Oracea 40 mg Kapsel med modifierad frisättning, hård

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

30-10-2019

Produktens egenskaper Produktens egenskaper (SPC)

25-10-2019

Aktiva substanser:
doxycyklinmonohydrat
Tillgänglig från:
Paranova Läkemedel AB
ATC-kod:
J01AA02
INN (International namn):
doxycycline monohydrate
Dos:
40 mg
Läkemedelsform:
Kapsel med modifierad frisättning, hård
Sammansättning:
sockersfärer Hjälpämne; allurarött AC aluminiumlack Hjälpämne; propylenglykol Hjälpämne; doxycyklinmonohydrat 31,2 mg Aktiv substans; doxycyklinmonohydrat 10,42 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Bemyndigande status:
Avregistrerad
Godkännandenummer:
53167
Tillstånd datum:
2016-04-13

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

26-10-2019

Produktens egenskaper Produktens egenskaper - engelska

20-05-2021

Läs hela dokumentet

Package leaflet: Information for the patient

Efracea/Oracea/Oraycea 40 mg modified release hard capsules

doxycycline

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to you doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Efracea/Oracea/Oraycea

is and what it is used for

What you need to know before you take Efracea/Oracea/Oraycea

How to take Efracea/Oracea/Oraycea

Possible side effects

How to store Efracea/Oracea/Oraycea

Contents of the pack and other information

1.

What Efracea/Oracea/Oraycea

is and what it is used for

Efracea/Oracea/Oraycea

is a medicine containing the active substance doxycycline. It is used in adults

to reduce the pimples or red bumps on the face caused by a condition called rosacea.

2.

What you need to know before you take Efracea/Oracea/Oraycea

Do not take Efracea/Oracea/Oraycea

if you are allergic (hypersensitive) to any medicinal product in the tetracycline family,

including doxycycline or minocycline, or to any of the other ingredients of this medicine

(listed in section 6.)

if you are

pregnant

Efracea/Oracea/Oraycea

should not be used from the 4

month of pregnancy

because it may harm the unborn child. If you suspect or learn that you are pregnant

whilst taking

Efracea/Oracea/Oraycea

, contact your doctor immediately.

in combination with retinoids (drugs used in the treatment of certain skin disorders such as

severe acne) administered by the oral route (see section Other medicines and

Efracea/Oracea/Oraycea).

if you have a condition causing absence of acid in the stomach (achlorhydria) or if you have

had surgery on the upper part of the gut (called the duodenum).

Efracea/Oracea/Oraycea must not be taken by infants or children under the age of 12, because

it may cause permanent discolouration of the teeth or problems with tooth development.

Warnings and precautions

Efracea/Oracea/Oraycea must not be used to treat infections caused by bacteria.

Talk to your doctor or pharmacist before taking

Efracea/Oracea/Oraycea if

-

you have liver disease

you have a history of predisposition to candidiasis overgrowth or are currently experiencing an

oral or vaginal yeast or fungal infection

you suffer from the muscle disease called myasthenia gravis

you suffer from colitis

you suffer from oesophageal irritation or ulceration

you have the type of rosacea which affects the eyes

you expose your skin to strong sunlight or artificial sunlight, because more severe sunburn may

occur in some people taking doxycycline. You should consider using sunscreen or sunblock to

reduce the risk of sunburn and you should stop using

Efracea/Oracea/Oraycea

if your skin

becomes sunburned.

- you have been told by your doctor that you have an intolerance to some sugars

Efracea/Oracea/Oraycea may cause permanent discolouration of the teeth.

During your treatment with Efracea/Oracea/Oraycea talk to your doctor or pharmacist if:

-you develop severe or prolonged or bloody diarrhoea during or after using Efracea/Oracea/Oraycea tell

your doctor immediately since it may be necessary to interrupt the treatment. This may be a sign of bowel

inflammation (pseudomembranous colitis) which can occur following treatment with antibiotics.

Take Efracea/Oracea/Oraycea exactly as prescribed by your doctor. Taking more than your

prescribed dose may increase the chance that intestinal bacteria will become resistant to

Efracea/Oracea/Oraycea.

Other medicines and Efracea/Oracea/Oraycea

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Efracea/Oracea/Oraycea and certain other medications may not work properly when taken

together. Tell your doctor about medications that you are taking or plan to take whilst you are taking

Efracea/Oracea/Oraycea.

Efracea/Oracea/Oraycea should not be used at the same time as the medicine isotretinoin

because of the risk of increased pressure in the brain. Isotretinoin is prescribed to patients

with a severe case of acne.

