactions were mild or moderate and resolved spontaneously” and change of “undesirable effect” by “adverse reactions”, then change of the explanation before the table “in order of decreasing seriousness” has been changed to “in order of decreasing frequency.”

-          Addition of the table legend: “The table lists adverse reactions according to system organ class and frequency: very common (≥1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1,000 to <1/100) and rare (≥1/10,000 to <1/1,000).”

-          Update of the table adverse reactions, for optimal uses and practices by health care professionals and users and to include

-          Addition of the Post experience information after the table of Adverse reactions.

-          Addition of e subtitle: ”Description of selections adverse reactions”

-          Addition of the paragraph related to the introduction of the PV contact in section 4.8 of SmPC (IMB details)

Section 4.9 Overdose

-          Addition of the experience of overdose usage. Before it was stated that experience was limited, on a limited number of patients. It now states:           “Experience with ulipristal acetate overdose is limited. Single doses up to 200 mg have been used in women without safety concern.  Such high doses were well-tolerated; however, these women had a shortened menstrual cycle (uterine bleeding occurring 2-3 days earlier than would be expected) and in some women, the duration of bleeding was prolonged, although not excessive in amount (spotting). There are no antidotes and further treatment should be symptomatic.”

Section 5.3.Preclinical safety data

-          Addition of the carcinogenicity studies results: “Carcinogenicity studies (in rats and mice) showed that ulipristal acetate is not carcinogenic.”

Section 10. Date of revision of the text

-          Update of the date of revision of the text: 21 March 2014

In Section 6.4 (Special precautions for storage) the information has been changed from:

Keep the blister in the outer carton in order to protect from light.

new SmPC says now:

 

Store below 25°C. Store in the original packaging to protect from moisture. Keep the blister in the outer carton to protect from light.

Section 4.4
The last paragraphe has been replaced by

Concomitant use of ellaOne  with CYP3A4 inducers is not recommended due to interaction (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, efavirenz, fosphenytoine, nevirapine, oxcarbazepine, primidone, rifabutine, St John’s wort/Hypericum perforatum, long term use of ritonavir).. Concomitant use of ulipristal acetate and emergency contraception containing levonorgestrel is not recommended (see section 4.5).

Section 4.5
After Ulipristal acetate is metabolized by CYP3A4, the following paragraphe has been added
- CYP3A4 inhibitors
In vivo results show that administration of ulipristal acetate with a potent and a moderate CYP3A4 inhibitor increased Cmax and AUC of ulipristal acetate with a maximum of 2- and 5.9-fold, respectively. The effects of CYP3A4 inhibitors are unlikely to have any clinical consequences.

After the paragraphe beginning with The CYP3A4 inhibitor ritonavir.... the following paragraphe has been added
- CYP3A4 inducers
In vivo results show that the administration of ulipristal acetate with a strong CYP3A4 inducer such as rifampicin markedly decreases Cmax and AUC of ulipristal acetate by 90% or more and decreases ulipristal acetate half-life by 2.2-fold corresponding to an approximately 10-fold decrease of ulipristal acetate exposure. Concomitant use of ellaOne with CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, efavirenz, fosphenytoine, nevirapine, oxcarbazepine, primidone, rifabutine, St John’s wort/Hypericum perforatum) therefore reduces plasma concentrations of ulipristal acetate and may result in a decreased efficacy of ellaOne and is therefore not recommended (see section 4.4).

Medicinal products affecting gatric pH has been added before paragraphe beginning with Administration of ulipristal acetate (10 mg tablet)

After Potential for ulipristal acetate to affect other medicinal products, the following paragraphe has been added
In vitro data indicate that ulipristal acetate and its active metabolite do not significantly inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4, at clinically relevant concentrations. After single dose administration induction of CYP1A2 and CYP3A4 by ulipristal acetate or its active metabolite is not likely. Thus, administration of ulipristal acetate is unlikely to alter the clearance of medicinal products that are metabolised by these enzymes.

P-gp substrates
In vitro data indicate that ulipristal acetate may be an inhibitor of P-gp at clinically relevant concentrations. Results in vivo with the P-gp substrate fexofenadine were inconclusive. The effects of the P-gp substrates are unlikely to have any clinical consequences.

Hormonal contraceptives has been added before paragraphe beginning with Because ulipristal acetate binds the progesterone receptor....

