chlorpheniramine, guaifenesin, hydrocodone, pseudoephedrine

Generic Name: chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine (KLOR fen IR a meen, gwye FEN e sin, HYE droe KOE done, SOO doe ee FED rin)

Brand Names: Z-Tuss 2

What is chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine?

Chlorpheniramine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Guaifenesin is an expectorant. It helps loosen mucus congestion in your chest and throat, making it easier to cough out through your mouth.

Hydrocodone is a narcotic cough suppressant similar to codeine. Hydrocodone affects the signals in the brain that trigger cough reflex.

Pseudoephedrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine is used to treat sinus congestion, runny nose, sneezing, itching, watery eyes, cough, and chest congestion caused by allergies, upper respiratory infections, or the common cold.

This medication will not treat a cough that is caused by smoking, asthma, or emphysema.

Chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine?

Do not use this medication if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take a cough and cold medicine before the MAO inhibitor has cleared from your body. Hydrocodone may be habit-forming and should be used only by the person it was prescribed for. Never share this medication with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it. Do not give this medication to a child younger than 6 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Ask a doctor or pharmacist before using any other cough, cold, allergy, or sleep medicine. Chlorpheniramine, guaifenesin, and pseudoephedrine are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine, decongestant, or expectorant.

What should I discuss with my healthcare provider before taking chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine?

Do not use a cough or cold medicine if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take cough or cold medicine before the MAO inhibitor has cleared from your body.

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

• 
  

  heart disease or high blood pressure;

  
  


• 
  

  asthma, COPD, sleep apnea, or other breathing disorders;

  
  


• 
  

  diabetes;

  
  


• 
  

  glaucoma;

  
  


• 
  

  a thyroid disorder;

  
  


• 
  

  epilepsy or other seizure disorder;

  
  


• 
  

  kidney or liver disease;

  
  


• 
  

  enlarged prostate or urination problems;

  
  


• 
  

  a stomach or intestinal disorder;

  
  


• 
  

  a history of head injury or brain tumor;

  
  


• 
  

  Addison's disease or other adrenal gland disorders; or

  
  


• 
  

  a history of drug or alcohol addiction.

  
  

FDA pregnancy category C. It is not known whether this medication will harm an unborn baby. Hydrocodone may cause addiction or withdrawal symptoms in a newborn if the mother takes the medication during pregnancy. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. This medication may pass into breast milk and could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Hydrocodone may be habit-forming and should be used only by the person it was prescribed for. Never share this medication with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it. Older adults may be more likely to have side effects from this medication.

How should I take chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. Cough or cold medicine is usually taken for only a short time until your symptoms clear up.

Do not give this medication to a child younger than 6 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Take this medication with food or milk if it upsets your stomach.

Measure liquid medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Drink plenty of water or other fluids to help loosen congestion and prevent dry mouth or throat. Talk with your doctor if your symptoms do not improve after 7 days of treatment, or if you have a fever with a headache, cough, or skin rash.

If you need surgery, tell the surgeon ahead of time if you have taken a cold medicine within the past few days.

This medication can cause you to have unusual results with allergy skin tests. Tell any doctor who treats you that you are taking an antihistamine.

Store at room temperature, away from heat, light, and moisture. Keep track of the amount of medicine used from each new bottle. Hydrocodone is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.

See also: Chlorpheniramine, guaifenesin, hydrocodone, pseudoephedrine dosage (in more detail)

What happens if I miss a dose?

Since cough or cold medicine is usually taken only as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

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

Overdose symptoms may include fast or uneven heart rate, extreme drowsiness, feeling restless or hyperactive, confusion, hallucinations, warmth or redness in your face, cold or clammy skin, blue-colored lips or fingernails, weak or shallow breathing, fainting, or seizure (convulsions).

What should I avoid while taking chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine?

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Drinking alcohol can increase certain side effects of chlorpheniramine, guaifenesin, or hydrocodone. Ask a doctor or pharmacist before using any other cough, cold, allergy, or sleep medicine. Chlorpheniramine, guaifenesin, and pseudoephedrine are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine, decongestant, or expectorant.

Chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine 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. Stop taking this medication and call your doctor at once if you have a serious side effect such as:

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  severe dizziness, fainting, anxiety, restless feeling, nervousness, or tremor;

  
  


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  fast, pounding, or uneven heartbeats;

  
  


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  slow heartbeat, weak pulse, shallow breathing;

  
  


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  confusion, hallucinations, unusual thoughts or behavior;

  
  


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  ringing in your ears;

  
  


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  painful or difficult urination;

  
  


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  pale skin, easy bruising or bleeding, unusual weakness; or

  
  


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  increased blood pressure (severe headache, blurred vision, trouble concentrating, chest pain, numbness, seizure).

  
  

Less serious side effects may include:

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  dizziness, drowsiness, headache;

  
  


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  blurred vision;

  
  


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  dry mouth, nose, or throat;

  
  


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  nausea, stomach pain, constipation; or

  
  


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  restless or excitability (especially in children).

  
  

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

Chlorpheniramine, guaifenesin, hydrocodone, pseudoephedrine Dosing Information

Usual Adult Dose for Cough and Nasal Congestion:

Chlorpheniramine/guaifenesin/hydrocodone/pseudoephedrine 2 mg-100 mg-2.5 mg-30 mg/5 mL oral liquid:
10 mL orally every 4 to 6 hours not to exceed 4 doses daily.

Usual Pediatric Dose for Cough and Nasal Congestion:

Chlorpheniramine/guaifenesin/hydrocodone/pseudoephedrine 2 mg-100 mg-2.5 mg-30 mg/5 mL oral liquid:
6 to 11 years: 5 mL orally every 4 to 6 hours not to exceed 4 doses daily.
12 years or older: 10 mL orally every 4 to 6 hours not to exceed 4 doses daily.

What other drugs will affect chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine?

Before taking this medication, tell your doctor if you regularly use other medicines that make you sleepy (such as narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by chlorpheniramine, guaifenesin, or hydrocodone.

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

• 
  

  sibutramine (Meridia);

  
  


• 
  

  memantine (Namenda);

  
  


• 
  

  methyldopa (Aldomet);

  
  


• 
  

  reserpine;

  
  


• 
  

  an antidepressant such as amitriptyline (Elavil), clomipramine (Anafranil), imipramine (Janimine, Tofranil), and others; or

  
  


• 
  

  a beta-blocker such as atenolol (Tenormin), carteolol (Cartrol), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), timolol (Blocadren), and others.

  
  

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

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• Cold Symptoms
• Cough and Nasal Congestion

Where can I get more information?

• Your pharmacist can provide more information about chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine.

Aggrastat Vial 250mcg / ml Concentrate for solution for Infusion

1. Name Of The Medicinal Product

AGGRASTAT^®*(250 micrograms/ml) Concentrate for solution for infusion

2. Qualitative And Quantitative Composition

1 ml of concentrate for solution for infusion contains 281 micrograms of tirofiban hydrochloride monohydrate which is equivalent to 250 micrograms tirofiban.

For excipients, see section 6.1.

3. Pharmaceutical Form

Concentrate for solution for infusion.

A clear, colourless concentrated solution.

