Isis Pharmaceuticals, Inc.

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Theophylline Oral Solution

Dosage Form: oral solution
Theophylline Oral Solution, USP 80 mg/ 15 mL

Theophylline Oral Solution Description

Theophylline is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous theophylline has the chemical name 1H-Purine- 2,6-dione, 3,7-dihydro-1 ,3 -dimethyl-, and is represented by the following structural formula:

The molecular formula of anhydrous theophylline is C7H8N4O2 with a molecular weight of 180.17.

Theophylline Oral Solution, USP is available as a liquid intended for oral administration, containing 80 mg of theophylline anhydrous in each 15 mL (tablespoonful).

Theophylline Oral Solution, USP also contains the following inactive ingredients: citric acid, sodium saccharin, sodium benzoate, glycerin, propylene glycol, FD and C Red #40, natural and artificial fruity flavor and purified water. Theophylline Oral Solution, USP has a pH of 4.0 - 5.0.

Theophylline Oral Solution - Clinical Pharmacology

Mechanism of Action:

Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).

Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.

Serum Concentration-Effect Relationship:

Bronchodilation occurs over the serum theophylline concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum theophylline concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum theophylline concentrations >20mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum theophylline concentrations between 10 and 15 mcg/mL will achieve most of the drug's potential therapeutic benefit while minimizing the risk of serious adverse events.

Pharmacokinetics:

OverviewTheophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

The pharmacokinetics of theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I) and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients (e.g., at 24-hour intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter theophylline clearance (see PRECAUTIONS, Laboratory tests).

Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states.

Population characteristics	Total body clearance* mean (range)†† (mL/kg/min)	Half-life mean (range)†† (hr)
For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples.
*Clearance represents the volume of blood completely cleared of theophylline by the liver in one minute. Values listed were generally determined at serum theophylline concentrations <20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics.
††Reported range or estimated range (mean ± 2 SD) where actual range not reported.
†NR = not reported or not reported in a comparable format.
**Median
Age
Premature neonates
postnatal age 3-15 days	0.29 (0.09-0.49)	30 (17-43)
postnatal age 25-57 days	0.64 (0.04-1.2)	20 (9.4-30.6)
Term infants
postnatal age 1-2 days	NR†	25.7 (25-26.5)
postnatal age 3-30 weeks	NR†	11 (6-29)
Children
1-4 years	1.7 (0.5-2.9)	3.4 (1.2-5.6)
4-12 years	1.6 (0.8-2.4)	NR†
13-15 years	0.9 (0.48-1.3)	NR†
16-17 years	1.4 (0.2-2.6)	3.7 (1.5-5.9)
Adults (16-60 years)
otherwise healthy
non-smoking asthmatics	0.65 (0.27-1.03)	8.7 (6.1-12.8)
Elderly (>60 years)
non-smokers with normal cardiac, liver, and renal function	0.41 (0.21-0.61)	9.8 (1.6-18)
Concurrent illness or altered physiological state
Acute pulmonary edema	0.33** (0.07-2.45)	19** (3.1-82)
COPD->60 years, stable non-smoker >1 year	0.54 (0.44-0.64)	11 (9.4-12.6)
COPD with cor pulmonale	0.48 (0.08-0.88)	NR†
Cystic fibrosis (14-28 years)	1.25 (0.31-2.2)	6.0 (1.8-10.2)
Fever associated with acute viral respiratory illness (children 9-15 years)	NR†	7.0 (1.0-13)
Liver disease - cirrhosis	0.31** (0.1-0.7)	32** (10-56)
acute hepatitis	0.35 (0.25-0.45)	19.2 (16.6-21.8)
cholestasis	0.65 (0.25-1.45)	14.4 (5.7-31.8)
Pregnancy - 1st trimester	NR†	8.5 (3.1-13.9)
2nd trimester	NR†	8.8 (3.8-13.8)
3rd trimester	NR†	13.0 (8.4-17.6)
Sepsis with multi-organ failure	0.47 (0.19-1.9)	18.8 (6.3-24.1)
Thyroid disease - hypothyroid	0.38 (0.13-0.57)	11.6 (8.2-25)
hyperthyroid	0.8 (0.68-0.97)	4.5 (3.7-5.6)

Note: In addition to the factors listed above, theophylline clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of theophylline.

Absorption Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single dose of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5-15 mcg/mL) can be expected 1-2 hr after the dose. Co-administration of theophylline with food or antacids does not cause clinically significant changes in the absorption of theophylline from immediate-release dosage forms.

Distribution Once theophylline enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound theophylline distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of theophylline is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Theophylline passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva theophylline concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. An increase in the volume of distribution of theophylline, primarily due to reduction in plasma protein binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected acidemia, the elderly and in women during the third trimester of pregnancy. In such cases, the patient may show signs of toxicity at total (bound + unbound) serum concentrations of theophylline in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased theophylline binding may have a subtherapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum theophylline concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum theophylline concentration provides a more reliable means of dosage adjustment than measurement of total serum theophylline concentration. Generally, concentrations of unbound theophylline should be maintained in the range of 6-12 mcg/mL.

