Pradaxa 150 mg hard capsules

1. Name Of The Medicinal Product

2. Qualitative And Quantitative Composition

Each hard capsule contains 150 mg of dabigatran etexilate (as mesilate).

Excipients: Each hard capsule contains 4 micrograms sunset yellow (E110).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Hard capsule

Imprinted capsules with light blue, opaque cap and cream-coloured, opaque body of size 0 filled with yellowish pellets. The cap is imprinted with the Boehringer Ingelheim company symbol, the body with "R150".

4. Clinical Particulars

4.1 Therapeutic Indications

Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation with one or more of the following risk factors:

• Previous stroke, transient ischemic attack, or systemic embolism (SEE)

• Left ventricular ejection fraction < 40 %

• Symptomatic heart failure,

• Age

• Age

4.2 Posology And Method Of Administration

Posology

The recommended daily dose of Pradaxa is 300 mg taken as one 150 mg capsule twice daily. Therapy should be continued long term.

In case of intolerability to dabigatran, patients should be instructed to immediately consult their treating physician in order to be switched to alternate acceptable treatment options for prevention of stroke and SEE associated with atrial fibrillation.

Elderly

Patients between 75-80 years should be treated with a daily dose of 300 mg taken as one 150 mg capsule twice daily. A dose of 220 mg taken as one 110 mg capsule twice daily can be individually considered, at the discretion of the physician, when the thromboembolic risk is low and the bleeding risk is high (see section 4.4).

Patients aged 80 years or above should be treated with a daily dose of 220 mg taken as one 110 mg capsule twice daily due to the increased risk of bleeding in this population.

Patients at risk of bleeding

Patients with an increased bleeding risk (see sections 4.4, 4.5, 5.1 and 5.2) should be closely monitored clinically (looking for signs of bleeding or anaemia). Dose adjustment should be decided at the discretion of the physician, following assessment of the potential benefit and risk to an individual patient. A coagulation test (see section 4.4) may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure. When excessive dabigatran exposure is identified in patients at high risk of bleeding, a dose of 220 mg taken as one 110 mg capsule twice daily is recommended. When clinically relevant bleeding occurs, treatment should be interrupted.

For subjects with gastritis, esophagitis, or gastroesophageal reflux, the dose of 220 mg taken as one 110 mg capsule twice daily may be considered due to the elevated risk of major gastro-intestinal bleeding (see section 4.4).

Renal impairment

Treatment with Pradaxa in patients with severe renal impairment (creatinine clearance (CrCL) < 30 ml/min) is contraindicated (see section 4.3).

No dose adjustment is necessary in patients with mild renal impairment (CrCL 50-

Concomitant use of Pradaxa with strong P-glycoprotein (P-gp) inhibitors, i.e. amiodarone, quinidine or verapamil

No dose adjustment is necessary for concomitant use of amiodarone or quinidine (see sections 4.4, 4.5 and 5.2).

Dosing should be reduced to 220 mg taken as one 110 mg capsule twice daily in patients who receive concomitantly dabigatran etexilate and verapamil (see sections 4.4 and 4.5). In this situation Pradaxa and verapamil should be taken at the same time.

Weight

Given the available clinical and kinetic data, no dose adjustment is necessary (see section 5.2), but close clinical surveillance is recommended in patients with a body weight < 50 kg (see section 4.4).

Gender

Given the available clinical and kinetic data, no dose adjustment is necessary (see section 5.2).

Hepatic impairment

Patients with elevated liver enzymes > 2 upper limit of normal (ULN) were excluded in the study investigating the prevention of stroke and SEE associated with atrial fibrillation. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population (see sections 4.4 and 5.2).

Switching

Pradaxa treatment to parenteral anticoagulant

It is recommended to wait 12 hours after the last dose before switching from dabigatran etexilate to a parenteral anticoagulant (see section 4.5).

Parenteral anticoagulants to Pradaxa

Dabigatran etexilate should be given 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) (see section 4.5).

Pradaxa treatment to Vitamin K antagonists (VKA)

Adjust the starting time of the VKA based on CrCL as follows:

• CrCL

• CrCL

VKA to Pradaxa

The VKA should be stopped. Dabigatran etexilate can be given as soon as the International Normalized Ratio (INR) is < 2.0.

Cardioversion

Patients can stay on dabigatran etexilate while being cardioverted.

Paediatric population

There is no relevant use of Pradaxa in the paediatric population in the indication: prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Pradaxa is not recommended for use in patients below 18 years due to lack of data on safety and efficacy.

Missed dose

A forgotten dabigatran etexilate dose may still be taken up to 6 hours prior to the next scheduled dose. From 6 hours prior to the next scheduled dose on, the missed dose should be omitted.

No double dose should be taken to make up for missed individual doses.

Method of administration

Pradaxa should be swallowed as a whole with water, with or without food.

Patients should be instructed not to open the capsule as this may increase the risk of bleeding (see sections 5.2 and 6.6).

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients

• Patients with severe renal impairment (CrCL < 30 ml/min)

• Active clinically significant bleeding

• Organic lesion at risk of bleeding

• Spontaneous or pharmacological impairment of haemostasis

• Hepatic impairment or liver disease expected to have any impact on survival

• Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole and tacrolimus (see section 4.5)

4.4 Special Warnings And Precautions For Use

Hepatic impairment

Patients with elevated liver enzymes > 2 ULN were excluded from the study investigating the prevention of stroke and SEE associated with atrial fibrillation. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population.