4. Clinical Particulars

4.1 Therapeutic Indications

'Aggrastat' is indicated for the prevention of early myocardial infarction in patients presenting with unstable angina or non-Q-wave myocardial infarction with the last episode of chest pain occurring within 12 hours and with ECG changes and/or elevated cardiac enzymes.

Patients most likely to benefit from 'Aggrastat' treatment are those at high risk of developing myocardial infarction within the first 3-4 days after onset of acute angina symptoms including for instance those that are likely to undergo an early PTCA (see also 4.2 'Posology and method of administration' and 5.1 'Pharmacodynamic properties').

'Aggrastat' is intended for use with acetylsalicylic acid and unfractionated heparin.

4.2 Posology And Method Of Administration

This product is for hospital use only, by specialist physicians experienced in the management of acute coronary syndromes.

'Aggrastat' concentrate for solution for infusion must be diluted before use.

'Aggrastat' is given intravenously at an initial infusion rate of 0.4 microgram/kg/min for 30 minutes. At the end of the initial infusion, 'Aggrastat' should be continued at a maintenance infusion rate of 0.1 microgram/kg/min. 'Aggrastat' should be given with unfractionated heparin (usually an intravenous bolus of 5,000 units [U] simultaneously with the start of 'Aggrastat' therapy, then approximately 1,000 U per hour, titrated on the basis of the activated thromboplastin time [APTT], which should be about twice the normal value) and ASA (see 5.1 'Pharmacodynamic properties', PRISM-PLUS study), unless contra-indicated.

No dosage adjustment is necessary for the elderly (see also 4.4 'Special warnings and special precautions for use').

Patients with severe kidney failure

In severe kidney failure (creatinine clearance <30 ml/min) the dosage of 'Aggrastat' should be reduced by 50% (see also 4.4 'Special warnings and precautions for use' and 5.2 'Pharmacokinetic properties').

The following table is provided as a guide to dosage adjustment by weight.

'Aggrastat' Concentrate for Solution for Infusion must be diluted to the same strength as 'Aggrastat' Injection Premixed, as noted under Instructions for Use.

	Most Patients	Severe Kidney Failure
Patient Weight (kg)	30 min Loading Infusion Rate (ml/hr)	Maintenance Infusion Rate (ml/hr)	30 min Loading Infusion Rate (ml/hr)	Maintenance Infusion Rate (ml/hr)
30-37	16	4	8	2
38-45	20	5	10	3
46-54	24	6	12	3
55-62	28	7	14	4
63-70	32	8	16	4
71-79	36	9	18	5
80-87	40	10	20	5
88-95	44	11	22	6
96-104	48	12	24	6
105-112	52	13	26	7
113-120	56	14	28	7
121-128	60	15	30	8
129-137	64	16	32	8
138-145	68	17	34	9
146-153	72	18	36	9

Start and duration of therapy with 'Aggrastat'

'Aggrastat' optimally should be initiated within 12 hours after the last anginal episode. The recommended duration should be at least 48 hours. Infusion of 'Aggrastat' and unfractionated heparin may be continued during coronary angiography and should be maintained for at least 12 hours and not more than 24 hours after angioplasty/atherectomy. Once a patient is clinically stable and no coronary intervention procedure is planned by the treating physician, the infusion should be discontinued. The entire duration of treatment should not exceed 108 hours.

Concurrent therapy (unfractionated heparin, ASA)

Treatment with unfractionated heparin is initiated with an i.v. bolus of 5,000 U and then continued with a maintenance infusion of 1,000 U per hour. The heparin dosage is titrated to maintain an APTT of approximately twice the normal value.

Unless contra-indicated, all patients should receive ASA orally before the start of 'Aggrastat' (see 5.1 'Pharmacodynamic properties', PRISM-PLUS study). This medication should be continued at least for the duration of the infusion of 'Aggrastat'.

If angioplasty (PTCA) is required, heparin should be stopped after PTCA, and the sheaths should be withdrawn once coagulation has returned to normal, e.g. when the activated clotting time (ACT) is less than 180 seconds (usually 2-6 hours after discontinuation of heparin).

Instructions for use

'Aggrastat' Concentrate must be diluted before use:

1. Draw 50 ml from a 250 ml container of sterile 0.9% saline or 5% glucose in water and replace with 50 ml 'Aggrastat' (from one 50 ml puncture vial) to make up a concentration of 50 microgram/ml. Mix well before use.

2. Use according to the dosage table above.

Where the solution and container permit, parenteral drugs should be inspected for visible particles or discoloration before use.

'Aggrastat' should only be given intravenously and may be administered with unfractionated heparin through the same infusion tube.

It is recommended that 'Aggrastat' be administered with a calibrated infusion set using sterile equipment.

Care should be taken to ensure that no prolongation of the infusion of the initial dose occurs and that miscalculation of the infusion rates for the maintenance dose on the basis of the patient's weight is avoided.

4.3 Contraindications

'Aggrastat' is contra-indicated in patients who are hypersensitive to the active substance or to any of the excipients of the preparation or who developed thrombocytopenia during earlier use of a GP IIb/IIIa receptor antagonist.

Since inhibition of platelet aggregation increases the bleeding risk, 'Aggrastat' is contra-indicated in patients with:

• History of stroke within 30 days or any history of haemorrhagic stroke.

• Known history of intracranial disease (e.g. neoplasm, arteriovenous malformation, aneurysm).

• Active or recent (within the previous 30 days of treatment) clinically relevant bleeding (e.g. gastro-intestinal bleeding).

• Malignant hypertension.

• Relevant trauma or major surgical intervention within the past six weeks.

• Thrombocytopenia (platelet count <100,000/mm³), disorders of platelet function.

• Clotting disturbances (e.g. prothrombin time>1.3 times normal or INR [International Normalised Ratio]>1.5).

• Severe liver failure.

4.4 Special Warnings And Precautions For Use

The administration of 'Aggrastat' alone without unfractionated heparin is not recommended.

There is limited experience with concomitant administration of 'Aggrastat' with enoxaparin (see also 5.1 'Pharmacodynamic properties' and 5.2 'Pharmacokinetic properties'). The concomitant administration of 'Aggrastat' with enoxaparin is associated with a higher frequency of cutaneous and oral bleeding events, but not in TIMI bleeds^**, when compared with the concomitant administration of 'Aggrastat' and unfractionated heparin. An increased risk of serious bleeding events associated with the concomitant administration of 'Aggrastat' and enoxaparin cannot be excluded, particularly in patients given additional unfractionated heparin in conjunction with angiography and/or PCI. The efficacy of 'Aggrastat' in combination with enoxaparin has not been established. The safety and efficacy of 'Aggrastat' with other low molecular weight heparins has not been investigated.

There is insufficient experience with the use of tirofiban hydrochloride in the following diseases and conditions, however, an increased risk of bleeding is suspected. Therefore, tirofiban hydrochloride is not recommended in:

• Traumatic or protracted cardiopulmonary resuscitation, organ biopsy or lithotripsy within the past two weeks

• Severe trauma or major surgery>6 weeks but <3 months previously

• Active peptic ulcer within the past three months

• Uncontrolled hypertension (>180/110 mm Hg)

• Acute pericarditis

• Active or a known history of vasculitis

• Suspected aortic dissection

• Haemorrhagic retinopathy

• Occult blood in the stool or haematuria

• Thrombolytic therapy (see 4.5 'Interaction with other medicinal products and other forms of interaction').