Metabolism Following oral dosing, theophylline does not undergo any measurable first-pass elimination. In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1 ,3-dimethyluric acid. 1 -methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine. Theophylline demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.

Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of theophylline and serum concentrations in adults with normal renal function are <1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect.

Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, non-linearity of elimination may begin in some patients at serum theophylline concentrations <10 mcg/mL. Since this non-linearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations (see DOSAGE AND ADMINISTRATION, Table VI). Accurate prediction of dose-dependency of theophylline metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady state serum theophylline concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum theophylline concentration in response to dosage changes.

Excretion In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1 ,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, the large fraction of the theophylline dose excreted in the urine as unchanged theophylline and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum theophylline concentrations in neonates with reduced renal function (See WARNINGS).

Serum Concentrations at Steady State After multiple doses of theophylline, steady state is reached in 30-65 hours (average 40 hours) in adults. At steady state, on a dosage regimen with 6-hour intervals, the expected mean trough concentration is approximately 60% of the mean peak concentration, assuming a mean theophylline half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid theophylline clearance. In patients with high theophylline clearance and half-lives of about 4-5 hours, such as children age 1 to 9 years, the trough serum theophylline concentration may be only 30% of peak with a 6-hour dosing interval. In these patients a slow release formulation would allow a longer dosing interval (8-12 hours) with a smaller peak/trough difference.

Special Populations

(See Table I for mean clearance and half-life values)

GeriatricThe clearance of theophylline is decreased by an average of 30% in healthy elderly adults (> 60 yrs) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in elderly patients (see WARNINGS).

Pediatrics The clearance of theophylline is very low in neonates (see WARNINGS). Theophylline clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Careful attention to dosage selection and monitoring of serum theophylline concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION).

Gender Gender differences in theophylline clearance are relatively small and unlikely to be of clinical significance. Significant reduction in theophylline clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy.

Race Pharmacokinetic differences in theophylline clearance due to race have not been studied.

Renal Insufficiency Only a small fraction, e.g., about 10%, of the administered theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, approximately 50% of the administered theophylline dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in neonates with decreased renal function (see WARNINGS).

Hepatic Insufficiency Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with reduced hepatic function (see WARNINGS).

Congestive Heart Failure (CHF) Theophylline clearance is decreased by 50% or more in patients with CHF. The extent of reduction in theophylline clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since theophylline clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with CHF (see WARNINGS).

Smokers Tobacco and marijuana smoking appears to increase the clearance of theophylline by induction of metabolic pathways. Theophylline clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase theophylline clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in theophylline clearance. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients who stop smoking (see WARNINGS). Use of nicotine gum has been shown to have no effect on theophylline clearance.

Fever Fever, regardless of its underlying cause, can decrease the clearance of theophylline. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of theophylline clearance. Precise data are lacking, but a temperature of 39oC (102oF) for at least 24 hours is probably required to produce a clinically significant increase in serum theophylline concentrations. Children with rapid rates of theophylline clearance (i.e., those who require a dose that is substantially larger than average [e.g., >22 mg/kg/day] to achieve a therapeutic peak serum theophylline concentration when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with sustained fever (see WARNINGS).

Miscellaneous

Other factors associated with decreased theophylline clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with any of these conditions (see WARNINGS). Other factors associated with increased theophylline clearance include hyperthyroidism and cystic fibrosis.

Clinical Studies:

In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that theophylline decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-2 agonists. Theophylline has also been shown to reduce the need for short courses of daily oral prednisone to relieve exacerbations of airway obstruction that are unresponsive to bronchodilators in asthmatics.

In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that theophylline decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.

Indications and Usage for Theophylline Oral Solution

Theophylline is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

Contraindications

THEOPHYLINE ORAL SOLUTION, USP is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

Warnings

Concurrent Illness:

Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:

                     Active peptic ulcer disease

                     Seizure disorders

                     Cardiac arrhythmias (not including bradyarrhythmias)

Conditions That Reduce Theophylline Clearance:

There are several readily identifiable causes of reduced theophylline clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline toxicity can occur. Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive motoring of serum theophylline concentrations in patients with the following risk factors:

Age

                    Neonates (term and premature)

                    Children <1 year

                    Elderly (>60 years)

Concurrent Diseases

                    Acute pulmonary edema

                    Congestive heart failure

                    Cor pulmonale

                    Fever; ≥102°F for 24 hours or more; or lesser temperature elevations for longer periods

                    Hypothyroidism

                    Liver disease; cirrhosis, acute hepatitis

                    Reduced renal function in infants <3 months of age

                    Sepsis with multi-organ failure

                    Shock

Cessation of Smoking

Drug Interactions Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II).