Haemorrhagic risk

As with all anticoagulants, dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding. Bleeding can occur at any site during therapy with dabigatran. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site.

Factors, such as decreased renal function (30-50 ml/min CrCL), age

Dabigatran was associated with higher rates of major gastrointestinal (GI) bleeding which was statistically significant for dabigatran etexilate 150 mg twice daily. This increased risk was seen in the elderly (₂)-blocker treatment increase the risk of GI bleeding. In these patients a dosage of 220 mg dabigatran given as 110 mg capsule twice daily should be considered (see section 4.2). The administration of a PPI can be considered to prevent GI bleeding.

Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment period, especially if risk factors are combined (see section 5.1).

Table 1 summarises factors which may increase the haemorrhagic risk.

Pharmacodynamic and kinetic factors	Age
Factors increasing dabigatran plasma levels	Major: • Moderate renal impairment (30-50 ml/min CrCL) • P-gp inhibitor co-medication Minor: • Low body weight (< 50 kg)
Pharmacodynamic interactions	• ASA • NSAID • Clopidogrel
Diseases / procedures with special haemorrhagic risks	• Congenital or acquired coagulation disorders • Thrombocytopenia or functional platelet defects • Active ulcerative GI disease • Recent gastro-intestinal bleeding • Recent biopsy or major trauma • Recent ICH • Brain, spinal or ophthalmic surgery • Bacterial endocarditis

The measurement of dabigatran related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors.

The activated partial thromboplastin time (aPTT) test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. In patients who are bleeding or at risk of bleeding, the aPTT test may be useful to assist in determining an excess of anticoagulant activity. However, the aPTT test has limited sensitivity and is not suitable for precise quantification of anticoagulant effect, especially at high plasma concentrations of dabigatran. High aPTT values should be interpreted with caution.

If required, more sensitive quantitative tests such as calibrated diluted Thrombin Time (dTT) should be performed (see section 5.1).

Patients who develop acute renal failure must discontinue Pradaxa (see section 4.3).

Limited data is available in patients < 50 kg (see section 5.2).

When severe bleedings occur treatment must be discontinued and the source of bleeding investigated (see section 4.9).

Agents that may enhance the risk of haemorrhage should not be administered concomitantly or should be administered with caution with Pradaxa (see section 4.5).

Interaction with P-gp inducers

Concomitant administration of P-gp inducers (such as rifampicin, St. John`s wort (Hypericum perforatum), carbamazepine, or phenytoin) is expected to result in decreased dabigatran plasma concentrations, and should be avoided (see sections 4.5 and 5.2).

Surgery and interventions

Patients on dabigatran etexilate who undergo surgery or invasive procedures are at increased risk for bleeding. Therefore surgical interventions may require the temporary discontinuation of dabigatran etexilate.

Caution should be exercised when treatment is temporarily discontinued for interventions and anticoagulant monitoring is warranted. Clearance of dabigatran in patients with renal insufficiency may take longer (see section 5.2). This should be considered in advance of any procedures. In such cases a coagulation test (see sections 4.4 and 5.1) may help to determine whether haemostasis is still impaired.

Preoperative phase

Table 2 summarizes discontinuation rules before invasive or surgical procedures.

Renal function (CrCL in ml/min)	Estimated half-life (hours)	Stop dabigatran before elective surgery
High risk of bleeding or major surgery	Standard risk
	~ 13	2 days before	24 hours before
	~ 15	2-3 days before	1-2 days before
	~ 18	4 days before	2-3 days before (> 48 hours)

If an acute intervention is required, dabigatran etexilate should be temporarily discontinued. A surgery / intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed the risk of bleeding may be increased. This risk of bleeding should be weighed against the urgency of intervention.

Spinal anaesthesia/epidural anaesthesia/lumbar puncture

Procedures such as spinal anaesthesia may require complete haemostatic function.

The risk of spinal or epidural haematoma may be increased in cases of traumatic or repeated puncture and by the prolonged use of epidural catheters. After removal of a catheter, an interval of at least 2 hours should elapse before the administration of the first dose of dabigatran etexilate. These patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma.

Post-surgical patients with an increased risk for bleeding

Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal impairment (CrCL 30-50 ml/min), should be treated with caution (see sections 4.4 and 5.1). Resume treatment after complete haemostasis is achieved.

Patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events

There are limited efficacy and safety data for dabigatran available in these patients and therefore they should be treated with caution.

Myocardial Infarction

In the phase III study RE-LY (see section 5.1.) the overall rate of myocardial infarction (MI) was 0.82, 0.81, and 0.64 % / year for dabigatran etexilate 110 mg twice daily, dabigatran etexilate 150 mg twice daily and warfarin, respectively, an increase in relative risk for dabigatran of 29 % and 27 % compared to warfarin. Irrespective of therapy, the highest absolute risk of MI was seen in the following subgroups, with similar relative risk: patients with previous MI, patients

Colorants

Pradaxa hard capsules contain the colorant sunset yellow (E110), which may cause allergic reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Anticoagulants and antiplatelet aggregation agents

The following treatments have not been studied and may increase the risk of bleeding when used concomitantly with Pradaxa: UFH, low molecular weight heparins (LMWH), and heparin derivatives (fondaparinux, desirudin), thrombolytic agents, GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, dextran, sulfinpyrazone, rivaroxaban, and vitamin K antagonists (see section 4.4).