• Concurrent use of drugs that increase the risk of bleeding to a relevant degree (see 4.5 'Interaction with other medicinal products and other forms of interaction').

There is no therapeutic experience with tirofiban hydrochloride in patients for whom thrombolytic therapy is indicated (e.g. acute transmural myocardial infarction with new pathological Q-waves or elevated ST-segments or left bundle-branch block in the ECG). Consequently, the use of tirofiban hydrochloride is not recommended in these circumstances.

'Aggrastat' infusion should be stopped immediately if circumstances arise that necessitate thrombolytic therapy (including acute occlusion during PTCA) or if the patient must undergo an emergency coronary artery bypass graft (CABG) operation or requires an intra-aortic balloon pump.

There are limited efficacy data in patients immediately undergoing PTCA.

There is no therapeutic experience with 'Aggrastat' in children, thus, the use of 'Aggrastat' is not recommended in these patients.

Other precautionary notes and measures

There are insufficient data regarding the re-administration of 'Aggrastat'.

Patients should be carefully monitored for bleeding during treatment with 'Aggrastat'. If treatment of haemorrhage is necessary, discontinuation of 'Aggrastat' should be considered (see also 4.9 'Overdose'). In cases of major or uncontrollable bleeding, tirofiban hydrochloride should be discontinued immediately.

'Aggrastat' should be used with special caution in the following conditions and patient groups:

• Recent clinically relevant bleeding (less than one year)

• Puncture of a non-compressible vessel within 24 hours before administration of 'Aggrastat'

• Recent epidural procedure (including lumbar puncture and spinal anaesthesia)

• Severe acute or chronic heart failure

• Cardiogenic shock

• Mild to moderate liver insufficiency

• Platelet count <150,000/mm³, known history of coagulopathy or platelet function disturbance or thrombocytopenia

• Haemoglobin concentration less than 11 g/dl or haematocrit <34%.

Special caution should be used during concurrent administration of, ticlopidine, clopidogrel, adenosine, dipyridamole, sulfinpyrazone, and prostacyclin.

Elderly patients, female patients, and patients with low body weight

Elderly and/or female patients had a higher incidence of bleeding complications than younger or male patients, respectively. Patients with a low body weight had a higher incidence of bleeding than patients with a higher body weight. For these reasons 'Aggrastat' should be used with caution in these patients and the heparin effect should be carefully monitored.

Impaired renal function

There is evidence from clinical studies that the risk of bleeding increases with decreasing creatinine clearance and hence also reduced plasma clearance of tirofiban. Patients with decreased renal function (creatinine clearance <60ml/min) should therefore be carefully monitored for bleeding during treatment with 'Aggrastat' and the heparin effect should be carefully monitored. In severe kidney failure the 'Aggrastat' dosage should be reduced (see also 4.2 'Posology and method of administration').

Femoral artery line

During treatment with 'Aggrastat' there is a significant increase in bleeding rates, especially in the femoral artery area, where the catheter sheath is introduced. Care should be taken to ensure that only the anterior wall of the femoral artery is punctured. Arterial sheaths may be removed when coagulation has returned to normal, e.g. when activated clotting time (ACT) is less than 180 seconds, (usually 2–6 hours after discontinuation of heparin).

After removal of the introducer sheath, careful haemostasis should be ensured under close observation.

General nursing care

The number of vascular punctures, and intramuscular injections should be minimised during the treatment with 'Aggrastat'. I.V. access should only be obtained at compressible sites of the body. All vascular puncture sites should be documented and closely monitored. The use of urinary catheters, nasotracheal intubation and nasogastric tubes should be critically considered.

Monitoring of laboratory values

Platelet count, haemoglobin and haematocrit levels should be determined before treatment with 'Aggrastat' as well as within 2-6 hours after start of therapy with 'Aggrastat' and at least once daily thereafter while on therapy (or more often if there is evidence of a marked decrease). In patients who have previously received GPIIb/IIIa receptor antagonists (cross reactivity can occur), the platelet count should be monitored immediately e.g. within the first hour of administration after re-exposure (see also 4.8 Undesirable effects). If the platelet count falls below 90,000/mm³, further platelet counts should be carried out in order to rule out pseudothrombocytopenia. If thrombocytopenia is confirmed, 'Aggrastat' and heparin should be discontinued. Patients should be monitored for bleeding and treated if necessary (see also 4.9 'Overdose').

In addition, activated thromboplastin time (APTT) should be determined before treatment and the anticoagulant effects of heparin should be carefully monitored by repeated determinations of APTT and the dose should be adjusted accordingly (see also 4.2 Posology and method of administration). Potentially life-threatening bleeding may occur especially when heparin is administered with other products affecting haemostasis, such as GPIIb/IIIa receptor antagonists.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The use of several platelet aggregation inhibitors increase the risk of bleeding, likewise their combination with heparin, warfarin and thrombolytics. Clinical and biological parameters of haemostasis should be regularly monitored.

The concomitant administration of 'Aggrastat' and ASA (acetylsalicyclic acid or aspirin) increases the inhibition of platelet aggregation to a greater extent than aspirin alone, as measured by ex vivo APD-induced platelet aggregation test. The concomitant administration of 'Aggrastat' and unfractionated heparin increases the prolongation of the bleeding time to a greater extent as compared to unfractionated heparin alone.

With the concurrent use of 'Aggrastat' and unfractionated heparin and ASA there was a higher incidence of bleeding than when only unfractionated heparin and ASA were used together (see also 4.4 'Special warnings and special precautions for use' and 4.8 'Undesirable effects').

'Aggrastat' prolonged bleeding time; however, the combined administration of 'Aggrastat' and ticlopidine did not additionally affect bleeding time.

Concomitant use of warfarin with 'Aggrastat' plus heparin was associated with an increased risk of bleeding.

'Aggrastat' is not recommended in thrombolytic therapy - concurrent or less than 48 hours before administration of tirofiban hydrochloride or concurrent use of drugs that increase the risk of bleeding to a relevant degree (e.g. oral anticoagulants, other parenteral GP IIb/IIIa inhibitors, dextran solutions). There is insufficient experience with the use of tirofiban hydrochloride in these conditions; however, an increased risk of bleeding is suspected.

4.6 Pregnancy And Lactation

Pregnancy

For tirofiban hydrochloride, no clinical data on exposed pregnancies are available. Animal studies provide limited information with respect to effects on pregnancy, embryonal/foetal development, parturition, and postnatal development. 'Aggrastat' should not be used during pregnancy unless clearly necessary.

Lactation

It is not known whether 'Aggrastat' is excreted in human milk but it is known to be excreted in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects On Ability To Drive And Use Machines

No data are available on whether 'Aggrastat' impairs the ability to drive or operate machinery.

4.8 Undesirable Effects

Bleeding

The adverse event causally related to 'Aggrastat' therapy (used concurrently with unfractionated heparin and ASA) most commonly reported was bleeding, which was usually of a milder nature.