When Signs or Symptoms of Theophylline Toxicity Are Present:

Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum theophylline concentration measured immediately. Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the clinician may instruct the patient to resume the drug at a lower dosage (see DOSAGE AND ADMINISTRATION, Dosing Guidelines, Table VI).

Dosage Increases:

Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady state serum theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the theophylline dose on the basis of a low serum concentration, the clinician should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see PRECAUTIONS, Laboratory Tests).

As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum theophylline concentration (see DOSAGE AND ADMINISTRATION, Table VI).

Precautions

General:

Careful consideration of the various interacting drugs and physiologic conditions that can alter theophylline clearance and require dosage adjustment should occur prior to initiation of theophylline therapy, prior to increases in theophylline dose, and during follow up (see WARNINGS). The dose of theophylline selected for initiation of therapy should be low and, if tolerated, increased slowly over a period of a week or longer with the final dose guided by monitoring serum theophylline concentrations and the patient's clinical response (see DOSAGE AND ADMINISTRATION, Table V).

Monitoring Serum Theophylline Concentrations:

Serum theophylline concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum theophylline concentration should be measured as follows:

1. When initiating therapy to guide final dosage adjustment after titration.

2. Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.

3. Whenever signs or symptoms of theophylline toxicity are present.

4. Whenever there is a new illness, worsening of a chronic illness or a change in the patient's treatment regimen that may alter theophylline clearance (e.g., fever >102°F sustained for 24 hours, hepatitis, or drugs listed in Table II are added or discontinued).

To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum theophylline concentration; 1-2 hours after a dose at steady-state. For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum theophylline concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than two hours after the dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of theophylline toxicity are present, the serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the clinician without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound theophylline should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

Saliva concentrations of theophylline cannot be used reliably to adjust dosage without special techniques.

Effects on Laboratory Tests:

As a result of its pharmacological effects, theophylline at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dl to 6 mg/dl), free fatty acids (from a mean of 451 μeq/l to 800 μeq/l), total cholesterol (from a mean of 140 vs 160 mg/dl), HDL (from a mean of 36 to 50 mg/dl), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Theophylline at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dl after 4 weeks of theophylline). The clinical importance of these changes should be weighed against the potential therapeutic benefit of theophylline in individual patients.

Information for Patients:

The patient (or parent/care giver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heart beat occurs during treatment with theophylline, even if another cause is suspected. The patient should be instructed to contact their clinician if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another clinician adds a new medication or discontinues a previously prescribed medication. Patients should be instructed to inform all clinicians involved in their care that they are taking theophylline, especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their clinician. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.

Drug Interactions:

Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to theophylline or another drug or occurrence of adverse effects without a change in serum theophylline concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in increased or decreased serum theophylline concentrations. Theophylline only rarely alters the pharmacokinetics of other drugs. The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state theophylline regimen. If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger. Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased. The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e., <15% change in theophylline clearance).

The listing of drugs in Table II and III are current as of February 9, 1995. New interactions are continuously being reported for theophylline, especially with new chemical entities. The clinician should not assume that a drug does not interact with theophylline if it is not listed in Table II. Before addition of a newly available drug in a patient receiving theophylline, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and theophylline has been reported.

Table II. Clinically significant drug interactions with theophylline*.

Drug		Type of Interaction	Effect**
*Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
**Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine		Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol		A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol		Decreases theophylline clearance at allopurinol doses >600 mg/day.	25% increase
Amino glutethimide		Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine		Similar to aminoglutethimide.	30% decrease
Cimetidine		Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin		Similar to cimetidine.	40% increase
Clarithromycin		Similar to erythromycin.	25% increase
Diazepam		Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram		Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin		Similar to cimetidine.	300% increase
Ephedrine		Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin		Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen		Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam		Similar to diazepam.	Similar to diazepam.
Fluvoxamine		Similar to cimetidine	Similar to cimetidine
Halothane		Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A		Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.		20% decrease
Ketamine	Pharmacologic		May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.		Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.		Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.		20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.		80% increase
Midazolam	Similar to diazepam.		Similar to diazepam.
Moricizine	Increases theophylline clearance.		25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.		Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.		30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.		25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.		Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.		40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.		100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.		20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.		20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.		90% increase
Thiabendazole	Decreases the

Loceryl 0.25% w / w Cream

1. Name Of The Medicinal Product

Loceryl 0.25% w/w cream

2. Qualitative And Quantitative Composition

Loceryl cream contains 0.25% w/w amorolfine in the form of hydrochloride. Amorolfine is chemically described as cis-4-[(RS)-3[4-(1,1-Dimethylpropyl)phenyl]-2-methylpropyl]-2,6-dimethylmorpholine.

Amorolfine hydrochloride HSE 0.279 w/w

(equivalent to 0.25% w/w base)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Cream.

4. Clinical Particulars

4.1 Therapeutic Indications

Dermatomycoses caused by dermatophytes: tinea pedis (athlete's foot), tinea cruris, tinea inguinalis, tinea corporis, tinea manuum. Pityriasis versicolor.