Section 5.2
The paragraphe Interactions has been removed

Section 10
Date of revision : 30 May 2013

Section 2
- addition of : Excipients with known effect

Section 4.4
- addition of : Although the use of ellaOne does not contraindicate the continued use of regular hormonal contraception, ellaOne may reduce its contraceptive action (see section 4.5). Therefore, after using emergency contraception, it is recommended that subsequent acts of intercourse be protected by a reliable barrier method until the next menstrual period starts. If a woman wishes to initiate hormonal contraception as a regular contraception method, she can do so immediately after using ellaOne, but the woman should use a reliable barrier method until the next menstrual period.

- suppression of : Concomitant use of ellaOne and the following active substances are not recommended due to potential for interaction: P-gp substrates (e.g. dabigatran etexilate, digoxin), CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St John’s wort/Hypericum perforatum), medicinal products that increase gastric pH (e.g. proton pump inhibitors, antacids and H2-receptor antagonists), long term use of ritonavir, and emergency contraception containing levonorgestrel (see section 4.5).


Section 4.5
- suppression of : No specific drug interaction studies have been performed in vivo.

- suppression of : The CYP3A4 inhibitor ritonavir can also have an inducing effect on CYP3A4 when ritonavir is used for a longer period. In such cases ritonavir might reduce plasma concentrations of ulipristal acetate. Concomitant use is therefore not recommended (see section 4.4). Enzyme induction wears off slowly and effects on the plasma concentrations of ulipristal acetate may occur even if a woman has stopped taking an enzyme inducer within the last 2 3 weeks.
Conversely, potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, telithromycin, clarithromycin, nefazodone) may increase exposure to ulipristal acetate. The clinical relevance is unknown.

- addition of : Administration of ulipristal acetate (10 mg tablet) together with the proton pump inhibitor esomeprazole (20 mg daily for 6 days) resulted in approximately 65% lower mean Cmax, a delayed tmax (from a median of 0.75 hours to 1.0 hours) and 13% higher mean AUC. The clinical relevance of this interaction for single dose administration of ulipristal acetate as emergency contraception is not known.

- suppression of : P-glycoprotein transporters: In vitro data indicate that ulipristal may be an inhibitor of P-gp at clinically relevant concentrations. Thus, in the absence of clinical data, coadministration of ulipristal acetate and P-gp substrates (e.g. dabigatran etexilate, digoxin) is not recommended (see section 4.4).


Section 4.6

Pregnancy
- suppression of : It is unknown whether ulipristal acetate is excreted in human or animal breast milk.

Breast-feeding
- addition & suppression : Ulipristal acetate is a lipophilic compound and may theoretically be excreted in breast milk excreted in breast milk (see section 5.2). The effect on newborn/infants has not been studied. A risk to the breast-fed breastfed child cannot be excluded. After intakeUse of ellaOne by breastfeeding women is therefore not recommended. After intake of ellaOne breastfeeding is not recommended for one week. During this time it is recommended to express and discard the breast milk in order to stimulate lactation.

Fertility
- addition of : A rapid return of fertility is likely following treatment with ellaOne for emergency contraception; therefore, routine regular contraception should be continued or initiated as soon as possible following use of ellaOne to ensure ongoing prevention of pregnancy.Advice on how to proceed is presented in section 4.4.

Section 5.2
Absorption
- suppression of : The absorption of ulipristal acetate is pH-dependent and may be reduced in situations where gastric pH is increased irrespective of cause.

Distribution
- addition of : Ulipristal acetate is a lipophilic compound and is distributed in breast milk, with a mean daily excretion of 13.35 µg [0-24 hours], 2.16 µg [24-48 hours], 1.06 µg [48-72 hours], 0.58 µg [72-96 hours], and 0.31 µg [96-120 hours].

Biotransformation/elimination
- suppression of : CYP2D6
- addition of : CYP2A6

Interactions
- addition of : In vitro data indicate that ulipristal acetate may be an inhibitor of P-gp at clinically relevant concentrations. Results in vivo with the P-gp substrate fexofenadine were inconclusive.
In vivo results show that administration of ulipristal acetate with a potent and a moderate CYP3A4 inhibitor increased Cmax and AUC of ulipristal acetate with a maximum of 2- and 5.9-fold, respectively. The effects of CYP3A4 inhibitors and P-gp substrates are unlikely to have any clinical consequences.

Section 9
- addition of : Date of first authorisation

Section 10
- Date of revision : 15 November 2012
- update of EMA website : http://www.ema.europa.eu.

None provided