In the PRISM-PLUS study, the overall incidence of major bleeding using the TIMI criteria (defined as a haemoglobin drop of>50 g/l with or without an identified site, intracranial haemorrhage, or cardiac tamponade) in patients treated with 'Aggrastat' in combination with heparin was not significantly higher than in the control group. The incidence of major bleeding using the TIMI criteria was 1.4% for 'Aggrastat' in combination with heparin and 0.8% for the control group (which received heparin). The incidence of minor bleeding using the TIMI criteria (defined as a haemoglobin drop of>30 g/l with bleeding from a known site, spontaneous gross haematuria, haematemesis or haemoptysis) was 10.5% for 'Aggrastat' in combination with heparin and 8.0% for the control group. There were no reports of intracranial bleeding for 'Aggrastat' in combination with heparin or in the control group. The incidence of retroperitoneal bleeding reported for 'Aggrastat' in combination with heparin was 0.0% and 0.1% for the control group. The percentage of patients who received a transfusion (including packed red blood cells, fresh frozen plasma, whole blood cryoprecipitates and platelets) was 4.0% for 'Aggrastat' and 2.8% for the control group.

'Aggrastat' given with unfractionated heparin and ASA was associated with gastro-intestinal, haemorrhoidal and post-operative bleeding, epistaxis, gum bleeds and surface dermatorrhagia as well as oozing haemorrhage (haematoma) in the area of intravascular puncture sites (e.g. in cardiac catheter examinations) significantly more often than was unfractionated heparin and ASA alone.

Non-bleeding-associated adverse reactions

The most common adverse drug reactions (incidence over 1%) associated with 'Aggrastat' given concurrently with heparin, apart from bleeding, were nausea (1.7%), fever (1.5%) and headache (1.1%); nausea, fever and headache occurred with incidences of 1.4%, 1.1% and 1.2%, respectively, in the control group.

The incidence of adverse non-bleeding-related events was higher in women (compared to men) and older patients (compared to younger patients). However, the incidences of non-bleeding-related adverse events in these patients were comparable for the '“Aggrastat”' with heparin' group and the 'heparin alone' group.

[Common: (>1/100, <1/10)]

Nervous system and psychiatric disorders:

Common: headache

Gastrointestinal disorders:

Common: nausea

General disorders and administration site conditions:

Common: fever

Investigations

The most common changes of laboratory parameters associated with 'Aggrastat' related to bleeding: reduction of haemoglobin and haematocrit levels and an increased occurrence of occult blood in urine and faeces.

Occasionally during 'Aggrastat' therapy an acute fall in the platelet count or thrombocytopenia occurred. The percentage of patients in whom the platelet count fell to below 90,000/mm³ was 1.5%. The percentage of patients in whom the platelet count fell to less than 50,000/mm³ was 0.3%. These decreases were reversible upon discontinuation of 'Aggrastat'. Acute and severe platelet decreases have been observed in patients with no prior history of thrombocytopenia upon re-administration of GPIIb/IIIa receptor antagonists.

The following additional adverse reactions have been reported infrequently in post-marketing experience; they are derived from spontaneous reports for which precise incidences cannot be determined:

Blood and lymphatic system disorders:

Intracranial bleeding, retroperitoneal bleeding, haemopericardium, pulmonary (alveolar) haemorrhage, and epidural haematoma in the spinal region. Fatal bleedings have been reported rarely.

Acute and/or severe (<20,000/mm³) decreases in platelet counts which may be associated with chills, low-grade fever or bleeding complications (see Investigations above)

Immune system disorders:

Severe allergic reactions (e.g., bronchospasm, urticaria) including anaphylactic reactions. The reported cases have occurred during initial treatment (also on the first day) and during readministration of tirofiban. Some cases have been associated with severe thrombocytopenia (platelet counts <10,000/mm³).

4.9 Overdose

Inadvertent overdosage with tirofiban hydrochloride occurred in the clinical studies, up to 50 microgram/kg as a three minute bolus or 1.2 microgram/kg/min as an initial infusion. Overdosage with up to 1.47 microgram/kg/min as a maintenance infusion rate has also occurred.

a) Symptoms of overdosage

The symptom of overdosage most commonly reported was bleeding, usually mucosal bleeding and localised bleeding at the arterial puncture site for cardiac catheterisation but also single cases of intracranial haemorrhages and retroperitoneal bleedings (see also 4.4 'Special warnings and precautions for use' and 5.1 'Pharmacodynamic properties', PRISM-PLUS study).

b) Measures

Overdosage with tirofiban hydrochloride should be treated in accordance with the patient's condition and the attending physician's assessment. If treatment of haemorrhage is necessary, the 'Aggrastat' infusion should be discontinued. Transfusions of blood and/or thrombocytes should also be considered. 'Aggrastat' can be removed by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC-Code: B01A C17

Tirofiban hydrochloride is a non-peptidal antagonist of the GP IIb/IIIa receptor, an important platelet surface receptor involved in platelet aggregation. Tirofiban hydrochloride prevents fibrinogen from binding to the GP IIb/IIIa receptor, thus blocking platelet aggregation.

Tirofiban hydrochloride leads to inhibition of platelet function, evidenced by its ability to inhibit ex vivo ADP-induced platelet aggregation and to prolong bleeding time (BT). Platelet function returns to baseline within eight hours after discontinuation.

The extent of this inhibition runs parallel to the tirofiban hydrochloride plasma concentration.

In the target population the recommended dosage of 'Aggrastat', in the presence of unfractionated heparin and ASA, produced a more than 70% (median 89%) inhibition of ex vivo ADP-induced platelet aggregation in 93% of the patients, and a prolongation of the bleeding time by a factor of 2.9 during infusion. Inhibition was achieved rapidly with the 30-minute loading infusion and was maintained over the duration of the infusion.

PRISM-PLUS study

The double-blind, multicentre, controlled PRISM-PLUS study compared the efficacy of tirofiban and unfractionated heparin (n=773) versus unfractionated heparin (n=797) in patients with unstable angina or acute non-Q-wave myocardial infarction (NQWMI).

Patients had to have prolonged, repetitive anginal pain, or post-infarction angina within 12 hours prior to randomisation, accompanied by new transient or persistent ST-T wave changes (ST depression or elevation

In this study, patients were randomised to either

− 'Aggrastat' (30 minute loading infusion of 0.4 microgram/kg/min followed by a maintenance infusion of 0.10 microgram/kg/min) and heparin (bolus of 5,000 units (U) followed by an infusion of 1,000 U/hr titrated to maintain an activated partial thromboplastin time (APTT) of approximately two times control),

− or heparin alone (bolus of 5,000 U followed by an infusion of 1,000 U/hr titrated to maintain an APTT of approximately two times control).

All patients received ASA unless contra-indicated; 300-325 mg orally per day were recommended for the first 48 hours and thereafter 80-325 mg orally per day (as determined by the physician). Study drug was initiated within 12 hours after the last anginal episode. Patients were treated for 48 hours, after which they underwent angiography and possibly angioplasty/atherectomy, if indicated, while tirofiban hydrochloride was continued. Tirofiban hydrochloride was infused for a mean period of 71.3 hours.

The combined primary study end-point was the occurrence of refractory ischaemia, myocardial infarction or death at seven days after the start of tirofiban hydrochloride.