4.2 Posology And Method Of Administration

Dermatomycoses

Cream: To be applied to affected skin areas once daily following cleansing (in the evening).

The treatment should be continued without interruption until clinical cure, and for 3 - 5 days thereafter. The required duration of treatment depends on the species of fungi and on the localisation of the infection. In general, treatment should be continued for at least two to three weeks. With foot mycoses, up to six weeks of therapy may be necessary.

Elderly

There are no specific dosage recommendations for use in elderly patients.

Children

There are no specific dosage recommendations for children owing to the lack of clinical experience available to date.

4.3 Contraindications

Loceryl cream must not be reused by patients who have shown hypersensitivity to the active substance or to any of the excipients.

No experience exists of use during pregnancy and nursing, therefore, the use of Loceryl should be avoided during pregnancy and lactation.

4.4 Special Warnings And Precautions For Use

Avoid contact of Loceryl cream with eyes, ears and mucous membranes.

This medicinal product contains stearyl alcohol which may cause local skin reaction (e.g. contact dermatitis)

Owing to the lack of clinical experience available to date, the use of Loceryl 0.25% cream in children is not recommended.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There are no specific studies involving concomitant treatment with other topical medicines. Use of nail varnish or artificial nails should be avoided during treatment.

4.6 Pregnancy And Lactation

Reproductive toxicology studies showed no evidence of teratogenicity in laboratory animals but embryotoxicity was observed at high oral doses. The systemic absorption of amorolfine during and after topical administration is very low and therefore the risk to the human foetus appears to be negligible. However, because there is no relevant experience Loceryl should be avoided during pregnancy and breast feeding. Breast-feeding women must not use the cream in the breast area.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

Adverse drug reactions are rare and mostly mild in nature.

System Organ Class	Frequency	Adverse drug reaction
Skin and subcutaneous tissue disorders	Rare (	Skin Irritation, erythema, pruritus, skin burning sensation
Very rare (	Contact dermatitis

4.9 Overdose

Accidental oral Ingestion

Loceryl is for topical use. In the event of accidental oral ingestion, an appropriate method of gastric emptying may be used.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other antifungals for topical use ATC code: D01AE16

Loceryl is a topical antimycotic. Amorolfine belongs to a new chemical class, and its fungicidal action is based on an alteration of the fungal cell membrane targeted primarily on sterol biosynthesis. The ergosterol content is reduced, and at the same time unusual sterically nonplanar sterols accumulate.

Amorolfine is a broad spectrum antimycotic. It is highly active (MIC < 2mcg/ml) in vitro against

yeasts: Candida, Cryptococcus, Malassezia

dermatophytes: Trichophyton, Microsporum, Epidermophyton

moulds: Hendersonula, Alternaria, Scopulariopsis

dematiacea: Cladosporium, Fonsecaea, Wangiella

dimorphic fungi: Coccidioides, Histoplasma, Sporothrix

With the exception of Actinomyces, bacteria are not sensitive to amorolfine. Propionibacterium acnes is only slightly sensitive.

5.2 Pharmacokinetic Properties

Amorolfine from cream penetrates into the stratum corneum. Nevertheless, systemic absorption is extremely low during and after therapeutic use.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Polyoxyl 40 stearate,

stearyl alcohol, paraffin

liquid,

white soft paraffin,

carbomer,

sodium hydroxide,

disodium edetate,

2 phenoxyethanol.

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Loceryl cream should be stored below 30°C.

6.5 Nature And Contents Of Container

20g collapsible aluminium tube, sealed with an aluminium membrane and fitted with a plastic screw cap.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Galderma (UK) Limited

Meridien House

69-71 Clarendon Road

Watford

Herts.

WD17 1DS

UK

8. Marketing Authorisation Number(S)

PL 10590/0041

9. Date Of First Authorisation/Renewal Of The Authorisation

April 1999

10. Date Of Revision Of The Text

April 2010

Corid

Dosage Form: FOR ANIMAL USE ONLY
Corid®

(amprolium)

9.6% Oral Solution

Coccidiostat

INDICATIONS

An aid in the treatment and prevention of coccidiosis caused by Eimeria bovis and E. zurnii in calves. For a satisfactory diagnosis a microscopic examination of the feces should be done before treatment. When treating outbreaks, drug should be administered promptly after diagnosis is determined.

Corid Dosage and Administration

5-Day Treatment Protocol	21-Day Prevention Protocol
Daily Dosage: 10 mg amprolium/kg (10 mg per 2.2 lb body weight)	Daily Dosage: 5 mg amprolium/kg (5 mg per 2.2 lb body weight)

USE DIRECTIONS

There are 96 mg of amprolium in every 1 mL of Corid 9.6% Solution.

1 fl oz = 29.57 mL		8 fl oz = 1/2 pint (236.56 mL)
1 fl oz = 2 measuring tablespoons		16 fl oz = 1 pint (473.12 mL)

IN DRINKING WATER

Mix Corid daily with fresh drinking water.

