Label: information for the user

Hepaxane 2,000 UI (20 mg)/0.2 mL injectable solution in preloaded syringe

Hepaxane 4,000 UI (40 mg)/0.4 mL injectable solution in preloaded syringe

Hepaxane 6,000 UI (60 mg)/0.6 mL injectable solution in preloaded syringe

Hepaxane 8,000 UI (80 mg)/0.8 mL injectable solution in preloaded syringe

Hepaxane 10,000 UI (100 mg)/1 mL injectable solution in preloaded syringe

Hepaxane 12,000 UI (120 mg)/0.8 mL injectable solution in preloaded syringe

Hepaxane 15,000 UI (150 mg)/1 mL injectable solution in preloaded syringe

Enoxaparin sodium

This medicine is subject to additional monitoring, which will expedite the detection of new information about its safety. You can contribute by reporting any adverse effects you may experience. The final part of section 4 includes information on how to report these adverse effects.

Read this label carefully before starting to use this medicine, as it contains important information for you.

• Keep this label, as you may need to read it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• This medicine has been prescribed only for you, and you should not give it to others even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this label. See section 4.

Hepaxane contains an active ingredient called enoxaparin sodium, which is a low molecular weight heparin (LMWH).

Hepaxane acts in two ways:

1. Preventing existing blood clots from growing larger. This helps your body break them down and prevent further damage.
2. Preventing the formation of blood clots.

Hepaxane may be used for:

• Treating blood clots.
• Preventing blood clots from forming in the following situations:

• Before and after surgery.
• When you have an acute illness and are expected to have reduced mobility.
• When you have developed blood clots due to cancer, to prevent new clots from forming.
• When you have unstable angina (a condition in which not enough blood reaches the heart).
• After a heart attack.

• Preventing blood clots in the tubes of the dialysis equipment (used by people with severe kidney problems).

Do not use Hepaxane

• If you are allergic to enoxaparin sodium or to any of the other components of this medication (listed in section 6). Signs of an allergic reaction include: rash, difficulty swallowing or breathing, swelling of the lips, face, throat, or tongue.
• If you are allergic to heparin or to other low molecular weight heparins such as nadroparin, tinzaparin, or dalteparin.
• If you have had a reaction to heparin that caused a severe decrease in the number of cells that participate in blood clotting (platelets) – this reaction is known as heparin-induced thrombocytopenia – in the last 100 days or if you have antibodies against enoxaparin in your blood.
• If you are bleeding heavily or have a high risk of bleeding (such as stomach ulcers, recent brain or eye surgery), including recent hemorrhagic stroke.
• If you are using Hepaxane to treat blood clots, and are to receive spinal or epidural anesthesia or lumbar puncture within 24 hours.

Warnings and precautions

Hepaxane should not be exchanged with other medications that belong to the group of low molecular weight heparins. This is because they are not exactly the same and do not have the same activity or instructions for use.

Consult with your doctor or pharmacist before starting to use Hepaxane if:

• You have ever had a reaction to heparin that caused a severe decrease in the number of platelets.
• You are to receive spinal or epidural anesthesia or lumbar puncture (see “Surgical procedures and anesthesia”): a time delay between the use of Hepaxane and these procedures should be respected.
• You have had a heart valve implanted.
• You have endocarditis (a heart infection).
• You have a history of stomach ulcers.
• You have recently had a stroke (cerebral hemorrhage).
• You have high blood pressure.
• You have diabetes or eye blood vessel problems caused by diabetes (diabetic retinopathy).
• You have recently undergone eye or brain surgery.
• You are an elderly person (over 65 years old), especially if you are over 75 years old.
• You have kidney problems.
• You have liver problems.
• You have a very low or high body weight.
• You have high potassium levels in your blood, which may be checked with a blood test.
• You are currently using medications that affect bleeding (see below “Other medications and Hepaxane”).

You may need to have a blood test before starting to use this medication and while you are using it to check the level of platelets and potassium levels in your blood.

Other medications and Hepaxane

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication.