The mean age of the population was 63 years; 32% of patients were female. At baseline approximately 58% of patients had ST segment depression; 53% had T-wave inversions; 46% of patients presented with elevated cardiac enzymes. During the study approximately 90% of patients underwent coronary angiography; 30% underwent early angioplasty and 23% underwent early coronary artery bypass surgery.

At the primary end-point, there was a 32% risk reduction (RR) (12.9% vs. 17.9%) in the tirofiban hydrochloride group for the combined end-point (p=0.004): this represents approximately 50 events avoided for 1,000 patients treated. Results of the primary end-point were principally attributed to the occurrence of myocardial infarction and refractory ischaemic conditions.

After 30 days the RR for the combined end-point (death/myocardial infarction/refractory ischaemic conditions/readmissions for unstable angina) was 22% (18.5% vs. 22.3%; p=0.029).

After six months the risk of the combined end-point (death/myocardial infarction/refractory ischaemic conditions/readmissions for unstable angina) was reduced by 19% (27.7% vs. 32.1%; p=0.024).

Regarding the most commonly used double combined end-point, death or myocardial infarction, the results at seven days, 30 days and six months were as follows: at seven days for the tirofiban group there was a 43% RR (4.9% vs. 8.3%; p=0.006); at 30 days the RR was 30% (8.7% vs. 11.9%; p=0.027) and at 6 months the RR was 23% (12.3% vs. 15.3%; p=0.063).

The reduction in the incidence of myocardial infarctions in patients receiving 'Aggrastat' appeared early during treatment (within the first 48 hours) and this reduction was maintained through six months, without significant effect on mortality.

In the 30% of patients who underwent angioplasty/atherectomy during initial hospitalisation, there was a 46% RR (8.8% vs. 15.2%) for the primary combined end-point at 30 days as well as a 43% RR (5.9% vs. 10.2%) for 'myocardial infarction or death'.

Based on a safety study, the concomitant administration of 'Aggrastat' with enoxaparin (n=315) was compared to the concomitant administration of 'Aggrastat' with unfractionated heparin (n=210) in patients presenting with unstable angina and non-Q-wave myocardial infarction. A 30 minute loading dose of tirofiban (0.4 microgram/kg/min) was followed by a maintenance infusion of 0.1 microgram/kg/min for up to 108 hours. Patients randomised to the enoxaparin group received a 1.0 mg/kg subcutaneous injection of enoxaparin every 12 hours for a period of at least 24 hours and a maximum duration of 96 hours. Patients randomised to the unfractionated heparin group received a 5000-unit intravenous bolus of unfractionated heparin followed by a maintenance infusion of 1000 units per hour for at least 24 hours and a maximum duration of 108 hours. The total TIMI bleed rate was 3.5% for the tirofiban/enoxaparin group and 4.8% for the tirofiban/unfractionated heparin group. Cutaneous bleeds and oral bleeds occurred more frequently in patients randomised to the enoxaparin group versus the unfractionated heparin group. Catheter site bleeds were more common in the enoxaparin group as compared to the unfractionated heparin group. Patients randomised to the enoxaparin group who subsequently required PCI were switched to unfractionated heparin peri-procedurally with the dose titrated to maintain an ACT of 250 seconds or higher. Although there was a significant difference in the rates of cutaneous bleeds between the two groups (29.2% in the enoxaparin converted to unfractionated heparin group and 15.2% in the unfractionated heparin group), there were no TIMI major bleeds (see also 4.4 'Special warnings and precautions for use') in either group. The efficacy of 'Aggrastat' in combination with enoxaparin has not been established.

Patients most likely to benefit from 'Aggrastat' treatment are those at high risk of developing myocardial infarction within the 3-4 days after onset of acute angina symptoms. According to epidemiological findings, a higher incidence of cardiovascular events has been associated with certain indicators, for instance: age, elevated heart rate or blood pressure, persistent or recurrent ischaemic cardiac pain, marked ECG changes (in particular ST-segment abnormalities), raised cardiac enzymes or markers (e.g. CK-MB, troponins) and heart failure.

5.2 Pharmacokinetic Properties

Distribution

Tirofiban is not strongly bound to plasma protein, and protein binding is concentration-independent in the range of 0.01–25 microgram/ml. The unbound fraction in human plasma is 35%.

The distribution volume of tirofiban in the steady state is about 30 litres.

Biotransformation

Experiments with ¹⁴C-labelled tirofiban showed the radioactivity in urine and faeces to be emitted chiefly by unchanged tirofiban. The radioactivity in circulating plasma originates mainly from unchanged tirofiban (up to 10 hours after administration). These data suggested limited metabolisation of tirofiban.

Elimination

After intravenous administration of ¹⁴C-labelled tirofiban to healthy subjects, 66% of the radioactivity was recovered in the urine, 23% in the faeces. The total recovery of radioactivity was 91%. Renal and biliary excretion contribute significantly to the elimination of tirofiban.

In healthy subjects the plasma clearance of tirofiban is about 250 ml/min. Renal clearance is 39–69% of plasma clearance. The half-life is about 1.5 hours.

Gender

The plasma clearance of tirofiban in patients with coronary heart disease is similar in men and women.

Elderly patients

The plasma clearance of tirofiban is about 25% less in elderly (>65 years) patients with coronary heart disease in comparison to younger (

Ethnic groups

No difference was found in the plasma clearance between patients of different ethnic groups.

Coronary Artery Disease

In patients with unstable angina pectoris or NQWMI the plasma clearance was about 200 ml/min, the renal clearance 39% of the plasma clearance. The half-life is about two hours.

Impaired renal function

In clinical studies, patients with decreased renal function showed a reduced plasma clearance of tirofiban depending on the degree of impairment of creatinine clearance. In patients with a creatinine clearance of less than 30 ml/min, including haemodialysis patients, the plasma clearance of tirofiban is reduced to a clinically relevant extent (over 50%) (see also 4.2 'Posology and method of administration'). Tirofiban is removed by haemodialysis.

Liver failure

There is no evidence of a clinically significant reduction of the plasma clearance of tirofiban in patients with mild to moderate liver failure. No data are available on patients with severe liver failure.

Effects of other drugs

The plasma clearance of tirofiban in patients receiving one of the following drugs was compared to that in patients not receiving that drug in a sub-set of patients (n=762) in the PRISM study. There were no substantial (>15%) effects of these drugs on the plasma clearance of tirofiban: acebutolol, alprazolam, amlodipine, aspirin preparations, atenolol, bromazepam, captopril, diazepam, digoxin, diltiazem, docusate sodium, enalapril, furosemide, glibenclamide, unfractionated heparin, insulin, isosorbide, lorazepam, lovastatin, metoclopramide, metoprolol, morphine, nifedipine, nitrate preparations, oxazepam, paracetamol, potassium chloride, propranolol, ranitidine, simvastatin, sucralfate and temazepam.

The pharmacokinetics and pharmacodynamics of 'Aggrastat' were investigated when concomitantly administered with enoxaparin (1mg/kg subcutaneously every 12 hours) and compared with the combination of 'Aggrastat' and unfractionated heparin. There was no difference in the clearance of 'Aggrastat' between the two groups.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

Tirofiban crosses the placenta in rats and rabbits.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride, sodium citrate dihydrate, citric acid anhydrous, water for injections, hydrochloric acid and/or sodium hydroxide (for pH adjustment).