5-DAY TREATMENT

Add Corid 9.6% Oral Solution to drinking water at the rate of 16 fl oz/100 gal. At the usual rate of water consumption this will provide an intake of approximately 10 mg amprolium/kg (2.2 lb) body weight. Offer this solution as the only source of water for 5 days. Use on a herd basis only; when one or more calves show signs of coccidiosis, it is likely that the rest of the group has been exposed, and all calves in the group should be treated.

21-DAY PREVENTION

During periods of exposure or when experience indicates that coccidiosis is likely to be a hazard, add Corid 9.6% Oral Solution to drinking water at the rate of 8 fl oz/100 gal. At usual rates of water consumption this will provide an intake of approximately 5 mg amprolium/kg (2.2 lb) body weight. Offer this solution as the only source of water for 21 days.

AS A DRENCH

Corid drench solutions may be stored in a clean, closed, labeled container for up to 3 days.

5-DAY TREATMENT

Add 3 fl oz Corid 9.6% Oral Solution to 1 pt of water and, with a dose syringe, give 1 fl oz of this drench solution for each 100 lb (45 kg) body weight. This will provide a dose of approximately 10 mg amprolium/kg (2.2 lb) body weight. Give daily for 5 days. Use on a herd basis only; when one or more calves show signs of coccidiosis, it is likely that the rest of the group has been exposed, and all calves in the group should be treated.

21-DAY PREVENTION

During periods of exposure or when experience indicates that coccidiosis is likely to be a hazard, add 1½ fl oz of Corid 9.6% Oral Solution to 1 pt of water and, with a dose syringe, give 1 fl oz of this drench solution for each 100 lb (45 kg) body weight. This will provide a dose of approximately 5 mg amprolium/kg (2.2 lb) body weight. Give daily for 21 days.

RESIDUE WARNINGS

Withdraw 24 hours before slaughter. A withdrawal period has not been established for this product in pre-ruminating calves. Do not use in calves to be processed for veal.

Warning

NOT FOR HUMAN USE. Keep this and all drugs out of the reach of children. The Material Safety Data Sheet (MSDS) contains more detailed occupational safety information. To report adverse reactions in users, to obtain more information, or to obtain a MSDS, contact Merial at 1-888-637-4251.

Precautions

FOR ORAL USE IN ANIMALS ONLY. MAY CAUSE EYE IRRITATION. For irritation, flush with plenty of water; get medical attention.

Restricted Drug (California) - Use only as directed.

STORAGE

Store between 5° - 25° C (41° - 77° F) with brief excursions to 40° C.

Benzoic acid 0.1% added as preservative

Technical Assistance: 1-888-637-4251

www.Corid.com

® Corid and the CATTLE HEAD logo are registered trademarks of Merial Limited.

1022-2220-02

Rev. 02-2008

PRINCIPAL DISPLAY PANEL - 473 mL Bottle Label

Corid®

(amprolium)

9.6% Oral Solution

Coccidiostat

Product # 66970

Net Contents: 16 oz (473 mL)

Active Ingredient: amprolium...............9.6%

NADA 013-149, Approved by FDA

Distributed By:

Merial Limited

3239 Satellite Blvd.

Duluth, GA 30096-4640, U.S.A.

MERIAL

Corid  amprolium  solution

Product Information Product Type OTC ANIMAL DRUG NDC Product Code (Source) 50604-2140 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength amprolium (amprolium) amprolium 96 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 50604-2140-2 473 mL In 1 BOTTLE, PLASTIC None 2 50604-2140-1 3785 mL In 1 BOTTLE, PLASTIC None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA013149	06/01/1962

Labeler - Merial Limited (034393582)

Revised: 08/2010Merial Limited

Diamorphine Injection BP 100mg (Wockhardt UK Ltd)

1. Name Of The Medicinal Product

Diamorphine Hydrochloride 100mg for Injection

2. Qualitative And Quantitative Composition

Each ampoule contains 100mg of diamorphine hydrochloride.

For full list of excipients, see section 6.1.

3. Pharmaceutical Form

A white to off-white, sterile, freeze dried powder of Diamorphine Hydrochloride BP for reconstitution for injection.

4. Clinical Particulars

4.1 Therapeutic Indications

Diamorphine may be used in the treatment of severe pain associated with surgical procedures, myocardial infarction or pain in the terminally ill and for the relief of dyspnoea in acute pulmonary oedema.

4.2 Posology And Method Of Administration

Diamorphine may be given by the intramuscular, intravenous or subcutaneous routes. Glucose intravenous infusion is the preferred diluent, particularly when the drug is administered by a continuous infusion pump over 24 to 48 hours, although it is also compatible with sodium chloride intravenous infusion.

The dose should be suited to the individual patient.

Adults:

Acute pain, 5mg repeated every four hours if necessary (up to 10mg for heavier, well muscled patients) by subcutaneous or intramuscular injection. By slow intravenous injection, one quarter to one half the corresponding intramuscular dose.