UFH can be administered at doses necessary to maintain a patent central venous or arterial catheter (see sections 4.2 and 4.4.

Clopidogrel: In a phase I study in young healthy male volunteers, the concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. In addition, dabigatran AUC_max,ss and the coagulation measures for dabigatran effect or the inhibition of platelet aggregation as measure of clopidogrel effect remained essentially unchanged comparing combined treatment and the respective mono-treatments. With a loading dose of 300 mg or 600 mg clopidogrel, dabigatran AUC_max,ss were increased by about 30-40 % (see section 4.4).

ASA: The effect of concomitant administration of dabigatran etexilate and ASA on the risk of bleeds was studied in patients with atrial fibrillation in a phase II study in which a randomized ASA co-administration was applied. Based on logistic regression analysis, co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase the risk for any bleeding from 12 % to 18 % and 24 % with 81 mg and 325 mg ASA, respectively (see section 4.4). From the data collected in the phase III study RE-LY (see section 5.1), it was observed that ASA or clopidogrel co-medication with dabigatran etexilate at dosages of 110 mg or 150 mg twice daily may increase the risk of major bleeding (see section 4.4). The higher rate of bleeding events by ASA or clopidogrel co-medication was also observed for warfarin.

NSAIDs: NSAIDs given for short-term perioperative analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. With chronic use in the RE-LY study, NSAIDs increased the risk of bleeding by approximately 50% on both dabigatran and warfarin. Therefore, due to the risk of haemorrhage, notably with NSAIDs with elimination half-lives > 12 hours, close observation for signs of bleeding is recommended (see section 4.4).

LMWH: The concomitant use of LMWHs, such as enoxaparin and dabigatran etexilate has not been specifically investigated. After switching from 3-day treatment of once daily 40 mg enoxaparin s.c., 24 hours after the last dose of enoxaparin the exposure to dabigatran was slightly lower than that after administration of dabigatran etexilate (single dose of 220 mg) alone. A higher anti-FXa/FIIa activity was observed after dabigatran etexilate administration with enoxaparin pre-treatment compared to that after treatment with dabigatran etexilate alone. This is considered to be due to the carry-over effect of enoxaparin treatment, and regarded as not clinically relevant. Other dabigatran related anti-coagulation tests were not changed significantly by the pre-treatment of enoxaparin.

Interactions linked to dabigatran etexilate and dabigatran metabolic profile

Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450 system and have no in vitro effects on human cytochrome P450 enzymes. Therefore, related medicinal product interactions are not expected with dabigatran.

Transporter interactions

P-gp inhibitors

Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of strong P-gp inhibitors (such as amiodarone, verapamil, quinidine, ketoconazole and clarithromycin) is expected to result in increased dabigatran plasma concentrations.

If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure (see sections 4.2, 4.4 and 5.1).

Systemic ketoconazole, cyclosporine, itraconazole and tacrolimus are contraindicated (see section 4.3). Caution should be exercised with other strong P-gp inhibitors (e.g. amiodarone, quinidine or verapamil) (see sections 4.2 and 4.4).

Ketoconazole: Ketoconazole increased total dabigatran AUC_0- and C_max values by 138 % and 135 %, respectively, after a single dose of 400 mg , and 153 % and 149 %, respectively, after multiple dosing of 400 mg ketoconazole once daily. The time to peak, terminal half-life and mean residence time were not affected by ketoconazole (see section 4.4). Concomitant treatment with systemic ketoconazole is contraindicated (see section 4.3).

Amiodarone: When Pradaxa was co-administered with a single oral dose of 600 mg amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran AUC and C_max were increased by about 60 % and 50 %, respectively. The mechanism of the interaction has not been completely clarified. In view of the long half-life of amiodarone the potential for drug interaction may exist for weeks after discontinuation of amiodarone (see sections 4.2 and 4.4 Close clinical surveillance is recommended when dabigatran etexilate is combined with amiodarone and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

Quinidine: Quinidine was given as 200 mg dose every 2nd hour up to a total dose of 1000 mg. Dabigatran etexilate was given twice daily over 3 consecutive days, on the 3^rd day either with or without quinidine. Dabigatran AUC_max,ss were increased on average by 53 % and 56 %, respectively with concomitant quinidine (see sections 4.2 and 4.4). Close clinical surveillance is recommended when dabigatran etexilate is combined with quinidine and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

Verapamil: When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the C_max and AUC of dabigatran were increased but magnitude of this change differs depending on timing of administration and formulation of verapamil (see sections 4.2 and 4.4).

The greatest elevation of dabigatran exposure was observed with the first dose of an immediate release formulation of verapamil administered one hour prior to dabigatran etexilate intake (increase of C_max by about 180 % and AUC by about 150 %). The effect was progressively decreased with administration of an extended release formulation (increased of C_max by about 90 % and AUC by about 70 %) or administration of multiple doses of verapamil (increased of C_max by about 60 % and AUC by about 50 %).

Patients concomitantly receiving dabigatran etexilate and verapamil, the dose of Pradaxa should be reduced to 220 mg taken as one 110 mg capsule twice daily (see section 4.2). Close clinical surveillance is recommended when dabigatran etexilate is combined with verapamil and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

There was no meaningful interaction observed when verapamil was given 2 hours after dabigatran etexilate (increased of C_max by about 10 % and AUC by about 20 %). This is explained by completed dabigatran absorption after 2 hours (see section 4.4).