Do not take antacids

,

multi-vitamins or other products that contain calcium (such as milk and

dairy products and calcium-containing fruit juices), aluminium, magnesium (including

quinapril tablets, which are taken for high blood pressure), iron or bismuth, or cholestyramine,

activated charcoal or sucralfate until 2 to 3 hours after taking Efracea/Oracea/Oraycea.

These medicines may reduce the effectiveness of Efracea/Oracea/Oraycea if taken at the same

time.

Other treatments for ulcers or heartburn may also reduce the effectiveness of

E f racea/Oracea/Oraycea and should not be taken until at least 2 hours after

Efracea/Oracea/Oraycea.

If you are taking blood thinners, your doctor may need to make changes to the dose of your

blood thinner.

If you are taking certain treatments for diabetes, your doctor may need to check whether the

dose of the diabetes treatment has to be changed.

- Efracea/Oracea/Oraycea may make certain antibiotics, including penicillins, less effective.

Taking barbiturates (sleeping pills or short-term pain-killers), rifampicin (tuberculosis),

carbamazepine (epilepsy), diphenylhydantoin and phenytoin (seizures of the brain), primidone

(anti-convulsant) or cyclosporin (organ transplant) may reduce the time that

Efracea/Oracea/Oraycea stays active in your system.

Using Efracea/Oracea/Oraycea with the general anaesthetic methoxyfluorane may cause serious

harm to the kidneys.

Efracea/Oracea/Oraycea with food and drink

Always take Efracea/Oracea/Oraycea with an adequate amount of water to wash down the

capsule, since this reduces the risk of irritation or ulcer in the throat or gullet.

Do not take milk or dairy products at the same time as Efracea/Oracea/Oraycea since these

products contain calcium which may reduce the effectiveness of

Efracea

. Leave 2 to 3 hours after

your daily dose of Efracea/Oracea/Oraycea before drinking or eating dairy products.

Pregnancy and breast-feeding

Efracea/Oracea/Oraycea must not be used during pregnancy since it may cause permanent

discolouration of the teeth in the unborn child.

Efracea/Oracea/Oraycea should not be used for long periods by breastfeeding mothers since it may

cause tooth discolouration and reduced bone growth in the suckling child.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your

doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Efracea/Oracea/Oraycea has no or negligible influence on the ability to drive and

use machines.

Efracea/Oracea/Oraycea contains sugar (sucrose) and allura red AC aluminium lake (E129).

If you

have been told by your doctor that you have an intolerance to some sugars, contact your doctor

before taking this medicine.

The ink used to print on the capsule contains Allura red AC aluminium lake (E129) which may cause

allergic reactions.

3.

How to take Efracea/Oracea/Oraycea

Always take Efracea/Oracea/Oraycea this medicine exactly as your doctor has told you. Check with

your doctor or pharmacist if you are not sure.

The recommended dose is one capsule of Efracea/Oracea/Oraycea each day in the morning, on an

empty stomach, preferably at least one hour prior to or two hours after the meal. Swallow the capsule

whole and do not chew it.

You should take Efracea/Oracea/Oraycea with a full glass of water whilst sitting or standing to avoid

any irritation to the throat.

If you take more Efracea/Oracea/Oraycea than you should

If you take an overdose of Efracea/Oracea/Oraycea, there is a risk of damage to the liver, kidneys

or pancreas. If you take more Efracea/Oracea/Oraycea capsules than you should, ask your doctor

immediately for advice.

If you forget to take Efracea/Oracea/Oraycea

Do not take a double dose to make up for a forgotten capsule.

If you stop taking Efracea/Oracea/Oraycea

You should continue to take Efracea/Oracea/Oraycea until your doctor tells you to stop.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

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

If any of the side effects listed below occur, contact your doctor as soon as possible:

The Jarisch-Herxheimer reaction which causes fever, chills, headache, muscle pain, and skin

rash that is usually self-limiting. This occurs shortly after starting doxycycline treatment for

infections with spirochete such as Lyme disease.

Common side effects

The following side effects may occur commonly (affects 1 to 10 users in 100) during treatment with

Efracea/Oracea/Oraycea:

Inflammation of the nose and throat

Inflammation of the sinuses

Fungal infection

Anxiety

Sinus headache

High or increased blood pressure

Diarrhoea

Pain in the upper part of the abdomen

Dry mouth

Back pain

Pain

Changes in some blood tests (amount of glucose in blood or tests of liver function).