Chronic pain, 5-10mg regularly every four hours by subcutaneous or intramuscular injection. The dose may be increased according to individual needs.

Myocardial infarction, 5mg by slow intravenous injection (1mg/minute) followed by a further 2.5mg to 5mg if necessary.

Acute pulmonary oedema, 2.5mg to 5mg by slow intravenous injection (1mg/minute).

Children and Elderly:

As diamorphine has a respiratory depressant effect, care should be taken when giving the drug to the very young and the elderly and a lower starting dose than normal is recommended.

Hepatic impairment:

A reduction in dosage should be considered in hepatic impairment.

Renal impairment:

The dosage should be reduced in moderate to severe renal impairment.

Debilitated patients:

A reduction in dosage should be considered in debilitated patients.

For concomitant illnesses/conditions where dose reduction may be appropriate see 4.4 Special Warnings and Precautions for Use.

4.3 Contraindications

Acute respiratory depression.

Known hypersensitivity to diamorphine or morphine.

Phaeochromocytoma (endogenous release of histamine may stimulate catecholamine release).

Biliary colic (see also biliary tract disorders, 4.4 Special Warnings and Precautions).

Coma. Raised intracranial pressure. Head injuries, as there is an increased risk of respiratory depression that may lead to elevation of CSF pressure. The sedation and pupillary changes produced may interfere with accurate monitoring of the patient

Acute alcoholism.

Diamorphine is also contra-indicated where there is a risk of paralytic ileus, or in acute diarrhoeal conditions associated with antibiotic-induced pseudomembranous colitis or diarrhoea caused by poisoning (until the toxic material has been eliminated).

4.4 Special Warnings And Precautions For Use

Repeated administration of diamorphine may lead to dependence and tolerance developing. Abrupt withdrawal in patients who have developed dependence may precipitate a withdrawal syndrome. Great caution should be exercised in patients with a known tendency or history of drug abuse.

Morphine-like opioids should either be avoided in patients with biliary tract disorders or they should be given with an antispasmodic (use in biliary colic is a contraindication see 4.3 Contraindications).

Diamorphine should be given in reduced doses or with caution to patients with asthma or decreased respiratory reserve (including kyphoscoliosis, emphysema, severe obesity, cor pulmonale). Avoid use during an acute asthma attack (see 4.3 Contraindications).

Use with caution or in reduced doses in patients with toxic psychosis, CNS depression, myxoedema, prostatic hypertrophy or urethral stricture, severe inflammatory or obstructive bowel disorders, hypotension, shock, convulsive disorders, adrenal insufficiency or debilitated patients.

Care should be exercised in treating the elderly, children or debilitated patients and those with hepatic or renal impairment (see 4.2 Posology for dosage recommendations).

Palliative care - in the control of pain in terminal illness, these conditions should not necessarily be a deterrent to use.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Alcohol: Alcohol may enhance the sedative and hypotensive effects of diamorphine.

Anti-arrhythmics: Diamorphine may delay the absorption of mexiletine.

Antidepressants, anxiolytics, hypnotics: Severe CNS excitation or depression (hypertension or hypotension) has been reported with the concomitant use of monoamine oxidase inhibitors (MAOIs) and pethidine. It is therefore possible that a similar interaction may occur with other opioid analgesics - avoid concomitant use and for two weeks after stopping MAOIs.

The depressant effects of diamorphine may be exaggerated and prolonged by tricyclic antidepressants, anxiolytics and hypnotics.

Antivirals: Plasma concentration of opioid analgesics (except methadone) is possibly increased by ritinovir.

Opioids potentiate the effects of CNS depressants including tricyclic antidepressants, anxiolytics and hypnotics.

Antipsychotics: enhanced sedative and hypotensive effect.

Antidiarrhoeal and antiperistaltic agents (such as loperamide and kaolin): concurrent use may increase the risk of severe constipation.

Antimuscarinics: The risk of severe constipation and/or urinary retention is increased by administration of antimuscarinic drugs (e.g. atropine).

Motility stimulants: There may be antagonism of the gastrointestinal effects of domperidone and metoclopramide.

Cimetidine inhibits metabolism of opioid analgesics.

4.6 Pregnancy And Lactation

Safety has not been established in pregnancy.

Administration during labour may cause respiratory depression in the neonate and gastric stasis during labour, increasing the risk of inhalation pneumonia. Babies born to diamorphine-dependant mothers have been reported to suffer withdrawal symptoms.

Diamorphine should not be given to women who are breast-feeding as there is limited information available on diamorphine in breast milk.

4.7 Effects On Ability To Drive And Use Machines

Diamorphine causes drowsiness and mental clouding. If affected patients should not drive or use machines.

4.8 Undesirable Effects

The most serious hazard of therapy is respiratory (see also 4.9 Overdose).