Clarithromycin: When clarithromycin (500 mg twice daily) was administered together with dabigatran etexilate in healthy volunteers, increase of AUC by about 19 % and C_max by about 15 % was observed without any clinical safety concern. However, in patients receiving dabigatran, a clinically relevant interaction cannot be excluded when combined with clarithromycin. Therefore, a close monitoring should be exercised when dabigatran etexilate is combined with clarithromycin and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

The following potent P-gp inhibitors have not been clinically studied but from in vitro results a similar effect as with ketoconazole may be expected:

Itraconazole, tacrolimus and cyclosporine, which are contra-indicated (see section 4.3).

Neither clinical nor in vitro test results are available for posaconazole which is not recommended for concomitant treatment with Pradaxa. Inadequate clinical data are available regarding the co-administration of Pradaxa and dronedarone, and their co-administration is not recommended (see section 4.4).

P-gp inducers

Concomitant administration of a P-gp inducer (such as rifampicin, St. John´s wort (Hypericum perforatum), carbamazepine, or phenytoin) is expected to result in decreased dabigatran concentrations and should be avoided (see sections 4.4 and 5.2).

Rifampicin: Pre-dosing of the probe inducer rifampicin at a dose of 600 mg once daily for 7 days decreased total dabigatran peak and total exposure by 65.5 and 67 %, respectively. The inducing effect was diminished resulting in dabigatran exposure close to the reference by day 7 after cessation of rifampicin treatment. No further increase in bioavailability was observed after another 7 days.

Other drugs affecting P-gp

Protease inhibitors including ritonavir and its combinations with other protease inhibitors affect P-gp (either as inhibitor or as inducer). They have not been studied and are therefore not recommended for concomitant treatment with Pradaxa.

P-gp substrate

Digoxin: In a study performed with 24 healthy subjects, when Pradaxa was co-administered with digoxin, no changes on digoxin and no clinical relevant changes on dabigatran exposure have been observed.

Gastric pH

Pantoprazole: When Pradaxa was co-administered with pantoprazole, a decrease in the dabigatran area under the plasma concentration-time curve of approximately 30 % was observed. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with Pradaxa in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Pradaxa.

Ranitidine: Ranitidine administration together with Pradaxa had no clinically relevant effect on the extent of absorption of dabigatran.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of Pradaxa in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Women of child-bearing potential should avoid pregnancy during treatment with dabigatran etexilate. Pradaxa should not be used during pregnancy unless clearly necessary.

Breast-feeding

There are no clinical data of the effect of dabigatran on infants during breast feeding.

Breast-feeding should be discontinued during treatment with Pradaxa.

Fertility

No human data available.

In animal studies an effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (representing a 5-fold higher plasma exposure level compared to patients). No other effects on female fertility were observed. There was no influence on male fertility. At doses that were toxic to the mothers (representing a 5- to 10-fold higher plasma exposure level to patients), a decrease in foetal body weight and embryofoetal viability along with an increase in foetal variations were observed in rats and rabbits. In the pre- and post-natal study, an increase in foetal mortality was observed at doses that were toxic to the dams (a dose corresponding to a plasma exposure level 4-fold higher than observed in patients).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

In the pivotal study investigating the prevention of stroke and SEE in patients with atrial fibrillation, a total of 12,091 patients were randomized. Of these 6,059 were treated with 150 mg twice daily of dabigatran etexilate, while 5,983 received doses of 110 mg twice daily.

In total, 22 % of patient with atrial fibrillation treated for the prevention of stroke and SEE (long-term treatment for up to 3 years) experienced adverse reactions.

The most commonly reported adverse reactions are bleedings occurring in total in approximately 16,5 % in patients with atrial fibrillation treated for the prevention of stroke and SEE.

Although low in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.

Adverse reactions

Table 3 shows the adverse reactions identified from the prevention of thromboembolic stroke and SEE in patients with atrial fibrillation program ranked under headings of System Organ Class (SOC) and frequency using the following convention: very common (