Side effects of unknown frequency

(cannot be estimated from the available data). The following side

effects may occur during the treatment with Efracea/Oracea/Oraycea:

Increased pressure in the brain

Headache

Rare side effects

The following side effects may occur rarely (affects 1 to 10 users in 10,000) during treatment with the

class of medicines to which Efracea/Oracea/Oraycea belongs (the tetracyclines):

Allergic (hypersensitivity) reaction throughout the body*

Changes in the number or type of certain blood cells

Increased pressure in the brain

Inflammation of the membrane surrounding the heart

Nausea, vomiting, diarrhoea, anorexia

Liver damage

Skin rashes or hives

Abnormal reaction of the skin to sunlight

Increased level of urea in the blood

Very rare side effects

The following side effects may occur very rarely (affects less than 1 user in 10,000) during treatment

with the class of medicines to which Efracea/Oracea/Oraycea belongs (the tetracyclines):

Allergic reaction causing swelling of the eyes, lips or tongue*

Yeast infection around the anus or genitals

Damage to red blood cells (haemolytic anaemia)

Brown-black microscopic discolouration of thyroid tissue has been reported with long-term use of

tetracyclines. Thyroid function is normal.

Increased pressure in the brain in infants

Inflammation of the tongue

Difficulty in swallowing

Inflammation of the intestine

Inflammation or ulceration of the gullet

Inflammation of the skin causing flakiness

Worsening of the immune system disease known as systemic lupus erythematosus (SLE)

Side effects of unknown frequency

(cannot be estimated from the available data)

The following side effects may occur during treatment with the class of medicines to which EFRACEA

belongs (the tetracyclines):

Loosening of the nail from the nail bed after exposure to the sun

* Tell your doctor immediately or go to casualty if you suffer side effects such as swollen face, lips,

tongue and throat, difficulty in breathing, hives or itchy skin and eyes, or rapid heartbeat

(palpitations) and feeling faint. These effects may be symptoms of a severe allergic (hypersensitivity)

reaction.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not

listed in this leaflet. You can also report side effects directly via the national reporting system listed in

Appendix V. By reporting side effects, you can help provide more information on the safety of this

medicine.

5.

How to store Efracea/Oracea/Oraycea

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the outer pack and blister after

EXP. The expiry date refers to the last day of that month.

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

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer used. These measures will help to protect the environment.

6.

Contents of the pack and other information

What Efracea/Oracea/Oraycea contains

The active substance is doxycycline. Each capsule contains 40 mg doxycycline (as monohydrate).

The other ingredients are:

hypromellose, methacrylic acid-ethyl acrylate copolymer (1:1), triethyl citrate, talc, titanium

dioxide, macrogol 400, yellow iron oxide, red iron oxide, polysorbate 80, sugar spheres (maize

starch, sucrose).

Capsules: gelatin, black iron oxide, red iron oxide, yellow iron oxide, titanium dioxide

Printing ink: shellac, propylene glycol, black iron oxide, indigo carmine aluminium lake, allura red

AC aluminium lake (E129), brilliant blue FCF aluminium lake, D & C yellow no. 10 aluminium lake.

See end of section 2 for information on sugar (sucrose) and allura red AC aluminium lake (E129).

What Efracea/Oracea/Oraycea looks like and contents of the pack

Efracea/Oracea/Oraycea is a modified-release hard capsule.

The capsules are beige in colour and bear the marking “GLD 40”.

Efracea/Oracea/Oraycea is available in packs containing 56, 28, or 14 capsules (not all pack

sizes may be marketed).

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

{Name and address}

<{tel}>

<{fax}>

<{e-mail}>

The manufacturer responsible for batch release is:

Patheon France, 40 boulevard de Champaret

38300 BOURGOIN JALLIEU

France

Laboratoires GALDERMA, Zone Industrielle Montdésir

74540 Alby sur Chéran, France

Galderma Laboratorium GmbH, Toulouser Allee 23a

40211 Düsseldorf, Germany

This medicinal product is authorized in the Member States of the EEA under the following

names:

DK, EL, ES, FI, IS, SE, NO – ORACEA 40 mg modified release hard capsules

DE, AT - ORAYCEA 40 mg modified release hard capsules

BE, FR, NL, UK, IE, IT, PL, PT, LU – EFRACEA 40 mg modified release hard capsules

This leaflet was last revised in 2019-10-26

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1.

NAME OF THE MEDICINAL PRODUCT

Efracea/Oracea/Oraycea 40 mg modified-release hard capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 40 mg doxycycline (as monohydrate).