The most common side effects are sedation, nausea and vomiting, constipation and sweating. Tolerance generally develops with long-term use, but not to constipation. Other side effects include the following:

Anaphylaxis: Anaphylactic reactions following intravenous injection have been reported rarely.

Cardiovascular: orthostatic hypotension, facial flushing, palpitations, tachycardia, bradycardia.

Central Nervous System: dizziness, vertigo, mental clouding, confusion (with large doses), hallucinations, headache, mood changes including dysphoria and euphoria.

Gastrointestinal: dry mouth, biliary spasm.

Disorders of the eye: blurred or double vision or other changes in vision, miosis.

Sexual dysfunction: long term use may lead to a reversible decrease in libido or potency.

Skin: rash, pruritus, urticaria.

Urinary: urinary retention, difficulty with micturition, ureteric spasm, antidiuretic effect. Tolerance develops to the effects of opioids on the bladder.

The euphoric activity of diamorphine has led to its abuse and physical and psychological dependence may occur (see also 4.4 Special Warnings and Precautions for use).

4.9 Overdose

a) Symptoms

The triad of respiratory depression, coma and constricted pupils is considered indicative of opioid overdosage with dilatation of the pupils occurring as hypoxia develops.

Pulmonary oedema after overdosage is a common cause of fatalities among diamorphine addicts.

Other opioid overdose symptoms include cold, clammy skin, hypotension, bradycardia, circulatory failure, muscle flaccidity, severe weakness, severe nervousness or restlessness, confusion, severe dizziness, severe drowsiness, hallucinations, convulsions (especially in infants and children), rhabdomyolysis progressing to renal failure.

b) Treatment

Respiration and circulation should be maintained and the specific opioid antagonist, naloxone is indicated if coma or bradypnoea are present, using one of the recommended dosage regimens. Oxygen and assisted ventilation should be administered if necessary.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Diamorphine is a narcotic analgesic which acts primarily on the central nervous system and smooth muscle. It is predominantly a central nervous system depressant but it has stimulant actions resulting in nausea, vomiting and miosis.

5.2 Pharmacokinetic Properties

Diamorphine is a potent opiate analgesic which has a more rapid onset of activity than morphine as the first metabolite, monoacetylmorphine, more readily crosses the blood brain barrier. In man, diamorphine has a half life of two to three minutes. Its first metabolite, monoacetylmorphine, is more slowly hydrolysed in the blood to be concentrated mainly in skeletal muscle, kidney, lung, liver and spleen. Monoacetylmorphine is metabolised to morphine. Morphine forms conjugates with glucuronic acid. The majority of the drug is excreted via the kidney as glucuronides and to a much lesser extent as morphine. About 7-10% is eliminated via the biliary system into the faeces.

Diamorphine does not bind to protein. However, morphine is about 35% bound to human plasma proteins, mainly to albumin. The analgesic effect lasts approximately three to four hours.

5.3 Preclinical Safety Data

There are no additional pre-cliical data of relevance to the prescriber.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Water for Injections (Not detectable in the finished product).

6.2 Incompatibilities

Physical incompatibility has been reported with mineral acids and alkalis and with chlorocresol. Mixtures of diamorphine with cyclizine, haloperidol or dexamethasone may result in precipitation. Mixtures of diamorphine and metoclopramide may become discoloured and should be discarded. Specialised references should be consulted for specific compatibility information.

6.3 Shelf Life

Three years from date of manufacture

6.4 Special Precautions For Storage

Do not store above 25°C.

Keep container in the outer carton.

6.5 Nature And Contents Of Container

5ml Neutral glass ampoules, PhEur. Type 1. Ampoules are packed into cartons of 5, 10 or 50.

6.6 Special Precautions For Disposal And Other Handling

The solution should be used immediately after preparation.

7. Marketing Authorisation Holder

Wockhardt UK Limited

Ash Road North

Wrexham

LL13 9UF

UK

8. Marketing Authorisation Number(S)

PL 29831/0061

9. Date Of First Authorisation/Renewal Of The Authorisation

27/04/2007

10. Date Of Revision Of The Text

27/04/2007

Fertinex

Generic Name: urofollitropin (Intramuscular route, Subcutaneous route, Injection route)

ure-oh-FOL-li-troe-pin

Commonly used brand name(s)

In the U.S.

• Bravelle


• Fertinex

In Canada

• Fertinorm Hp


• Metrodin

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Female Reproductive Agent

Pharmacologic Class: Human Follicle Stimulating Hormone

Uses For Fertinex

Urofollitropin is a fertility drug that is identical to the hormone called follicle-stimulating hormone (FSH) that is produced naturally by the pituitary gland.

FSH is primarily responsible for stimulating growth of the ovarian follicle, which includes the developing egg, the cells surrounding the egg that produce the hormones needed to support a pregnancy, and the fluid around the egg. As the ovarian follicle grows, an increasing amount of the hormone estrogen is produced by the cells in the follicle and released into the bloodstream. Estrogen causes the endometrium (lining of the uterus) to thicken before ovulation occurs. The higher blood levels of estrogen will also provide a cue to the hypothalamus and pituitary gland to slow the production and release of FSH.