	Stroke and SEE prevention in patients with atrial fibrillation
SOC / Preferred Term.	Dabigatran etexilate 110 mg twice daily	Dabigatran etexilate 150 mg twice daily
Number of patients treated	5,983	6,059
Blood and lymphatic system disorders
Anaemia	Common	Common
Haemoglobin decreased	Uncommon	Uncommon
Thrombocytopenia	Uncommon	Uncommon
Haematocrit decreased	Rare	Rare
Immune system disorder
Drug hypersensitivity	Uncommon	Uncommon
Rash	Uncommon	Uncommon
Pruritus	Uncommon	Uncommon
Urticaria	Rare	Rare
Bronchospasm	Not known	Very Rare
Nervous system disorders
Intracranial haemorrhage	Uncommon	Uncommon
Vascular disorders
Haematoma	Uncommon	Uncommon
Haemorrhage	Uncommon	Uncommon
Respiratory, thoracic and mediastinal disorders
Epistaxis	Common	Common
Haemoptysis	Uncommon	Uncommon
Gastrointestinal disorders
Gastrointestinal haemorrhage	Common	Common
Abdominal pain	Common	Common
Diarrhoea	Common	Common
Dyspepsia	Common	Common
Nausea	Common	Common
Rectal haemorrhage	Uncommon	Uncommon
Haemorrhoidal haemorrhage	Uncommon	Uncommon
Gastrointestinal ulcer	Uncommon	Uncommon
Gastroesophagitis	Uncommon	Uncommon
Gastroesophageal reflux disease	Uncommon	Uncommon
Vomiting	Uncommon	Uncommon
Dysphagia	Uncommon	Uncommon
Hepatobiliary disorders
Alanine aminotransferase increased	Uncommon	Uncommon
Aspartate aminotransferase increased	Uncommon	Uncommon
Hepatic function abnormal/ Liver function Test abnormal	Uncommon	Uncommon
Hepatic enzyme increased	Rare	Rare
Hyperbilirubinaemia	Rare	Rare
Skin and subcutaneous tissue disorder
Skin haemorrhage	Uncommon	Uncommon
Musculoskeletal and connective tissue and bone disorders
Haemarthrosis	Rare	Rare
Renal and urinary disorders
Genitourological haemorrhage	Uncommon	Common
Haematuria	Uncommon	Uncommon
General disorders and administration site conditions
Injection site haemorrhage	Rare	Rare
Catheter site haemorrhage	Rare	Rare
Injury, poisoning and procedural complications
Incision site haemorrhage	Rare	Rare

Bleeding

The table 4 shows bleeding events broken down to major and any bleeding in the pivotal study testing the prevention of thromboembolic stroke and SEE in patients with atrial fibrillation.

	Dabigatran etexilate 110 mg twice daily	Dabigatran etexilate 150 mg twice daily	Warfarin
Subjects randomized	6,015	6,076	6,022
Major Bleeding	342 (2.87 %)

prazosin

Generic Name: prazosin (PRA zoe sin)

Brand Names: Minipress

What is prazosin?

Prazosin is in a group of drugs called alpha-adrenergic (AL-fa ad-ren-ER-jik) blockers. Prazosin relaxes your veins and arteries so that blood can more easily pass through them.

Prazosin is used to treat hypertension (high blood pressure).

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

What is the most important information I should know about prazosin?

You should not use this medication if you are allergic to prazosin or similar medicines such as alfuzosin (Uroxatral), doxazosin (Cardura), silodosin (Rapaflo), tamsulosin (Flomax), or terazosin (Hytrin). Prazosin may cause dizziness or fainting, especially when you first start taking it or whenever your dose is changed. Be careful if you drive or do anything that requires you to be alert. Avoid standing for long periods of time or becoming overheated during exercise and in hot weather. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy.

Prazosin can affect your pupils during cataract surgery. Tell your eye surgeon ahead of time that you are using this medication. Do not stop using prazosin before surgery unless your surgeon tells you to.

Tell your doctor about all other medications you use, especially other blood pressure medications including diuretics (water pills).

What should I discuss with my healthcare provider before taking prazosin?

You should not use this medication if you are allergic to prazosin or similar medicines such as alfuzosin (Uroxatral), doxazosin (Cardura), silodosin (Rapaflo), tamsulosin (Flomax), or terazosin (Hytrin).

Prazosin can affect your pupils during cataract surgery. Tell your eye surgeon ahead of time that you are using this medication. Do not stop using prazosin before surgery unless your surgeon tells you to.

FDA pregnancy category C. It is not known whether prazosin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Prazosin can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take prazosin?

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.

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

Prazosin lowers blood pressure and may cause dizziness or fainting, especially when you first start taking it or whenever your dose is changed. Call your doctor if you have severe dizziness or feel like you might pass out.

You may feel very dizzy when you first wake up. Be careful when standing or sitting up from a lying position.

Your blood pressure will need to be checked often. Visit your doctor regularly.

Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Some things can cause your blood pressure to get too low. This includes vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low-salt diet, or taking diuretics (water pills). Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.

Store at room temperature away from moisture and heat.

See also: Prazosin dosage (in more detail)

What happens if I miss a dose?

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.

Overdose symptoms may include extreme drowsiness or fainting.

What should I avoid while taking prazosin?

Prazosin may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

To prevent dizziness, avoid standing for long periods of time or becoming overheated during exercise and in hot weather.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Drinking alcohol can increase certain side effects of prazosin.

Prazosin side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

• 
  

  fast or pounding heartbeats or fluttering in your chest;

  
  


• 
  

  feeling like you might pass out;

  
  


• 
  

  trouble breathing;

  
  


• 
  

  swelling in your hands, ankles, or feet; or

  
  


• 
  

  penis erection that is painful or lasts 4 hours or longer.

  
  

Less serious side effects may include:

• 
  

  mild dizziness;

  
  


• 
  

  weakness, tired feeling, drowsiness;

  
  


• 
  

  headache; or

  
  


• 
  

  nausea.

  
  

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.

Prazosin Dosing Information

Usual Adult Dose for Congestive Heart Failure:

Initial dose: 1 mg orally 2-3 times a day.
Maintenance dose: 6-15 mg daily given in divided doses.

Usual Adult Dose for Hypertension:

Initial dose: 1 mg orally 2-3 times a day.
Maintenance dose: 6-15 mg daily given in divided doses.

Usual Adult Dose for Benign Prostatic Hyperplasia:

Initial dose: 1 mg orally 2-3 times a day.
Maintenance dose: 6-15 mg daily given in divided doses.