• Warfarin used to reduce blood clotting.
• Aspirin (also known as acetylsalicylic acid or AAS), clopidogrel, or other medications used to prevent blood clots (see also section 3 “Change of anticoagulant treatment”).
• Dextran injection used as a blood substitute.
• Ibuprofen, diclofenac, ketorolac, or other medications known as nonsteroidal anti-inflammatory drugs, used to treat pain and inflammation in arthritis and other diseases.
• Prednisolone, dexamethasone, and other medications used to treat asthma, rheumatoid arthritis, and other diseases.
• Medications that increase potassium levels in the blood, such as potassium salts, diuretics, and some medications for heart problems.

Surgical procedures and anesthesia

If you are to undergo a lumbar puncture or undergo a surgical procedure where spinal or epidural anesthesia will be used, inform your doctor that you are using Hepaxane (see “Do not use Hepaxane”). Also inform your doctor if you have any problems with your spine or if you have undergone spinal surgery.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or if you think you may be pregnant or intend to become pregnant, consult your doctor or pharmacist before using this medication.

If you are pregnant and have a mechanical heart valve, you may be at higher risk of developing blood clots. Your doctor will discuss this with you.

Driving and operating machinery

Hepaxane does not affect the ability to drive and operate machinery.

Hepaxane contains sodium

This medication contains less than 1 mmol of sodium (23 mg) per dose, which is essentially “sodium-free”.

It is recommended that the healthcare professional note the commercial name and batch number of the medication you are using.

Follow exactly the administration instructions of this medication indicated by your doctor or pharmacist. In case of doubt, consult your doctor or pharmacist again.

Medication use

• Your doctor or nurse will usually administer Hepaxane to you. This is because it has to be administered by injection.
• When you return home, you may need to continue using Hepaxane and administer it yourself (see instructions on how to do it).

• Hepaxane is usually administered by subcutaneous injection.
• Hepaxane can be administered by intravenous injection after certain types of heart attacks and surgical operations.
• Hepaxane can be added to the tube that comes out of the body (arterial line) at the beginning of the dialysis session.

Do not administer Hepaxane intramuscularly.

How much will be administered

• Your doctor will decide how much Hepaxane will be administered to you. The amount will depend on the reason you need to use it.
• If you have any kidney problems, you may be administered a smaller amount of Hepaxane.

1. Treatment of blood clot formation:

• The usual dose is 150 UI (1.5 mg) per kilogram of body weight per day or 100 UI (1 mg) per kilogram of body weight, twice a day.
• Your doctor will decide how long you will receive Hepaxane.

1. Prevention of blood clot formation in the following situations:
   1. Surgical procedures or periods of limited mobility due to illness

• The dose will depend on your likelihood of developing a clot. You will be administered 2,000 UI (20 mg) or 4,000 UI (40 mg) of Hepaxane per day.
• If you are to undergo surgery, you will usually be administered the first injection 2 or 12 hours before the operation.
• If you have limited mobility due to illness, you will usually be administered 4,000 UI (40 mg) of Hepaxane per day.
• Your doctor will decide how long you will receive Hepaxane.

Hepaxane can be used in two different types of heart attacks, called STEMI (ST-elevation myocardial infarction) or non-STEMI (NSTEMI). The amount of Hepaxane you should receive will depend on your age and the type of heart attack you had.

Non-STEMI heart attack:

• The usual dose is 100 UI (1 mg) per kilogram of body weight, every 12 hours.
• You will usually be told to also take aspirin (acetylsalicylic acid).
• Your doctor will decide how long you will receive Hepaxane.

STEMI heart attack, if you are under 75 years old:

• You will be administered an initial intravenous injection of 3,000 UI (30 mg) of Hepaxane.
• You will also be administered a subcutaneous injection of Hepaxane. The usual dose is 100 UI (1 mg) per kilogram of body weight, every 12 hours.
• You will usually be told to also take aspirin (acetylsalicylic acid).
• Your doctor will decide how long you will receive Hepaxane.

STEMI heart attack, if you are 75 years old or older:

• The usual dose is 75 UI (0.75 mg) per kilogram of body weight, every 12 hours.
• The maximum amount of Hepaxane administered in the first two injections is 7,500 UI (75 mg).
• Your doctor will decide how long you will receive Hepaxane.