Excipients with known effect: 102 – 150 mg of sucrose and 26.6 - 29.4 μg of Allura red AC

aluminium lake (E129).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Modified-release hard capsule

Beige capsule, No. 2 size, bear the marking “GLD 40”.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Efracea/Oracea/Oraycea is indicated to reduce papulopustular lesions in adult patients with facial

rosacea.

4.2

Posology and method of administration

Posology

Adults, including older people:

Oral use.

The daily dose is 40 mg (1 capsule). It can be taken as monotherapy or as part of combination

treatment (see section 5.1).

Patients with renal impairment

No dosage adjustment is necessary in patients with renal impairment.

Patients with hepatic impairment

Efracea/Oracea/Oraycea should be administered with caution to patients with hepatic impairment or

to those receiving potentially hepatotoxic medicinal products (see section 4.4)

Paediatric population

Efracea/Oracea/Oraycea is contraindicated in children below 12 years of age (see section 4.3).

Method of administration

The capsule should be taken in the morning, on an empty stomach, preferably at least one hour

prior to or two hours after the meal.

The capsule should be taken with adequate amounts of water in order to reduce the risk of

oesophageal irritation and ulceration (see section 4.4).

Patients should be evaluated after 6 weeks and, if no effect is seen, consideration should be given to

stopping treatment. In clinical trials patients were treated for 16 weeks. Upon discontinuation,

lesions tended to reappear at 4 weeks follow-up. Therefore, it is recommended that patients should be

assessed 4 weeks after stopping treatment.

4.3

Contraindications

Hypersensitivity to the active substance, to other tetracyclines or to any of the excipients listed in

section 6.1.

Infants and children up to 12 years of age.

Second and third trimesters of pregnancy (see section 4.6).

Concomitant treatment with oral retinoids (see section 4.5).

Patients known to have, or suspected to have, achlorhydria or who have had surgery that bypasses or

excludes the duodenum must not be prescribed doxycycline.

4.4

Special warnings and precautions for use

Efracea/Oracea/Oraycea contains doxycycline in a formulation designed to yield anti-

inflammatory plasma levels below the antimicrobial threshold. Efracea/Oracea/Oraycea must

not be used to treat infections caused by organisms susceptible (or suspected to be susceptible)

to doxycycline.

Solid dosage forms of the tetracyclines may cause oesophageal irritation and ulceration. To avoid

oesophageal irritation and ulceration, adequate fluids (water) should be taken with this medicinal

product (see section 4.2). Efracea/Oracea/Oraycea should be swallowed whilst in an upright sitting or

standing posture.

Whilst no overgrowth by opportunistic microorganisms such as yeasts were noted during the clinical

studies

with

Efracea/Oracea/Oraycea,

therapy

with

tetracyclines

higher

doses

result

overgrowth of non-susceptible microorganisms including fungi. Although not observed in clinical

trials

with

Efracea/Oracea/Oraycea,

tetracyclines

higher

doses

increase

incidence of vaginal candidiasis. Efracea/Oracea/Oraycea should be used with caution in patients

with a history of predisposition to candidiasis overgrowth. If superinfection is suspected, appropriate

measures should be taken, including consideration of discontinuing Efracea/Oracea/Oraycea.

Treatment with higher doses of tetracyclines is associated with emergence of resistant intestinal

bacteria, such as enterococci and enterobacteria. Although not observed during clinical studies with

low dose doxycycline (40 mg/day), the risk for development of resistance in the normal microflora

cannot be excluded in patients treated with Efracea/Oracea/Oraycea.

Doxycycline blood levels in patients treated with Efracea/Oracea/Oraycea are lower than in those

treated with conventional antimicrobial formulations of doxycycline. However, as there are no data to

support

safety

hepatic

impairment

this

lower

dose,

Efracea/Oracea/Oraycea

should

administered with caution to patients with hepatic impairment or to those receiving potentially

hepatotoxic medicinal products. The antianabolic action of tetracyclines may cause an increase in

BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with

impaired renal function.

The bioavailability of doxycycline is reported to be reduced at high pH (also see section 4.5).

Caution should be observed in the treatment of patients with myasthenia gravis who may be at risk of

worsening of the condition.

All patients receiving doxycycline, including Efracea/Oracea/Oraycea, should be advised to avoid

excessive sunlight or artificial ultraviolet light whilst receiving doxycycline and to discontinue

therapy if phototoxicity (eg skin eruption etc) occurs. Use of sunscreen or sunblock should be

considered. Treatment should cease at the first sign of photosensitivity.