What other drugs will affect prazosin?

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

• 
  

  propranolol (Inderal, Innopran); or

  
  


• 
  

  other blood pressure medications, including diuretics (water pills).

  
  

This list is not complete and other drugs may interact with prazosin. 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.

More prazosin resources

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

• prazosin Advanced Consumer (Micromedex) - Includes Dosage Information


• Prazosin Professional Patient Advice (Wolters Kluwer)


• Prazosin MedFacts Consumer Leaflet (Wolters Kluwer)


• Prazosin Prescribing Information (FDA)


• Minipress Monograph (AHFS DI)


• Minipress Prescribing Information (FDA)

Compare prazosin with other medications

• Anxiety and Stress
• Benign Prostatic Hyperplasia
• Heart Failure
• High Blood Pressure
• Post Traumatic Stress Disorder
• Raynaud's Syndrome

Where can I get more information?

• Your pharmacist can provide more information about prazosin.

See also: prazosin side effects (in more detail)

Cryselle

norgestrel and ethinyl estradiol

Dosage Form: tablets
Cryselle™ - 28 TABLETS

(NORGESTREL AND ETHINYL ESTRADIOL TABLETS, USP)

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Rx only

Revised JANUARY 2004

31090480104

DESCRIPTION:

21 white Cryselle™ tablets, each containing 0.3 mg of norgestrel (dl-13-beta-ethyl-17-alpha-ethinyl-17-beta-hydroxygon-4-en-3-one), a totally synthetic progestogen, and 0.03 mg of ethinyl estradiol (19-nor-17α-pregna-1,3,5 (10)-trien-20-yne-3,17-diol), and 7 light-green inert tablets. The inactive ingredients present are hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol and pregelatinized starch. The light-green inactive tablets also contain D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake.

Norgestrel MW: 312.45 MF: C21H28O2

Ethinyl Estradiol MW: 296.40 MF: C20H24O2

CLINICAL PHARMACOLOGY:

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

INDICATIONS AND USAGE:

Oral contraceptives are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception. Oral contraceptives are highly effective. Table I lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization and the IUD, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

TABLE I: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF USE OF A CONTRACEPTIVE METHOD

Adapted from Hatcher RA et al, Contraceptive Technology: 17th Revised Edition. NY, NY: Ardent Media, Inc., 1998.
* NA - not available † Depending on method (calendar, ovulation, symptothermal, post-ovulation)
Method	Perfect Use	Typical Use
Levonorgestrel implants	0.05	0.05
Male sterilization	0.1	0.15
Female sterilization	0.5	0.5
Depo-Provera® (injectable progestogen)	0.3	0.3
Oral contraceptives		5
Combined	0.1	NA*
Progestin only	0.5	NA*
IUD
Progesterone	1.5	2.0
Copper T 380A	0.6	0.8
Condom (male) without spermicide	3	14
(Female) without spermicide	5	21
Cervical cap
Nulliparous women	9	20
Parous women	26	40
Vaginal sponge
Nulliparous women	9	20
Parous women	20	40
Diaphragm with spermicidal cream or jelly	6	20
Spermicides alone (foam, creams, jellies, and vaginal suppositories)	6	26
Periodic abstinence (all methods)	1-9†	25
Withdrawal	4	19
No contraception (planned pregnancy)	85	85

CONTRAINDICATIONS:

Oral contraceptives should not be used in women with any of the following conditions:

Thrombophlebitis or thromboembolic disorders.

A past history of deep-vein thrombophlebitis or thromboembolic disorders.

Cerebral-vascular or coronary-artery disease.

Known or suspected carcinoma of the breast.

Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia.

Undiagnosed abnormal genital bleeding.

Cholestatic jaundice of pregnancy or jaundice with prior pill use.

Hepatic adenomas or carcinomas.

Known or suspected pregnancy.

WARNINGS:

Cigarette smoking increases the risk of serious cardiovascular side effects from oral-contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.

The information contained in this package insert is based principally on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of disease, namely, a ratio of the incidence of a disease among oral-contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral-contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiological methods.

1. Thromboembolic disorders and other vascular problems:

a. Myocardial Infarction:

An increased risk of myocardial infarction has been attributed to oral-contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral-contraceptive users has been estimated to be two to six. The risk is very low under the age of 30. Smoking in combination with oral-contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Table II) among women who use oral contraceptives.

TABLE II. (Adapted from P. M. Layde and V. Beral, Lancet, 1:541-546, 1981.)

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 9 in "WARNINGS"). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

b. Thromboembolism:

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep-vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.

A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery in women who elect not to breast-feed, or a midtrimester pregnancy termination.

c. Cerebrovascular diseases:

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension. The attributable risk is also greater in older women.

d. Dose-related risk of vascular disease from oral contraceptives:

A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogen used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral-contraceptive agents should be started on preparations containing less than 50 mcg of estrogen.

e. Persistence of risk of vascular disease:

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40 to 49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral-contraceptive formulations containing 50 micrograms or higher of estrogens.

2. Estimates of mortality from oral contraceptive use:

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table III). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral-contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is less than that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral-contraceptive users is based on data gathered in the 1970's—but not reported until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral-contraceptive use to women who do not have the various risk factors listed in this labeling.

Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular-disease risks may be increased with oral-contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.