6.2 Incompatibilities

Incompatibility has been found with diazepam. Therefore, 'Aggrastat' and diazepam should not be administered in the same intravenous line.

6.3 Shelf Life

Three years.

From a microbiological point of view the diluted solution for infusion should be used immediately. If not used immediately, in use storage conditions are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Do not freeze. Keep container in outer carton, to protect from light.

6.5 Nature And Contents Of Container

50 ml Type I glass vial.

6.6 Special Precautions For Disposal And Other Handling

No incompatibilities have been found with 'Aggrastat' and the following intravenous formulations: atropine sulfate, dobutamine, dopamine, epinephrine HCl, furosemide, heparin, lidocaine, midazolam HCl, morphine sulfate, nitroglycerin, potassium chloride, propanolol HCl and famotidine injection.

'Aggrastat' concentrate for solution for infusion must be diluted before use. See 4.2 'Posology and method of administration'.

7. Marketing Authorisation Holder

Iroko Cardio (UK) Ltd., 201 Bishopsgate, London, EC2M 3AF, UK.

8. Marketing Authorisation Number(S)

PL 35173/0001

9. Date Of First Authorisation/Renewal Of The Authorisation

First authorisation: 15 July 1999

First renewal: 14 May 2003

10. Date Of Revision Of The Text

30 November 2009

11. LEGAL STATUS

POM

^* in the following 'Aggrastat' means 'Aggrastat' concentrate for solution for infusion.

^* in the following 'Aggrastat' means 'Aggrastat' concentrate for solution for infusion.

^**TIMI major bleeds are defined as a haemoglobin drop of> 50 g/l with or without an identified site, intracranial haemorrhage, or cardiac tamponade. TIMI minor bleeds are defined as a haemoglobin drop of> 30 g/l by

Sulpor 200mg / 5ml Oral Solution

Sulpor 200mg/5ml Oral Solution

Sulpiride

Read all of this leaflet carefully before you start taking this medicine.

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


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


• This medicine has been prescribed only for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of these side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet

• 1. What Sulpor is and what it is used for


• 2. Before you take Sulpor


• 3. How to take Sulpor


• 4. Possible side effects


• 5. How to store Sulpor


• 6. Further information

What Sulpor is and what it is used for

The name of your medicine is Sulpor. It contains sulpiride. This belongs to a group of medicines called benzamides. These act on the brain to reduce abnormal behaviour.

Sulpor is used for treating schizophrenia.

Before you take Sulpor

Do not take Sulpor and tell your doctor if:

• you are allergic (hypersensitive) to sulpiride or any other ingredients in this liquid (listed in Section 6). The signs of an allergic reaction include a rash, itching or shortness of breath


• you have high blood pressure due to a growth on your adrenal glands (phaeochromocytoma)


• you have porphyria, a problem with your metabolism that can cause skin blisters, pain in and around your stomach (abdomen) and brain or nervous system problems


• severe kidney, blood or liver problems


• you have an alcohol-related illness or any other problems that affect your nervous system


• you have ever had breast cancer or a type of brain tumour called ‘pituitary prolactinoma’


• you are taking levodopa (see section ‘Taking other medicines’).

Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking this medicine.

Take special care with Sulpor

Before you take Sulpor, tell your doctor if:

• you have ‘hypomania’. These are mood swings that may show as excitability, anger, irritability and a lower need for sleep


• you have heart problems. If you or members of your family suffer from heart problems, your doctor may give you some tests on your heart and blood before giving you Sulpor


• you or someone else in your family has a history of blood clots, as medicines like these have been associated with formation of blood clots


• you have epilepsy


• you have Parkinson’s Disease


• you have had a stroke.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Sulpor.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines you buy without a prescription, including herbal medicines. This is because Sulpor can affect the way some other medicines work. Also, some medicines can affect the way Sulpor works.

In particular, tell your doctor if you are taking any of the following:

• Levodopa, used to treat Parkinson’s Disease (sometimes this is called L-dopa). You must not take this at the same time as Sulpor


• medicines to treat high blood pressure or migraine such as beta-blockers, clonidine or diuretics (water tablets)


• medicines used to treat abnormal heart rhythms (quinidine, disopyramide, amiodarone, sotalol) or angina (diltiazem, verapamil) and other heart problems (digoxin)


• sucralfate, cisapride and antacids used to treat stomach problems or laxatives


• lithium used to treat depression


• medicines used to treat epilepsy


• steroids such as prednisolone, dexamethasone and tetracosactide


• medicines to treat infections such as erythromycin or amphotericin B that are injected into a vein or pentamidine that is breathed in or given by injection


• medicines used to treat Parkinson’s Disease, including ropinirole


• medicines used to treat mental or emotional problems such as pimozide, thioridazine, haloperidol or imipramine.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Sulpor.

Taking Sulpor with food and drink

Do not drink alcohol while taking Sulpor. This is because Sulpor can make you drowsy and alcohol will make you even more drowsy.

Pregnancy and breast-feeding

Talk to your doctor before taking this medicine if you are pregnant, planning to become pregnant or are breast-feeding.

Driving and using machines

Sulpor may make you drowsy or less alert to your surroundings. If this happens to you, do not drive or use machinery.

Important information about what is in Sulpor

This medicine contains:

• methyl and propyl parahydroxybenzoates. These may cause an allergic reaction. This allergy may happen some time after starting the medicine


• liquid maltitol (a type of sugar). If your doctor has told you that you cannot tolerate some sugars, talk to your doctor before taking this medicine.

How to take Sulpor

Take this medicine as your doctor or pharmacist has told you. Look on the label and ask the doctor or pharmacist if you are not sure.

Taking this medicine

• this medicine contains 200mg of sulpiride in each 5ml


• take this medicine by mouth.

Adults:

The usual dose for adults is:

• the doctor will start you on a dose of 200mg (5ml) to 400mg (10ml) two times a day (usually morning and early evening)


• the doctor may reduce the dose or increase it to a maximum of 1200mg (30ml) two times a day


• if you are an older person the dose will be the same as that for adults unless you have a kidney or liver problem. The doctor may lower the dose in this case.

Children:

This medicine must not be given children under the age of 14.

If you take more Sulpor than you should

If you take more Sulpor than you should, talk to a doctor or go to a hospital straight away. Take the medicine pack with you so the doctor knows what you have taken.

If you forget to take Sulpor

• if you forget a dose, skip the missed dose then go on as before.


• do not take a double dose (two doses at the same time) to make up for a forgotten dose.

If you stop taking Sulpor

Keep taking this medicine until your doctor tells you to stop, as it may be necessary to lower the dose gradually.

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

Possible side effects

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

Stop taking this medicine and see a doctor straight away if you have an allergic reaction to Sulpor.

Signs of an allergic reaction may include:

• any kind of skin rash, flaking skin, boils or sore lips and mouth


• sudden wheezing, fluttering or tightness of the chest or collapse.

Stop taking this medicine and see a doctor straight away if you have any of the following:

• early warning signs such as unusually fast heart beats and sweating


• over heating, muscle stiffness, change in consciousness leading to a coma.