In common with the use of antimicrobial medicinal products in general, there is a risk of the

development

pseudomembranous

colitis

with

doxycycline

treatment.

event

development

diarrhoea

during

treatment

with

Efracea/Oracea/Oraycea,

possibility

pseudomembranous colitis should be considered and appropriate therapy instituted. This may include

the discontinuation of doxycycline and the institution of specific antibiotic therapy. Agents inhibiting

peristalsis should not be employed in this situation.

Efracea/Oracea/Oraycea should not be used in patients with ocular manifestations of rosacea (such as

ocular rosacea and/or blepharitis/meibomianitis) as there are limited efficacy and safety data in this

population. If these manifestations appear during the course of the treatment Efracea/Oracea/Oraycea

should be discontinued and the patient should be referred to an ophthalmologist.

In humans, the use of tetracyclines during tooth development may cause permanent discolouration of

the teeth (yellow-grey-brown). This reaction is more common during long-term use of the medicinal

product but has been observed following repeated short-term courses. Enamel hypoplasia has also

been reported. As for other tetracyclines, doxycycline forms a stable calcium complex in any bone-

forming tissue. A decrease in fibula growth has been observed in premature infants given oral

tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the

medicinal product was discontinued.

event

severe

acute

hypersensitivity

reaction

anaphylaxis),

treatment

with

Efracea/Oracea/Oraycea must be stopped at once and the usual emergency measures taken (eg

administration

antihistamines,

corticosteroids,

sympathomimetics

and,

necessary,

artificial

respiration).

Some patients with spirochete infections may experience a Jarisch-Herxheimer reaction shortly after

doxycycline treatment is started. Patients should be reassured that this is a usually self-limiting

consequence of antibiotic treatment of spirochete infections.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or

sucrase-isomaltase insufficiency should not take this medicinal product.

Capsule printing ink contains Allura red AC aluminium lake (E129) which may cause allergic

reactions.

4.5

Interaction with other medicinal products and other forms of interaction

The recommendations below regarding the potential interactions between doxycycline and other

medicinal products are based upon experience with the larger doses generally used in antimicrobial

formulations of doxycycline rather than with Efracea/Oracea/Oraycea. However, at the present time,

insufficient data exist for reassurance that the interactions described with higher doses of doxycycline

will not occur with Efracea/Oracea/Oraycea.

Interactions affecting doxycycline:

The absorption of doxycycline from the gastro-intestinal tract may be inhibited by bi- or tri-valent

ions such as aluminium, zinc, calcium (found for example in milk, dairy products and calcium-

containing fruit juices), by magnesium (found for example in antacids) or by iron preparations,

activated

charcoal,

cholestyramine,

bismuth

chelates

sucralfate.

Therefore,

such

medicinal

products

foodstuffs

should

taken

after

period

3 hours

following

ingestion

doxycycline.

Medicinal products which increase gastric pH may reduce the absorption of doxycycline and should

be taken at least 2 hours after doxycycline.

Quinapril may reduce the absorption of doxycycline due to the high magnesium content in quinapril

tablets.

Rifampicin,

barbiturates,

carbamazepine,

diphenylhydantoin,

primidone,

phenytoin

chronic

alcohol abuse may accelerate the decomposition of doxycycline due to enzyme induction in the liver

thereby decreasing its half-life. Sub-therapeutic doxycycline concentrations may result.

Concurrent use of cyclosporin has been reported to decrease the half-life of doxycycline.

Interactions affecting other medicinal products:

Concomitant use not recommended:

When doxycycline is administered shortly before, during or after courses of isotretinoin, there is the

possibility of potentiation between the medicinal products to cause reversible pressure increase in the

intracranial

cavity

(intracranial

hypertension).

Concomitant

administration

should

therefore

avoided.

Bacteriostatic medicinal products including doxycycline may interfere with the bacteriocidal action of

penicillin and beta-lactam antibiotics. It is advisable that doxycycline and beta-lactam antibiotics

should not therefore be used in combination.

Other interactions:

Tetracyclines and methoxyflurane used in combination have been reported to result in fatal renal

toxicity.

Doxycycline has been shown to potentiate the hypoglycaemic effect of sulphonylurea oral antidiabetic

agents. If administered in combination with these medicinal products, blood glucose levels should be

monitored and, if necessary, the doses of the sulphonylureas should be reduced.