Therefore, the Committee recommended that the benefits of oral-contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.

TABLE III: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY-CONTROL METHOD ACCORDING TO AGE

Adapted from H.W. Ory, Family Planning Perspectives, 15:57-63, 1983.
* Deaths are birth-related † Deaths are method-related
Method of control and outcome	15-19	20-24	25-29	30-34	35-39	40-44
No fertility- control methods*	7.0	7.4	9.1	14.8	25.7	28.2
Oral contraceptives non-smoker†	0.3	0.5	0.9	1.9	13.8	31.6
Oral contraceptives smoker†	2.2	3.4	6.6	13.5	51.1	117.2
IUD†	0.8	0.8	1.0	1.0	1.4	1.4
Condom*	1.1	1.6	0.7	0.2	0.3	0.4
Diaphragm/spermicide*	1.9	1.2	1.2	1.3	2.2	2.8
Periodic abstinence*	2.5	1.6	1.6	1.7	2.9	3.6

3. Carcinoma of the reproductive organs:

Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. The overwhelming evidence in the literature suggests that use of oral contraceptives is not associated with an increase in the risk of developing breast cancer, regardless of the age and parity of first use or with most of the marketed brands and doses. The Cancer and Steroid Hormone (CASH) study also showed no latent effect on the risk of breast cancer for at least a decade following long-term use. A few studies have shown a slightly increased relative risk of developing breast cancer, although the methodology of these studies, which included differences in examination of users and nonusers and differences in age at start of use, has been questioned.

Some studies suggest that oral-contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

In spite of many studies of the relationship between oral-contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established.

4. Hepatic neoplasia:

Benign hepatic adenomas are associated with oral-contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use. Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral-contraceptive users. However, these cancers are extremely rare in the U.S., and the attributable risk (the excess incidence) of liver cancers in oral-contraceptive users approaches less than one per million users.

5. Ocular lesions:

There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.

6. Oral-contraceptive use before or during early pregnancy:

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral-contraceptive use. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral-contraceptive use should be discontinued if pregnancy is confirmed.

7. Gallbladder disease:

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral-contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral-contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

8. Carbohydrate and lipid metabolic effects:

Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.

A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see "Warnings," 1a. and 1d.), changes in serum triglycerides and lipoprotein levels have been reported in oral-contraceptive users.

9. Elevated blood pressure:

An increase in blood pressure has been reported in women taking oral contraceptives, and this increase is more likely in older oral-contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing quantities of progestogens.

Women with a history of hypertension or hypertension-related diseases, or renal disease, should be encouraged to use another method of contraception. If women with hypertension elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users.

10. Headache:

The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause.

11. Bleeding irregularities:

Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. The type and dose of progestogen may be important.

Nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding.

If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out.

Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent.

PRECAUTIONS:

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

1. Physical examination and follow-up:

A periodic history and physical examination is appropriate for all women, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

2. Lipid disorders:

Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. (See "WARNINGS," 1d.)

3. Liver function:

If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.

4. Fluid retention:

Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.

5. Emotional disorders:

Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related. Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

6. Contact lenses:

Contact-lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

7. Drug interactions:

Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin. A similar association, though less marked, has been suggested with barbiturates, phenylbutazone, phenytoin sodium, and possibly with griseofulvin, ampicillin, and tetracyclines.

8. Interactions with laboratory tests:

Certain endocrine- and liver-function tests and blood components may be affected by oral contraceptives:

1. 
   
   1. 
      
      1. 
         
         1. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
         
         
         2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.
         
         
         3. Other binding proteins may be elevated in serum.
         
         
         4. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged.
         
         
         5. Triglycerides may be increased.
         
         
         6. Glucose tolerance may be decreased.
         
         
         7. Serum folate levels may be depressed by oral-contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.
         
         
      
      
   
   

9. Carcinogenesis:

See "WARNINGS" section.

10. Pregnancy:

Pregnancy Category X.

See "CONTRAINDICATIONS" and "WARNINGS" sections.

11. Nursing mothers:

Small amounts of oral-contraceptive steroids have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.

12. Pediatric use:

Safety and efficacy of norgestrel and ethinyl estradiol tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and users 16 and older. Use of this product before menarche is not indicated.

INFORMATION FOR THE PATIENT:

See Patient Labeling Printed Below.

ADVERSE REACTIONS:

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see "WARNINGS" section):

• Thrombophlebitis


• Arterial thromboembolism


• Pulmonary embolism


• Myocardial infarction


• Cerebral hemorrhage


• Cerebral thrombosis


• Hypertension


• Gallbladder disease


• Hepatic adenomas or benign liver tumors

There is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed:

• Mesenteric thrombosis


• Retinal thrombosis

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related:

• Nausea


• Vomiting


• Gastrointestinal symptoms (such as abdominal cramps and bloating)


• Breakthrough bleeding


• Spotting


• Change in menstrual flow


• Amenorrhea


• Temporary infertility after discontinuation of treatment


• Edema


• Melasma which may persist


• Breast changes: tenderness, enlargement, secretion


• Change in weight (increase or decrease)


• Change in cervical erosion and secretion


• Diminution in lactation when given immediately postpartum


• Cholestatic jaundice


• Migraine


• Rash (allergic)


• Mental depression


• Reduced tolerance to carbohydrates


• Vaginal candidiasis


• Change in corneal curvature (steepening)


• Intolerance to contact lenses

The following adverse reactions have been reported in users of oral contraceptives, and the association has been neither confirmed nor refuted:

• Congenital anomalies


• Premenstrual syndrome


• Cataracts


• Optic neuritis


• Changes in appetite


• Cystitis-like syndrome


• Headache


• Nervousness


• Dizziness


• Hirsutism


• Loss of scalp hair


• Erythema multiforme


• Erythema nodosum


• Hemorrhagic eruption


• Vaginitis


• Porphyria


• Impaired renal function


• Hemolytic uremic syndrome


• Budd-Chiari syndrome


• Acne


• Changes in libido


• Colitis


• Sickle-cell disease


• Cerebral-vascular disease with mitral valve prolapse


• Lupus-like syndromes

OVERDOSAGE:

Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.