If you get any of the following side effects, see your doctor as soon as possible:

• blood clots in the veins especially in the legs (symptoms include swelling, pain and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing. If you notice any of these symptoms seek medical advice immediately


• changes in the rhythm of your heart beat or heart attack


• muscle spasms, jerky movements of your hands or feet, unusual facial movements, shaking or a large amount of saliva in your mouth


• jaundice, which normally shows as yellowing of your skin and whites of the eyes


• inflammation of your liver (hepatitis). The signs of this include feeling sick (nausea), being sick (vomiting), swelling in your upper abdomen


• feeling more agitated and restless


• having fits


• feeling dizzy when standing up. This may be a sign of low blood pressure

Tell your doctor if you get any of these side effects:

• feeling sleepy or drowsy


• unable to sleep


• swelling and breast pain (men or women) and secretion of breast milk in women


• irregular or absent periods


• changes in sexual function


• diarrhoea that may be caused by the liquid maltitol in the medicine


• weight gain

There have been reports of unexplained deaths, but it is not proven that they were due to sulpiride. In elderly people with dementia, a small increase in the number of deaths has been reported for patients taking antipsychotics compared with those not receiving antipsychotics.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store Sulpor

• keep out of the reach and sight of children


• do not store above 25°C.


• get rid of the medicine 3 months after opening


• do not use after the expiry date which is stated on the label and carton (Exp: month, year)


• the expiry date refers to the last day of that month


• do not use Sulpor if you notice a change in the appearance or smell of the medicine. Talk to your pharmacist


• medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

What Sulpor contains

• the active ingredient is sulpiride.


• the other ingredients are methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), propylene glycol (E1520), citric acid monohydrate (E330), liquid maltitol (E965), lemon flavour, aniseed flavour and purified water.

What Sulpor looks like and contents of the pack

A colourless to slightly yellow liquid with an odour of lemon and aniseed

It comes in a brown glass bottle holding 150ml of liquid.

Marketing Authorisation Holder and Manufacturer

Rosemont Pharmaceuticals Ltd

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

UK

This leaflet was last revised in January 2010

P0497

Phrenilin

Generic Name: butalbital and acetaminophen combination (Oral route)

Commonly used brand name(s)

In the U.S.

• Anolor 300


• Cephadyn


• Dolgic LQ


• Esgic


• Esgic-Plus


• Ezol


• Fioricet


• Geone


• Margesic


• Medigesic


• Phrenilin


• Phrenilin Forte

Available Dosage Forms:

• Tablet


• Capsule


• Solution

Uses For Phrenilin

Butalbital and acetaminophen combination is a pain reliever and relaxant. It is used to treat tension headaches. Butalbital belongs to the group of medicines called barbiturates. Barbiturates act in the central nervous system (CNS) to produce their effects.

When you take butalbital for a long time, your body may get used to it so that larger amounts are needed to produce the same effects. This is called tolerance to the medicine. Also, butalbital may become habit-forming (causing mental or physical dependence) when it is used for a long time or in large doses. Physical dependence may lead to withdrawal side effects when you stop taking the medicine. In patients who get headaches, the first symptom of withdrawal may be new (rebound) headaches.

Some butalbital and acetaminophen combinations also contain caffeine. Caffeine may help to relieve headaches. However, caffeine can also cause physical dependence when it is used for a long time. This may lead to withdrawal (rebound) headaches when you stop taking it.

Butalbital and acetaminophen combination may also be used for other kinds of headaches or other kinds of pain as determined by your doctor.

These medicines are available only with your doctor's prescription.

Before Using Phrenilin

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

For butalbital:

• Although barbiturates such as butalbital often cause drowsiness, some children become excited after taking them.

For acetaminophen:

• Acetaminophen has been tested in children and, in effective doses, has not been shown to cause different side effects or problems than it does in adults.

For caffeine:

• There is no specific information comparing use of caffeine in children up to 12 years of age with use in other age groups. However, caffeine is not expected to cause different side effects or problems in children than it does in adults.

Geriatric

For butalbital:

• Certain side effects, such as confusion, excitement, or mental depression, may be especially likely to occur in elderly patients, who are usually more sensitive than younger adults to the effects of the butalbital in this combination medicine.

For acetaminophen:

• Acetaminophen has been tested and has not been shown to cause different side effects or problems in older people than it does in younger adults.

For caffeine:

• Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of caffeine in the elderly with use in other age groups.

Pregnancy

For butalbital:

• Barbiturates such as butalbital have been shown to increase the chance of birth defects in humans. Also, one study in humans has suggested that barbiturates taken during pregnancy may increase the chance of brain tumors in the baby.


• Butalbital may cause breathing problems in the newborn baby if taken just before or during delivery.

For acetaminophen:

• Although studies on birth defects with acetaminophen have not been done in pregnant women, it has not been reported to cause birth defects or other problems.

For caffeine:

• Studies in humans have not shown that caffeine (contained in some of these combination medicines) causes birth defects. However, use of large amounts of caffeine during pregnancy may cause problems with the heart rhythm and the growth of the fetus. Also, studies in animals have shown that caffeine causes birth defects when given in very large doses (amounts equal to those present in 12 to 24 cups of coffee a day).

Breast Feeding

For butalbital:

• Barbiturates such as butalbital pass into the breast milk and may cause drowsiness, unusually slow heartbeat, shortness of breath, or troubled breathing in nursing babies.

For acetaminophen:

• Although acetaminophen has not been shown to cause problems in nursing babies, it passes into the breast milk in small amounts.

For caffeine:

• Caffeine (present in some butalbital and acetaminophen combinations) passes into the breast milk in small amounts. Taking caffeine in the amounts present in these medicines has not been shown to cause problems in nursing babies. However, studies have shown that nursing babies may appear jittery and have trouble in sleeping when their mothers drink large amounts of caffeine-containing beverages. Therefore, breast-feeding mothers who use caffeine-containing medicines should probably limit the amount of caffeine they take in from other medicines or from beverages.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking any of these medicines, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using medicines in this class with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Adinazolam


• Alfentanil


• Alprazolam


• Amobarbital


• Anileridine


• Anisindione


• Aprobarbital


• Bromazepam


• Brotizolam


• Butabarbital


• Butalbital


• Carisoprodol


• Chloral Hydrate


• Chlordiazepoxide


• Chlorzoxazone


• Clobazam


• Clonazepam


• Clorazepate


• Codeine


• Dantrolene


• Diazepam


• Dicumarol


• Estazolam


• Ethchlorvynol


• Fentanyl


• Flunitrazepam


• Flurazepam


• Halazepam


• Hydrocodone


• Hydromorphone


• Ketazolam


• Levorphanol


• Lorazepam


• Lormetazepam


• Medazepam


• Meperidine


• Mephenesin


• Mephobarbital


• Meprobamate


• Metaxalone


• Methocarbamol


• Methohexital


• Midazolam


• Morphine


• Morphine Sulfate Liposome


• Nitrazepam


• Nordazepam


• Oxazepam


• Oxycodone


• Oxymorphone


• Pentobarbital


• Phenindione


• Phenobarbital


• Phenprocoumon


• Prazepam


• Primidone


• Propoxyphene


• Quazepam


• Quetiapine


• Remifentanil


• Secobarbital


• Sodium Oxybate


• Sufentanil


• Temazepam


• Thiopental


• Triazolam

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Using medicines in this class with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use your medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of medicines in this class. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse (or history of) or


• Drug abuse or dependence (or history of)—Dependence on butalbital may develop. Also, acetaminophen may cause liver damage in people who abuse alcohol.

