Salspray may be available in the countries listed below.
Salmeterol xinafoate (a derivative of Salmeterol) is reported as an ingredient of Salspray in the following countries:
International Drug Name Search
Sentinel Spectrum may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Lufenuron is reported as an ingredient of Sentinel Spectrum in the following countries:
Milbemycin Oxime is reported as an ingredient of Sentinel Spectrum in the following countries:
Praziquantel is reported as an ingredient of Sentinel Spectrum in the following countries:
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Sandoz Mirtazapine may be available in the countries listed below.
Mirtazapine is reported as an ingredient of Sandoz Mirtazapine in the following countries:
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Securon IV
Verapamil Hydrochloride BP 2.5 mg/ml
Aqueous solution for intravenous injection.
Securon IV is indicated for the treatment of paroxysmal supraventricular tachycardia and the reduction of ventricular rate in atrial flutter/fibrillation.
For slow intravenous injection.
Adults: 5-10 mg by slow intravenous injection over a period of 2 minutes. The patient should be observed continuously, preferably under ECG and blood pressure control. If necessary, e.g. in paroxysmal tachycardia, a further 5 mg may be given after 5 to 10 minutes.
Children: Securon IV must always be administered under ECG monitoring in young patients.
0-1 year: 0.1-0.2 mg/kg bodyweight (usual single dose range: 0.75-2 mg).
1-15 years: 0.1-0.3 mg/kg bodyweight (usual single dose range: 2-5 mg).
The dose may be repeated after 30 minutes if necessary. Many cases are controlled by doses at the lower end of the range. The injection should be stopped at the onset of the desired effect.
Elderly: The dosage should be administered over 3 minutes to minimise the risk of adverse effects.
Dosage in impaired liver and renal function: Significant hepatic and renal impairment should not increase the effects of a single intravenous dose but may prolong its duration of action.
For use with beta-blocker therapy, see 'Contra-indications' and 'Special Warnings and Precautions for Use'.
Hypersensitivity to the active substance or to any of the excipients.
Cardiogenic shock; acute myocardial infarction complicated by bradycardia, marked hypotension or left ventricular failure; second or third degree AV block (except in patients with a functioning artificial ventricular pacemaker); sino-atrial block; sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker); uncompensated heart failure; bradycardia of less than 50 beats/minute; hypotension of less than 90 mmHg systolic; simultaneous administration of intravenous beta-blockers.
Patients with atrial flutter/fibrillation in the presence of an accessory pathway (e.g. WPW syndrome) may develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated.
Verapamil may affect impulse conduction. For this reason, Securon IV should be used with caution in patients with bradycardia or first degree AV block. Verapamil may affect left ventricular contractility; this effect is small and normally not important but cardiac failure may be precipitated or aggravated. In patients with poor ventricular function, therefore, Securon IV should only be given after cardiac failure has been controlled with appropriate therapy, e.g. digitalis.
Although the pharmacokinetics of verapamil in patients with renal impairment are not affected, caution should be exercised and careful patient monitoring is recommended. Verapamil is not removed during dialysis.
Caution should be exercised in treatment with HMG CoA reductase inhibitors (e.g., simvastatin, atorvastatin or lovastatin) for patients taking verapamil. These patients should be started at the lowest possible dose of verapamil and titrated upwards. If verapamil treatment is to be added to patients already taking an HMG CoA reductase inhibitor (e.g., simvastatin, atorvastatin or lovastatin), refer to advice in the respective statin product information.
Use with caution in the presence of diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy)
In rare instances, including when patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction were given intravenous beta-adrenergic blocking agents or disopyramide concomitantly with intravenous verapamil hydrochloride, serious adverse effects have occurred. Concomitant use of verapamil hydrochloride with agents that decrease adrenergic function may result in an exaggerated hypotensive response.
In vitro metabolic studies indicate that verapamil hydrochloride is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.
The following are potential drug interactions associated with verapamil:
Acetylsalicylic acid
Concomitant use of verapamil with aspirin may increase the risk of bleeding
Alpha blockers
Verapamil may increase the plasma concentrations of prazosin and terazosin which may have an additive hypotensive effect.
Antiarrhythmics
Verapamil may slightly decrease the plasma clearance of flecainide whereas flecainide has no effect on the verapamil plasma clearance.