Another pituitary hormone, luteinizing hormone (LH), also helps to increase the amount of estrogen produced by the follicle cells. However, the main function of LH is to cause ovulation. The sharp rise in the blood level of LH that triggers ovulation is sometimes called the LH surge. After ovulation, the group of hormone-producing follicle cells become what is called the corpus luteum and will produce estrogen and large amounts of another hormone, progesterone. Progesterone causes the endometrium to mature so that it can support the egg after it is fertilized. If implantation of a fertilized egg does not occur, the levels of estrogen and progesterone decrease, the endometrium sloughs off, and menstruation occurs.

Urofollitropin is usually given in combination with human chorionic gonadotropin (hCG). The actions of hCG are almost identical to those of LH. It is given to simulate the natural LH surge. This results in predictable ovulation.

Urofollitropin is often used in women who have low levels of FSH and too-high levels of LH. Women with polycystic ovary syndrome usually have hormone levels such as this and are treated with urofollitropin to make up for the low amounts of FSH. Many women being treated with urofollitropin have already tried clomiphene (e.g., Serophene) and have not been able to conceive yet. Urofollitropin may also be used to cause the ovary to produce several follicles, which can then be harvested for use in gamete intrafallopian transfer (GIFT) or in vitro fertilization (IVF).

Urofollitropin is to be given only by or under the supervision of your doctor.

Before Using Fertinex

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine 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.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	X	Studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. This drug should not be used in women who are or may become pregnant because the risk clearly outweighs any possible benefit.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

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. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

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.

Other Medical Problems

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

• Cyst on ovary—Urofollitropin can cause further growth of cysts on the ovary

• Unusual vaginal bleeding—Some irregular vaginal bleeding is a sign that the endometrium is growing too rapidly, possibly of endometrial cancer, or some hormone imbalances; the increases in estrogen production caused by urofollitropin can make these problems worse. If a hormonal imbalance is present, it should be treated before beginning menotropins therapy

Proper Use of urofollitropin

This section provides information on the proper use of a number of products that contain urofollitropin. It may not be specific to Fertinex. Please read with care.

Dosing

The dose of this medicine 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 this medicine. 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 injection dosage form:
  
  • For becoming pregnant while having a condition called polycystic ovary syndrome:
    
    • Adults—75 Units injected under the skin or into a muscle once a day for seven or more days. Usually, another medicine called chorionic gonadotropin (hCG) will be given the day after the last dose. If needed, your doctor may then increase your dose of urofollitropin to 150 Units a day for another seven or more days. Higher doses may be prescribed by your doctor.
    
    
  
  
  • For becoming pregnant while using other pregnancy-promoting methods (assisted reproductive technology [ART]):
    
    • Adults—150 Units injected under the skin or into a muscle once a day. Your treatment will probably begin on Day 2 or Day 3 after your menstrual period begins. Usually, another medicine called chorionic gonadotropin (hCG) will be given the day after the last dose.
    
    
  
  

Precautions While Using Fertinex

It is very important that your doctor check your progress at regular visits to make sure that the medicine is working properly and to check for unwanted effects. Your doctor will likely want to monitor the development of the ovarian follicle(s) by measuring the amount of estrogen in your bloodstream and by checking the size of the follicle(s) with ultrasound examinations.

If your doctor has asked you to record your basal body temperature (BBT) daily, make sure that you do this every day. It is important that intercourse take place around the time of ovulation to give you the best chance of becoming pregnant.

Fertinex 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 as soon as possible if any of the following side effects occur:

More common

• Abdominal or pelvic pain


• bloating (mild)


• redness, pain, or swelling at the injection site

Less common or rare

• Abdominal or stomach pain (severe)


• bloating (moderate to severe)


• decreased amount of urine


• feeling of indigestion


• fever and chills


• nausea, vomiting, or diarrhea (continuing or severe)


• pelvic pain (severe)


• shortness of breath


• skin rash or hives


• swelling of lower legs


• weight gain (rapid)

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:

Less common or rare

• Breast tenderness


• diarrhea (mild)


• nausea


• vomiting

After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

• Abdominal or stomach pain (severe)


• bloating (moderate to severe)


• decreased amount of urine


• feeling of indigestion


• nausea, vomiting, or diarrhea (continuing or severe)


• pelvic pain (severe)


• shortness of breath


• swelling of lower legs


• weight gain (rapid)

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.

See also: Fertinex side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

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More Fertinex resources

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

• Fertinex MedFacts Consumer Leaflet (Wolters Kluwer)


• Urofollitropin Professional Patient Advice (Wolters Kluwer)


• Bravelle Prescribing Information (FDA)


• Bravelle Concise Consumer Information (Cerner Multum)


• Bravelle MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Fertinex with other medications

• Female Infertility
• Follicle Stimulation