• Asthma (or history of), emphysema, or other chronic lung disease or


• Hepatitis or other liver disease or


• Hyperactivity (in children) or


• Kidney disease—The chance of serious side effects may be increased.

• Type 2 diabetes mellitus or


• Mental depression or


• Overactive thyroid or


• Porphyria (or history of)—Butalbital can make these conditions worse.

• Heart disease (severe)—The caffeine in some butalbital and acetaminophen combinations can make some kinds of heart disease worse.

Proper Use of butalbital and acetaminophen combination

This section provides information on the proper use of a number of products that contain butalbital and acetaminophen combination. It may not be specific to Phrenilin. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. If butalbital and acetaminophen combination is taken regularly (for example, every day), it may become habit-forming (causing mental or physical dependence). The caffeine in some butalbital and acetaminophen combinations can also increase the chance of dependence. Dependence is especially likely to occur in patients who take these medicines to relieve frequent headaches. Taking too much of this medicine may also lead to liver damage or other medical problems.

This medicine will relieve a headache best if you take it as soon as the headache begins. If you get warning signs of a migraine, take this medicine as soon as you are sure that the migraine is coming. This may even stop the headache pain from occurring. Lying down in a quiet, dark room for a while after taking the medicine also helps to relieve headaches.

People who get a lot of headaches may need to take a different medicine to help prevent headaches. It is important that you follow your doctor's directions about taking the other medicine, even if your headaches continue to occur. Headache-preventing medicines may take several weeks to start working. Even after they do start working, your headaches may not go away completely. However, your headaches should occur less often, and they should be less severe and easier to relieve than before. This will reduce the amount of headache relievers that you need. If you do not notice any improvement after several weeks of headache-preventing treatment, check with your doctor.

Dosing

The dose medicines in this class will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage forms (capsules or tablets):
  
  • For tension headaches:
    
    • Adults—One or 2 capsules or tablets every four hours as needed. If your medicine contains 325 or 500 milligrams (mg) of acetaminophen in each capsule or tablet, you should not take more than six capsules or tablets a day. If your medicine contains 650 mg of acetaminophen in each capsule or tablet, you should not take more than four capsules or tablets a day.
    
    
    • Children—Dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Phrenilin

Check with your doctor:

• If the medicine stops working as well as it did when you first started using it. This may mean that you are in danger of becoming dependent on the medicine. Do not try to get better pain relief by increasing the dose.


• If you are having headaches more often than you did before you started taking this medicine. This is especially important if a new headache occurs within 1 day after you took your last dose of this medicine, headaches begin to occur every day, or a headache continues for several days in a row. This may mean that you are dependent on the medicine. Continuing to take this medicine will cause even more headaches later on. Your doctor can give you advice on how to relieve the headaches.

Check the labels of all nonprescription (over-the-counter [OTC]) or prescription medicines you now take. If any contain a barbiturate or acetaminophen, check with your health care professional. Taking them together with this medicine may cause an overdose.

The butalbital in this medicine will add to the effects of alcohol and other CNS depressants (medicines that slow down the nervous system, possibly causing drowsiness). Some examples of CNS depressants are antihistamines or medicine for hay fever, other allergies, or colds; sedatives, tranquilizers, or sleeping medicine; other prescription pain medicine; narcotics; other barbiturates; medicine for seizures; muscle relaxants; or anesthetics, including some dental anesthetics. Also, drinking large amounts of alcoholic beverages regularly while taking this medicine may increase the chance of liver damage, especially if you take more of this medicine than your doctor ordered or if you take it regularly for a long time. Therefore, do not drink alcoholic beverages, and check with your doctor before taking any of the medicines listed above, while you are using this medicine.

This medicine may cause some people to become drowsy, dizzy, or lightheaded. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert and clearheaded.

Before you have any medical tests, tell the person in charge that you are taking this medicine. Caffeine (present in some butalbital and acetaminophen combinations) interferes with the results of certain tests that use dipyridamole (e.g., Persantine) to help show how well blood is flowing to your heart. Caffeine should not be taken for 8 to 12 hours before the test. The results of other tests may also be affected by butalbital and acetaminophen combinations.

Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking this medicine. Serious side effects can occur if your medical doctor or dentist gives you certain medicines without knowing that you have taken butalbital.

If you have been taking large amounts of this medicine, or if you have been taking it regularly for several weeks or more, do not suddenly stop taking it without first checking with your doctor. Your doctor may want you to reduce gradually the amount you are taking before stopping completely in order to lessen the chance of withdrawal side effects.

If you think you or anyone else may have taken an overdose of this medicine, get emergency help at once. Taking an overdose of this medicine or taking alcohol or CNS depressants with this medicine may lead to unconsciousness or possibly death. Signs of butalbital overdose include severe drowsiness, confusion, severe weakness, shortness of breath or unusually slow or troubled breathing, slurred speech, staggering, and unusually slow heartbeat. Signs of severe acetaminophen poisoning may not occur until 2 to 4 days after the overdose is taken, but treatment to prevent liver damage or death must be started within 24 hours or less after the overdose is taken.

Phrenilin Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Rare

• Bleeding or crusting sores on lips


• chest pain


• fever with or without chills


• hive-like swellings (large) on eyelids, face, lips, and/or tongue


• muscle cramps or pain


• red, thickened, or scaly skin


• shortness of breath, troubled breathing, tightness in chest, or wheezing


• skin rash, itching, or hives


• sores, ulcers, or white spots in mouth (painful)

Symptoms of overdose

• Anxiety, confusion, excitement, irritability, nervousness, restlessness, or trouble in sleeping (severe, especially with products containing caffeine)


• convulsions (seizures) (for products containing caffeine)


• diarrhea, especially if occurring together with increased sweating, loss of appetite, and stomach cramps or pain


• dizziness, lightheadedness, drowsiness, or weakness, (severe)


• frequent urination (for products containing caffeine)


• hallucinations (seeing, hearing, or feeling things that are not there)


• increased sensitivity to touch or pain (for products containing caffeine)


• muscle trembling or twitching (for products containing caffeine)


• nausea or vomiting, sometimes with blood


• ringing or other sounds in ears (for products containing caffeine)


• seeing flashes of "zig-zag" lights (for products containing caffeine)


• shortness of breath or unusually slow or troubled breathing


• slow, fast, or irregular heartbeat


• slurred speech


• staggering


• swelling, pain, or tenderness in the upper abdomen or stomach area


• unusual movements of the eyes

Check with your doctor as soon as possible if any of the following side effects occur:

Less common

• Confusion (mild)


• mental depression


• unusual excitement (mild)

Rare

• Bloody or black, tarry stools


• bloody urine


• pinpoint red spots on skin


• swollen or painful glands


• unusual bleeding or bruising


• unusual tiredness or weakness (mild

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Bloated or "gassy" feeling


• dizziness or lightheadedness (mild)


• drowsiness (mild)


• nausea, vomiting, or stomach pain (occurring without other symptoms of overdose)

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

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