Doxycycline has been shown to depress plasma prothrombin activity thereby potentiating the effect of

anticoagulants of the dicoumarol type. If administered in combination with these agents, coagulation

parameters including INR should be monitored and, if necessary, the doses of the anticoagulant

medicinal products reduced. The possibility of an increased risk of bleeding events should be borne

in mind.

4.6

Fertility, pregnancy and lactation

Pregnancy

Studies in animals have not demonstrated a teratogenic effect. In humans, the use of tetracyclines

during a limited number of pregnancies has not revealed any specific malformation to date.

The administration of tetracyclines during the second and the third trimesters results in permanent

discolouration

deciduous

teeth

offspring.

consequence,

doxycycline

contraindicated during the second and third trimesters of

pregnancy (see section 4.3).

Breatsfeeding

Low levels of tetracyclines are secreted into the milk of lactating women. Doxycycline can be used

by breast-feeding mothers for short term use only. Long term use of doxycycline may result in

significant

absorption

suckling

infant

therefore

recommended

because

theoretical risk of dental discolouration and decreased bone growth of the suckling child.

Fertility

Oral administration of doxycycline to male and female Sprague-Dawley rats adversely affected

fertility and reproductive performance (see section 5.3)

The effect of Efracea/Oracea/Oraycea on human fertility is unknown.

4.7

Effects on ability to drive and use machines

Efracea/Oracea/Oraycea has no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects

Summary of the safety profile

In the pivotal placebo-controlled studies with Efracea/Oracea/Oraycea in rosacea, 269 patients were

treated with Efracea/Oracea/Oraycea 40 mg once daily and 268 patients were treated with placebo for

16 weeks. Gastrointestinal adverse reactions overall occurred in a higher proportion of patients on

Efracea/Oracea/Oraycea (13.4%) than on placebo (8.6%). The most commonly reported adverse

reactions in patients treated with Efracea/Oracea/Oraycea, ie those which occurred with ≥ 3%

frequency on Efracea/Oracea/Oraycea and with a frequency at least 1% higher than on placebo, were

nasopharyngitis, diarrhoea and hypertension.

Tabulated list of adverse reactions

The table below lists adverse reactions on Efracea/Oracea/Oraycea in the pivotal clinical trials, ie

adverse reactions for which the frequency on Efracea/Oracea/Oraycea was greater than the frequency

on placebo (by

1%).

Adverse reactions reported for tetracycline antibiotics as a class are listed following the table. The

adverse reactions are classified by System Organ Class and frequency, using the following

convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100),

rare (≥ 1/10,000 to <1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the

available data) and were reported with Efracea/Oracea/Oraycea in clinical studies (see Table 1).

Table 1 - Adverse reactions

on Efracea/Oracea/Oraycea in pivotal placebo-controlled studies in

rosacea:

MedDRA system organ class

Common:

Frequency

1/100, < 1/10

Infections and infestations

Nasopharyngitis

Sinusitis

Fungal infection

Psychiatric disorders

Anxiety

Nervous system disorders

Sinus headache

Vascular disorders

Hypertension

Gastrointestinal disorders

Diarrhoea

Abdominal pain, upper

Dry mouth

Musculoskeletal and connective tissue

disorders

Back pain

General disorders and administration

site conditions

Pain

Investigations

ASAT increased

Blood pressure increased

Blood LDH increased

Blood glucose increased

Defined as adverse events for which the frequency on Efracea/Oracea/Oraycea was higher than on

placebo (by at least 1%)

Benign intracranial hypertension and headache (unknown frequency: cannot be estimated from the

available data) have been reported during Efracea/Oracea/Oraycea postmarketing surveillance.

The following adverse reactions have been observed in patients receiving tetracyclines:

Infections and infestations:

Very rare:

Anogenital candidiasis

Blood and lymphatic system disorders:

Rare:

Thrombocytopenia, neutropenia, eosinophilia

Very rare:

Haemolytic anaemia

Immune system disorders:

Rare:

Hypersensitivity reactions including anaphylaxis

There have also been reports of: Anaphylactoid purpura

Endocrine disorders:

Very rare:

Brown-black microscopic discolouration of thyroid tissue has been reported with long-

term use of tetracyclines. Thyroid function is normal.

Nervous system disorders:

Rare:

Benign intracranial hypertension

Very rare:

Bulging fontanelle in infants

Treatment should cease if evidence of raised intracranial pressure develops. These conditions

disappeared rapidly when the drug was discontinued.

Cardiac disorders:

Rare:

Pericarditis

Gastrointestinal disorders

Rare:

Nausea, vomiting, diarrhoea, anorexia

Very rare:

Glossitis, dysphagia, enterocolitis. Oesophagitis and oesophageal ulceration have been

reported most often in patients administered the hyclate salt in capsule form. Most of

these patients took medication just prior to going to bed.