If you are to undergo a percutaneous coronary intervention (PCI):

Depending on when you were last administered a Hepaxane injection, your doctor may decide to administer an additional dose of Hepaxane before the PCI procedure. This will be administered intravenously.

1. Prevention of blood clot formation in dialysis tubing

• The usual dose is 100 UI (1 mg) per kilogram of body weight.
• Hepaxane is added to the tube that comes out of the body (arterial line) at the beginning of the dialysis session. This amount is usually sufficient for a 4-hour session. However, your doctor may perform a new injection of 50 UI to 100 UI (0.5 to 1 mg) per kilogram of body weight, if necessary.

Administration form

The pre-filled syringe is prepared for immediate use.

This medication should not be administered intramuscularly.

Injection through the arterial line of the extracorporeal circuit

To prevent blood clot formation in the dialysis tubing, this medication will be injected into the tube that comes out of the body (arterial line).

Intravenous injection technique [only for STEMI heart attack indication]

In the treatment of STEMI heart attack, treatment should begin with a single rapid intravenous injection, followed immediately by a subcutaneous injection.

Subcutaneous injection technique (injection under the skin)

This medication is usually administered by subcutaneous injection.

The injection is best performed by subcutaneous injection while the patient is lying down. The injection site should be alternated between the anterolateral and posterolateral walls, alternating between the left and right sides of the abdomen. The skin should be pinched between the thumb and index finger, and the needle should be inserted vertically. The skin should not be released until the injection is complete.

Do not massage the injection site after administration.

Do not attempt to remove the air bubble from the pre-filled syringe before injection, as this may result in a reduced dose being administered.

The pre-filled syringe is for single use only.

Do not use this medication if you notice any alteration in the appearance of the solution.

How to administer Hepaxane yourself

If you are able to administer Hepaxane yourself, your doctor or nurse will teach you how to do it. Do not attempt to inject yourself if you have not been trained to do so. If you have any doubts, consult your doctor or nurse immediately.

Before injecting Hepaxane yourself

• Check the expiration date of the medication. Do not use it if it has expired.
• Check that the syringe is not damaged and that the product contains a clear solution. If not, use another syringe.
• Do not use this medication if you notice any change in the appearance of the product.
• Make sure you know how much to inject.
• Check your abdomen to see if the last injection caused any redness, change in skin color, swelling, exudate, or pain. If so, talk to your doctor or nurse.
• Decide where you will inject the medication. Change the injection site each time you administer the medication, from the left to the right side of your stomach. Hepaxane should be injected just below the skin of your stomach, but not too close to the navel or any scars (at least 5 cm away from these).

The pre-filled syringe is for single use only and has a system that covers the needle after use.

• with a safety system that protects the needle after injection.
• without a safety system that protects the needle after injection

Instructions for injecting Hepaxane yourself

You should lie down and administer Hepaxane by subcutaneous injection. Choose a site on the right or left side of your stomach. It should be more than 5 cm from the navel and towards the sides.

The pre-filled syringes of Hepaxane are for single use only and may or may not have a safety system that covers the needle after use.

Remove the pre-filled syringe from the packaging by pulling the arrow as indicated on the packaging. Do not remove the syringe by pulling the plunger, as this may damage it.

4)For pre-filled syringes equipped with a needle protection system. After completing the injection, hold the syringe cylinder firmly with one hand. With the other hand, hold the base of the cylinder (with wings) and pull until you hear a click. Now the needle is completely covered and protected. The safety system comes with a closure that allows you to unlock and lock the safety system.

Dispose of the syringe immediately in the appropriate container.

4b)For pre-filled syringes that are not equipped with a needle protection system

Dispose of the syringe immediately in the appropriate container.

Change of anticoagulant treatment

• Change from Hepaxane to medications that reduce blood clotting called vitamin K antagonists (e.g. warfarin)

Your doctor will request a blood test to determine a parameter called INR and tell you when to stop taking Hepaxane.

• Change from vitamin K antagonists (e.g. warfarin) to Hepaxane

Stop using the vitamin K antagonist. Your doctor will request a blood test to determine the INR parameter and tell you when to start taking Hepaxane.

• Change from Hepaxane to oral direct anticoagulants

Stop using Hepaxane. Start taking the oral direct anticoagulant 0-2 hours before the next scheduled injection, and then continue as usual.