NONCONTRACEPTIVE HEALTH BENEFITS:

The following noncontraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral-contraceptive formulations containing doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol.

Effects on menses:

• Increased menstrual cycle regularity


• Decreased blood loss and decreased incidence of iron-deficiency anemia


• Decreased incidence of dysmenorrhea

Effects related to inhibition of ovulation:

• Decreased incidence of functional ovarian cysts


• Decreased incidence of ectopic pregnancies

Effects from long-term use:

• Decreased incidence of fibroadenomas and fibrocystic disease of the breast


• Decreased incidence of acute pelvic inflammatory disease


• Decreased incidence of endometrial cancer


• Decreased incidence of ovarian cancer

DOSAGE AND ADMINISTRATION:

To achieve maximum contraceptive effectiveness, Cryselle™-28 (norgestrel and ethinyl estradiol Tablets, USP) 0.3 mg/0.03 mg must be taken exactly as directed and at intervals not exceeding 24 hours. The dosage of Cryselle™-28 is one white tablet daily for 21 consecutive days, followed by one light-green inert tablet daily for 7 consecutive days, according to prescribed schedule. It is recommended that tablets be taken at the same time each day, preferably after the evening meal or at bedtime.

During the first cycle of medication, the patient is instructed to begin taking Cryselle™-28 on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, the first tablet (white) is taken that day. One white tablet should be taken daily for 21 consecutive days followed by one light-green inert tablet daily for 7 consecutive days.

Withdrawal bleeding should usually occur within three days following discontinuation of white tablets. During the first cycle, contraceptive reliance should not be placed on Cryselle™-28 until a white tablet has been taken daily for 7 consecutive days. The possibility of ovulation and conception prior to initiation of medication should be considered.

The patient begins her next and all subsequent 28-day courses of tablets on the same day of the week (Sunday) on which she began her first course, following the same schedule: 21 days on white tablets—7 days on light-green inert tablets. If in any cycle the patient starts tablets later than the proper day, she should protect herself by using another method of birth control until she has taken a white tablet daily for 7 consecutive days.

If spotting or breakthrough bleeding occurs, the patient is instructed to continue on the same regimen. This type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her physician. Although the occurrence of pregnancy is highly unlikely if Cryselle™-28 is taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. If the patient has not adhered to the prescribed schedule (missed one or more tablets or started taking them on a day later than she should have), the probability of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures taken before the medication is resumed. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.

For additional patient instructions regarding missed pills, see the "WHAT T0 DO IF YOU MISS PILLS" section in the DETAILED PATIENT LABELING below.

Any time the patient misses two or more white tablets, she should also use another method of contraception until she has taken a white tablet daily for seven consecutive days. If the patient misses one or more light-green tablets, she is still protected against pregnancy provided she begins taking white tablets again on the proper day. If breakthrough bleeding occurs following missed white tablets, it will usually be transient and of no consequence. While there is little likelihood of ovulation occurring if only one or two tablets are missed, the possibility of ovulation increases with each successive day that scheduled white tablets are missed.

In the nonlactating mother, Cryselle™-28 may be initiated postpartum, for contraception. When the tablets are administered in the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered (see "CONTRAINDICATIONS," "WARNINGS," and "PRECAUTIONS" concerning thromboembolic disease). It is to be noted that early resumption of ovulation may occur if Parlodel® (bromocriptine mesylate) has been used for the prevention of lactation.

HOW SUPPLIED:

Cryselle™-28 tablets (0.3 mg norgestrel and 0.03 mg ethinyl estradiol tablets, USP), NDC 0555-9049-58 are available in packages of 6 cyclic tablet dispensers, each containing 28 tablets, as follows: 21 active tablets, white, round, coated tablets marked “dp” and “543” and 7 inert tablets, light-green colored, uncoated tablets marked “dp” and “331”.

Store at controlled room temperature 15°-30°C (59°-86°F) [See USP].

REFERENCES AVAILABLE UPON REQUEST.

BRIEF SUMMARY PATIENT PACKAGE INSERT:

This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Oral contraceptives, also known as "birth-control pills" or "the pill," are taken to prevent pregnancy, and when taken correctly, have a failure rate of less than 1.0% per year when used without missing any pills. The typical failure rate of large numbers of pill users is less than 3.0% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy.

For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be life-threatening or may cause temporary or permanent disability or death. The risks associated with taking oral contraceptives increase significantly if you:

• smoke.


• have high blood pressure, diabetes, high cholesterol.


• have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, or malignant or benign liver tumors.

You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding.

Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels from oral-contraceptive use. This risk increases with