Hepatobiliary disorders:

Rare:

Hepatotoxicity

Skin and subcutaneous tissue disorders

Rare:

Maculopapular and erythematous rashes, skin photosensitivity, urticaria

Very rare:

Exfoliative dermatitis, angioneurotic oedema

Unknown frequency: photo-onycholysis

Musculoskeletal and connective tissue disorders:

Very rare:

Exacerbation of systemic lupus erythematosus

Renal and urinary disorders:

Rare:

Increased blood urea.

Adverse reactions typical of the tetracycline class of medicinal products are less likely to occur during

medication with Efracea/Oracea/Oraycea, due to the reduced dosage and the relatively low plasma

levels involved. However, the clinician should always be aware of the possibility of adverse events

occurring and should monitor patients accordingly.

The following adverse reaction has been observed in patients receiving doxycycline:

Immune system disorders:

Unknown frequency: Jarisch-Herxheimer reaction (see section 4.4)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows

continued

monitoring

benefit/risk

balance

medicinal

product.

Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in Appendix V.

4.9

Overdose

Symptoms

To date no significant acute toxicity has been described in the case of a single oral intake of a multiple

of therapeutic doses of doxycycline. In case of overdose there is, however, a risk of parenchymatous

hepatic and renal damage and of pancreatitis.

Treatment

The usual dose of Efracea/Oracea/Oraycea is less than half the usual doses of doxycycline used for

antimicrobial therapy. Therefore clinicians should bear in mind that in many cases overdose is likely

to produce blood concentrations of doxycycline within the therapeutic range for antimicrobial

treatment, for which there is a large quantity of data supporting the safety of the medicinal product.

In these cases observation is recommended. In cases of significant overdose, doxycycline therapy

should be stopped immediately and symptomatic measures undertaken as required.

Intestinal absorption of unabsorbed doxycycline should be minimised by administering magnesium or

calcium salt-containing antacids to produce non-absorbable chelate complexes with doxycycline.

Gastric lavage should be considered.

Dialysis does not alter serum doxycycline half-life and thus would not be of benefit in treating cases

of overdose.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, Tetracyclines. ATC code: J01AA02.

Mechanism of Action

The pathophysiology of the inflammatory le

sions of rosacea is, in part, a

manifestation of a

neutrophil-mediated process. Doxycycline has been shown to inhibit neutrophil activity and several

pro-inflammatory reactions including those associated with phospholipase A

, endogenous nitric

oxide and interleukin-6. The clinical significance of these findings is not known.

Pharmacodynamic effects

The plasma concentration of doxycycline following administration of Efracea/Oracea/Oraycea is well

below the level required to inhibit mircoorganisms commonly associated with bacterial diseases.

In vivo microbiological studies using similar exposure to the active substance for 6 to 18 months

could not demonstrate any effect on the dominating bacterial flora sampled from the oral cavity, skin,

intestinal tract and vagina. However, it cannot be excluded that long-term use of

Efracea/Oracea/Oraycea can lead to emergence of resistant intestinal bacteria such as

Enterobacteriaceae and enterococci, as well as to enrichment of resistance genes.

Clinical efficacy and safety

Efracea/Oracea/Oraycea

been

evaluated

pivotal

randomised,

double-blind,

placebo-

controlled, 16-week studies in 537 patients with rosacea (10 to 40 papules and pustules, and two or

fewer nodules). In both studies, the mean reduction in the total inflammatory lesion count was

significantly greater in the Efracea/Oracea/Oraycea group than in the placebo group:

Table 2 - Mean change from baseline to Week 16 in total inflammatory lesion count:

Study 1

Study 2

Efracea/Oracea/Orayce

a 40 mg

(N = 127)

Placebo

(N = 124)

Efracea/Oracea/Orayce

a 40 mg

(N = 142)

Placebo

(N = 144)

Mean (SD) change

from baseline

-11.8 (9.8)

-5.9 (13.9)

-9.5 (9.6)

-4.3 (11.6)

Mean between-

group difference

-5.9

-5.2

(95% confidence

limits)

(-8.9, -2.9)

(-7.7, -2.7)

p-Value

0.0001

< 0.0001

p-Value for treatment difference in change from baseline (ANOVA)

Treatment with doxycycline 40 mg modified release capsules plus ivermectin

The ANSWER study evaluated the relative efficacy of doxycycline 40 mg modified release capsules

(DMR) in combination with Soolantra (IVM) vs IVM plus DMR placebo (PBO) in the treatment of

severe rosacea. It was a 12-week, randomized, investigator-blind, controlled, parallel-group study of

273 male and female subjects aged ≥18 years with 20-70 inflammatory lesions (papules and pustules)

on the face and a baseline Investigator’s Global Assessment (IGA) score of 4.