• Change from oral direct anticoagulants to Hepaxane

Stop taking the oral direct anticoagulant. Do not start taking Hepaxane until 12 hours after the last dose of the oral direct anticoagulant.

Use in children and adolescents

The safety and efficacy of Hepaxane have not been evaluated in children or adolescents.

If you use more Hepaxane than you should

If you think you have used too much or too little Hepaxane, inform your doctor, nurse, or pharmacist immediately, even if you do not show any signs of a problem. If a child accidentally injects or swallows Hepaxane, take them immediately to the emergency department of a hospital.

You can also contact the Toxicology Information Service, phone 915620420, indicating the medication and the amount used.

If you forget to use Hepaxane

If you forget to administer a dose, do it as soon as you remember. Do not use a double dose on the same day to compensate for the missed doses. To ensure that you do not forget any doses, you may find it helpful to use a calendar.

If you interrupt treatment with Hepaxane

If you have any other doubts about the use of this medication, ask your doctor, pharmacist, or nurse. It is essential that you continue to receive Hepaxane until your doctor decides to stop treatment. If you stop using it, a blood clot may form, which can be very dangerous.

Like all medicines, this medicine may cause side effects, although not everyone will experience them.

Severe side effects

Stop taking Hepaxane and immediately inform your doctor or nurse if you experience any signs of severe allergic reaction (such as difficulty breathing, swelling of lips, mouth, throat, or eyes).

Stop takingHepaxaneand immediately inform your doctor or nurse if you experience any of the following symptoms:

• A generalized, red, scaly rash, with bumps under the skin and blisters, accompanied by fever. Symptoms usually appear at the beginning of treatment (acute generalized exanthematous pustulosis).

Like other similar medicines (blood-thinning medicines), Hepaxane may cause bleeding that could potentially put your life at risk. In some cases, the bleeding may not be apparent.

Contact your doctor immediately if:

• You notice any episode of bleeding that does not stop on its own
• You notice signs of excessive bleeding such as feeling very weak, fatigue, paleness, dizziness, headache, or unexplained swelling.

Your doctor may decide to keep you under close observation or change your medication.

You must inform your doctor immediately.

• If you experience any signs of a blood clot blocking a blood vessel, such as:

• Cramping pain, redness, heat, or swelling in one of your legs, which are symptoms of deep vein thrombosis.
• Difficulty breathing, chest pain, fainting, or coughing up blood, which are symptoms of pulmonary embolism.

• If you have painful skin rash with dark red spots under the skin that do not disappear when pressed.

Your doctor may request a blood test to check your platelet count.

Other possible side effects:

Very common(may affect more than 1 in 10 people)

• Bleeding.
• Increased liver enzymes.

Common(may affect up to 1 in 10 people)

• If you notice frequent bruising. This may be due to a blood problem caused by low platelet count.
• Pink patches on the skin. They appear more frequently in the area where Hepaxane has been injected.
• Skin rash (hives, urticaria).
• Redness and itching on the skin.
• Ecchymosis or pain at the injection site.
• Decreased red blood cell count in the blood.
• Increased platelet count in the blood.
• Headache.

Uncommon(may affect up to 1 in 100 people)

• Severe sudden headache. This may be a sign of brain hemorrhage.
• Sensation of tenderness and swelling of the stomach. It may indicate gastric hemorrhage.
• Large, irregular skin lesions with or without blisters.
• Skin irritation (local irritation).
• You may notice that your skin or eyes turn yellow, as well as a darkening of the urine color. This may be due to liver problems.

Rare(may affect up to 1 in 1,000 people)

• Severe allergic reaction. Signs of this reaction may include: skin rash, difficulty swallowing or breathing, swelling of lips, face, throat, or tongue.
• Increased potassium in the blood. This is more likely to occur in people with kidney problems or diabetes. Your doctor will be able to check it by performing a blood test.
• Increased eosinophil count (a type of white blood cell) in the blood. Your doctor will be able to check it by performing a blood test.
• Hair loss.
• Osteoporosis (a condition in which bones may be more prone to fracture).
• Tickling, numbness, and weakness in muscles (especially in the lower body), when you have had a lumbar puncture or spinal anesthesia.
• Loss of bladder or bowel control (so you cannot control your needs).
• Hardening or nodule at the injection site.