Verapamil may increase the plasma concentrations of quinidine.
The combination of verapamil and antiarrhythmic agents may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure). Care must be exercised if Securon IV is combined with anti-arrhythmic agents by any route.
Anticonvulsants
Verapamil may increase the plasma concentrations of carbamazepine. This may produce side effects such as diplopia, headache, ataxia or dizziness. Verapamil may also increase the plasma concentrations of phenytoin.
Antidepressants
Verapamil may increase the plasma concentrations of imipramine.
Antidiabetics
Verapamil may increase the plasma concentrations of glibenclamide (glyburide).
Anti-infectives
Rifampicin may reduce the plasma concentrations of verapamil which may produce a reduced blood pressure lowering effect. Erythromycin, clarithromycin and telithromycin may increase the plasma concentrations of verapamil.
Antineoplastics
There is no significant difference between the pharmacokinetic parameters of doxorubicin with intravenous verapamil administration.
Barbiturates
Phenobarbital may reduce the plasma concentrations of verapamil.
Benzodiazepines and other anxiolytics
Verapamil may increase the plasma concentrations of buspirone and midazolam.
Beta blockers
Verapamil may increase the plasma concentrations of metoprolol and propranolol which may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).
Securon IV should not be given in combination with intravenous beta-blocker therapy and care must be exercised if Securon IV is combined with oral beta-blocker therapy.
Cardiac glycosides
Verapamil may increase the plasma concentrations of digitoxin and digoxin. Verapamil has been shown to increase the serum concentration of digoxin and caution should be exercised with regard to digitalis toxicity. The digitalis level should be determined and the glycoside dose reduced, if required.
Colchicine
Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (P-gp). Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine. Combined use is not recommended.
H2 Receptor antagonists
Cimetidine may increase the plasma concentrations of verapamil following intravenous verapamil administration.
HIV antiviral agents
Due to the metabolic inhibitory potential of some of the HIV antiviral agents, such as ritonavir, plasma concentrations of verapamil may increase. Caution should be used or dose of verapamil may be decreased.
Immunosuppressants
Verapamil may increase the plasma concentrations of ciclosporin, everolimus, sirolimus and tacrolimus.
Inhaled anaesthetics
When used concomitantly, inhalation anaesthetics and calcium antagonists, such as verapamil hydrochloride, should each be titrated carefully to avoid additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).
Lipid lowering agents
Verapamil may increase the plasma concentrations atorvastatin, lovastatin and simvastatin.
Treatment with HMG CoA reductase inhibitors (e.g., simvastatin, atorvastatin or lovastatin) in a patient taking verapamil should be started at the lowest possible dose and titrated upwards. If verapamil treatment is to be added to patients already taking an HMG CoA reductase inhibitor (e.g., simvastatin, atorvastatin or lovastatin), consider a reduction in the statin dose and retitrate against serum cholesterol concentrations.
Atorvastatin has been shown to increase verapamil levels. Although there is no direct in vivo clinical evidence, there is strong potential for verapamil to significantly affect atorvastatin pharmacokinetics in a similar manner to simvastatin or lovastatin. Consider using caution when atorvastatin and verapamil are concomitantly administered.
Fluvastatin, pravastatin and rosuvastatin are not metabolized by CYP3A4 and are less likely to interact with verapamil.
Lithium
Serum levels of lithium may be reduced. However there may be increased sensitivity to lithium causing enhanced neurotoxicity.
Neuromuscular blocking agents employed in anaesthesia
The effects may be potentiated.
Protein-bound drugs
As verapamil hydrochloride is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly protein-bound drugs.
Serotonin receptor agonists
Verapamil may increase the plasma concentrations of almotriptan.
Theophylline
Verapamil may increase the plasma concentrations of theophylline.
Uricosurics
Sulfinpyrazone may reduce the plasma concentrations of verapamil which may produce a reduced blood pressure lowering effect.
Other
St. John's Wort may reduce the plasma concentrations of verapamil, whereas grapefruit juice may increase the plasma concentrations of verapamil.