The primary efficacy endpoint was the percentage change from baseline in inflammatory lesion

counts at Week 12. A significantly greater mean percentage reduction in inflammatory lesion count

was seen for IVM + DMR compared to IVM + PBO (mean ± standard deviation: -80.29 ± 21.65 % vs

-73.56 ± 30.52 %; p=0.032).

5.2

Pharmacokinetic properties

Absorption

Doxycycline is almost completely absorbed after oral administration. Following oral administration

of Efracea/Oracea/Oraycea, mean peak plasma concentrations were 510 ng/mL after a single dose and

600 ng/mL at steady state (Day 7). Peak plasma levels were generally achieved at 2 to 3 hours after

administration. Coadministration with a high-fat, high-protein meal that included dairy products

reduced the bioavailability (AUC) of doxycycline from Efracea/Oracea/Oraycea by about 20% and

reduced the peak plasma level by 43%.

Distribution

Doxycycline is greater than 90% bound to plasma proteins and has an apparent volume of distribution

of 50 L.

Biotransformation

Major metabolic pathways of doxycycline have not been identified but enzyme inducers decrease the

half-life of doxycycline.

Elimination

Doxycycline is excreted in the urine and faeces as unchanged active substance. Between 40% and

60% of an administered dose can be accounted for in the urine by 92 hours, and approximately 30% in

faeces.

terminal

elimination

half-life

doxycycline

after

administration

Efracea/Oracea/Oraycea was approximately 21 h after a single dose and approximately 23 h at steady

state.

Other special populations

The half-life of doxycycline is not significantly altered in patients with severely impaired renal

function. Doxycycline is not eliminated to any great extent during haemodialysis.

There is no information on the pharmacokinetics of doxycycline in patients with hepatic impairment.

5.3

Preclinical safety data

Adverse reactions seen in repeat dose studies in animals include hyperpigmentation of the thyroid and

tubular degeneration in the kidney. These effects were seen at exposure levels of 1.5 to 2 times those

seen in humans administered Efracea/Oracea/Oraycea at the proposed dose. The clinical relevance of

these findings remains unknown.

Doxycycline showed no mutagenic activity and no convincing evidence of clastogenic activity. In a

rat carcinogenicity study increases in benign tumours of the mammary gland (fibroadenoma), uterus

(polyp) and thyroid (C-cell adenoma) were noted in females.

In rats, doses of 50 mg/kg/day doxycycline caused a decrease in the straight-line velocity of sperm but

did not affect male or female fertility or sperm morphology. At this dose systemic exposure

experienced by rats is likely to have been approximately 4 times that seen in humans taking the

recommended dose of Efracea/Oracea/Oraycea. At doses greater than 50 mg/kg/day fertility and

reproductive performance were adversely affected in rats. A peri/postnatal toxicity study in rats

revealed no significant effects at therapeutically relevant doses. Doxycycline is known to cross the

placenta and literature data indicate that tetracyclines can have toxic effects on the developing foetus.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Capsule shell

Gelatin

Black iron oxide

Red iron oxide

Yellow iron oxide

Titanium dioxide

Printing inks

Shellac

Propylene glycol

Black iron oxide

Indigo Carmine aluminium lake

Allura Red AC aluminium lake (E129)

Brilliant Blue FCF aluminium lake

D & C Yellow No. 10 aluminium lake

Capsule contents

Hypromellose

Methacrylic acid-ethyl acrylate copolymer (1:1)

Triethyl citrate

Talc

Hypromellose, Titanium dioxide, Macrogol 400, Yellow iron oxide, Red iron oxide, Polysorbate 80

Sugar spheres (Maize starch, Sucrose)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years

6.4

Special precautions for storage

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

6.5

Nature and contents of container

Aluminium/PVC/Aclar blister

Pack size: 56 capsules in 4 strips of 14 each

28 capsules in 2 strips of 14 each

14 capsules in 1 strip of 14

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements

7.

MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

8.

MARKETING AUTHORISATION NUMBERS

<[To be completed nationally]>

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<[To be completed nationally]>

10.

DATE OF REVISION OF THE TEXT

2021-04-21

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