Reporting side effects

If you experience any type of side effect, consult your doctor, pharmacist, or nurse, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through the Spanish System for Pharmacovigilance of Medicines for Human Use:https://www.notificaram.es.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the packaging after “EXP”. The expiration date is the last day of the month indicated.

Do not use this medication if you observe visible changes in the appearance of the solution.

Do not freeze.

Hepaxane pre-filled syringes are for single use only. Dispose of unused medication.

Medications should not be thrown down the drain or in the trash. Deposit empty packaging and unused medications at the SIGRE collection point at the pharmacy. If in doubt, ask your pharmacist how to dispose of empty packaging and unused medications. By doing so, you will help protect the environment.

Composition of Hepaxane

• Each pre-filled syringe contains enoxaparin sodium with an anti-Xa activity of 2,000 UI (equivalent to 20 mg) in 0.2 mL of water for injection.
• Each pre-filled syringe contains enoxaparin sodium with an anti-Xa activity of 4,000 UI (equivalent to 40 mg) in 0.4 mL of water for injection.
• Each pre-filled syringe contains enoxaparin sodium with an anti-Xa activity of 6,000 UI (equivalent to 60 mg) in 0.6 mL of water for injection.
• Each pre-filled syringe contains enoxaparin sodium with an anti-Xa activity of 8,000 UI (equivalent to 80 mg) in 0.8 mL of water for injection.
• Each pre-filled syringe contains enoxaparin sodium with an anti-Xa activity of 10,000 UI (equivalent to 100 mg) in 1 mL of water for injection.
• Each pre-filled syringe contains enoxaparin sodium with an anti-Xa activity of 12,000 UI (equivalent to 120 mg) in 0.8 mL of water for injection.
• Each pre-filled syringe contains enoxaparin sodium with an anti-Xa activity of 15,000 UI (equivalent to 150 mg) in 1 mL of water for injection.
• The other ingredient is water for injection.

Appearance of the product and contents of the package

Hepaxane is a clear, colorless to pale yellow solution in a type I glass pre-filled syringe equipped with a needle and needle protector. The syringe may or may not be equipped with a system that protects the needle after injection.

• Hepaxane 2,000 UI (20 mg)/0.2 mL solution for injection in pre-filled syringes:

Boxes containing 2, 6, and 10 pre-filled syringes and multiple packs containing 12 (2 boxes of 6), 20 (2 boxes of 10), 24 (4 boxes of 6), 30 (3 boxes of 10), 50 (5 boxes of 10), and 90 (9 boxes of 10) pre-filled syringes.

• Hepaxane 4,000 UI (40 mg)/0.4 mL solution for injection in pre-filled syringes:

Boxes containing 2, 6, and 10 pre-filled syringes and multiple packs containing 12 (2 boxes of 6), 20 (2 boxes of 10), 24 (4 boxes of 6), 30 (3 boxes of 10), 50 (5 boxes of 10), and 90 (9 boxes of 10) pre-filled syringes.

• Hepaxane 6,000 UI (60 mg)/0.6 mL solution for injection in pre-filled syringes:

Boxes containing 2, 6, and 10 graduated pre-filled syringes and multiple packs containing 12 (2 boxes of 6), 20 (2 boxes of 10), 24 (4 boxes of 6), 30 (3 boxes of 10), 50 (5 boxes of 10), and 90 (9 boxes of 10) graduated pre-filled syringes.

• Hepaxane 8,000 UI (80 mg)/0.8 mL solution for injection in pre-filled syringes:

Boxes containing 2, 6, and 10 graduated pre-filled syringes and multiple packs containing 12 (2 boxes of 6), 20 (2 boxes of 10), 24 (4 boxes of 6), 30 (3 boxes of 10), 50 (5 boxes of 10), and 90 (9 boxes of 10) graduated pre-filled syringes.

• Hepaxane 10,000 UI (100 mg)/1 mL solution for injection in pre-filled syringes:

Boxes containing 2, 6, and 10 graduated pre-filled syringes and multiple packs containing 12 (2 boxes of 6), 20 (2 boxes of 10), 24 (4 boxes of 6), 30 (3 boxes of 10), 50 (5 boxes of 10), and 90 (9 boxes of 10) graduated pre-filled syringes.

• Hepaxane 12,000 UI (120 mg)/0.8 mL solution for injection in pre-filled syringes:

Boxes containing 10 graduated pre-filled syringes and multiple packs containing 30 (3 boxes of 10) and 50 (5 boxes of 10) graduated pre-filled syringes.

• Hepaxane 15,000 UI (150 mg)/1 mL solution for injection in pre-filled syringes:

Boxes containing 10 graduated pre-filled syringes and multiple packs containing 30 (3 boxes of 10) and 50 (5 boxes of 10) graduated pre-filled syringes.

• Hepaxane 2,000 UI (20 mg)/0.2 mL solution for injection in pre-filled syringes:

Boxes containing 2 and 10 pre-filled syringes.

• Hepaxane 4,000 UI (40 mg)/0.4 mL solution for injection in pre-filled syringes:

Boxes containing 2 and 10 pre-filled syringes and multiple packs containing 30 (3 boxes of 10) pre-filled syringes.

• Hepaxane 6,000 UI (60 mg)/0.6 mL solution for injection in pre-filled syringes:

Boxes containing 2 and 10 graduated pre-filled syringes and multiple packs containing 30 (3 boxes of 10) graduated pre-filled syringes.

• Hepaxane 8,000 UI (80 mg)/0.8 mL solution for injection in pre-filled syringes:

Boxes containing 2 and 10 graduated pre-filled syringes and multiple packs containing 30 (3 boxes of 10) graduated pre-filled syringes.

• Hepaxane 10,000 UI (100 mg)/1 mL solution for injection in pre-filled syringes:

Boxes containing 2 and 10 graduated pre-filled syringes and multiple packs containing 30 (3 boxes of 10) graduated pre-filled syringes.

• Hepaxane 12,000 UI (120 mg)/0.8 mL solution for injection in pre-filled syringes:

Boxes containing 10 graduated pre-filled syringes and multiple packs containing 30 (3 boxes of 10) graduated pre-filled syringes.

• Hepaxane 15,000 UI (150 mg)/1 mL solution for injection in pre-filled syringes:

Boxes containing 10 graduated pre-filled syringes and multiple packs containing 30 (3 boxes of 10) graduated pre-filled syringes.

The graduated syringes of 6,000 UI (60 mg)/0.6 mL, 8,000 UI (80 mg)/0.8 mL, 10,000 UI (100 mg)/1 mL, 12,000 UI (120 mg)/0.8 mL, and 15,000 UI (150 mg)/1 mL are graduated.

Only some package sizes may be marketed.

Marketing authorization holder and manufacturer responsible

Marketing authorization holder

Chemi S.p.A

Via dei Lavoratori 54,

20092 Cinisello Balsamo, Milan

Italy

Manufacturer responsible

Italfarmaco S.p.A

Viale Fulvio Testi 330

20126 Milan

Italy

or

EUROFINS BIOLAB S.R.L.

Via Bruno Buozzi, 2 - Vimodrone - 20090 - Italy

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

ITALFARMACO S.A.

C/ San Rafael 3,

28108 Alcobendas

Madrid

Spain

This medicine is authorized in the member states of the European Economic Area with the following names:

Belgium:Ghemaxan

Germany:Hepaxane

Denmark:Ghemaxan

Greece:Havetra

Spain:Hepaxane

Finland:Ghemaxan

Italy:Ghemaxan

Netherlands:Ghemaxan

Norway:Ghemaxan

Austria:Ghemaxan

France:Ghemaxan

Ireland:Ghemaxan

Sweden:Ghemaxan

Portugal:Hepaxane

Hungary:Hepaxane

Romania:Hepaxane

Slovakia:Ghemaxan

Last review date of this leaflet: January 2023

Other sources of information

The detailed information about this medicine is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es.

You can access detailed and updated information on how to administer this medicine by scanning the QR code included in the leaflet and packaging with your mobile phone (smartphone). You can also access the same information on the following internet addresses