Although animal studies have not shown any teratogenic effects, verapamil should not be given during the first trimester of pregnancy unless, in the clinician's judgement, it is essential for the welfare of the patient. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Also, verapamil is excreted in human breast milk. Limited human data from oral administration has shown that the infant relative dose of verapamil is low (0.1-1% of the mother's oral dose) and that verapamil use may be compatible with breastfeeding. However, there are currently no reports of verapamil injection or infusion use during breastfeeding. Due to the potential for serious adverse reactions in nursing infants, verapamil should only be used during lactation if it is essential for the welfare of the mother.
None stated.
Adverse events observed in clinical trials are depicted in the following table. Within each system organ class, the adverse drug reactions are ranked under headings of frequency, using the following convention: common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports.
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Cases of seizures during verapamil hydrochloride injection have been reported.
In rare cases of hypersensitivity, bronchospasm accompanied by pruritis and urticaria has been reported.
Other Reactions from Postmarketing Surveillance or Phase IV Clinical Trials
Other adverse events reported with verapamil are listed below by system organ class:
Psychiatric disorders: on rare occasions, nervousness has been reported.
Nervous system disorders: somnolence and extrapyramidal syndrome.
Ear and labyrinth disorders: vertigo.
Cardiac disorders/vascular disorders: decreased myocardial contractility has been reported. On rare occasions, 2nd and 3rd block may occur and in extreme cases, this may lead to asystole. The asystole is usually of short duration and cardiac action returns spontaneously after a few seconds, usually in the form of sinus rhythm. If necessary, the procedures for the treatment of overdosage should be followed as described below. On rare occasions, flushing has been reported.
Gastrointestinal disorders: gingival hyperplasia may occur very rarely when the drug is administered over prolonged periods, and is fully reversible when the drug is discontinued. On rare occasions, vomiting has also been reported.
Skin and subcutaneous tissue disorders: Steven-Johnson syndrome, erythema and hyperhidrosis.
Reproductive system and breast disorders: On very rare occasions, gynaecomastia has been observed in elderly male patients under long-term verapamil treatment; this was fully reversible in all cases when the drug was discontinued.
Investigations: A reversible impairment of liver function characterized by an increase of transaminase and/or alkaline phosphatase may occur on very rare occasions during verapamil treatment and is most probably a hypersensitivity reaction.
The symptoms of overdosage include hypotension, shock, loss of consciousness, first and second degree AV block (frequently as Wenckebach's phenomenon with or without escape rhythms), total AV block with total AV dissociation, escape rhythm, asystole, bradycardia up to high degree AV block and, sinus arrest, hyperglycaemia, stupor and metabolic acidosis. Fatalities have occurred as a result of overdose.
Treatment of overdosage depends on the type and severity of symptoms. The specific antidote is calcium, e.g. 10-20 ml of 10% calcium gluconate solution i.v. (2.25-4.5 mmol) if necessary by repeated injection or continuous infusion (e.g. 5 mmol/hour). The usual emergency measures for acute cardiovascular collapse should be applied and followed by intensive care. Verapamil hydrochloride cannot be removed by haemodialysis. Similarly, in the case of second or third degree AV block, atropine, orciprenaline, isoprenaline and if required, pacemaker therapy should be considered. If there are signs of myocardial insufficiency, dopamine, dobutamine, cardiac glycosides or calcium gluconate (10-20 ml of a 10% solution) can be administered.
In the case of hypotension, after appropriately positioning the patient, dopamine, dobutamine or noradrenaline may be given.
Verapamil is a calcium antagonist which blocks the inward movement of calcium ions in cardiac muscle cells, in smooth muscle cells of the coronary and systemic arteries and in cells of the intracardiac conduction system. Because of its effect on the movement of calcium in the intracardiac conduction system, verapamil reduces automaticity, decreases conduction velocity and increases the refractory period.
Following intravenous infusion in man, verapamil is eliminated bi-exponentially with a rapid distribution phase (half-life about 4 minutes) and a slower terminal elimination phase (half-life 2-5 hours). Plasma protein binding of verapamil is about 90%. Renal insufficiency does not affect the kinetics of verapamil. In patients with liver cirrhosis, elimination half
Not applicable.
Water for injections, sodium chloride (8.5 mg/ml), hydrochloric acid as pH adjuster.
Securon IV is incompatible with alkaline solutions.
Ampoule: 60 months.
Syringe: 36 months.
Store at room temperature. Protect from light.
2 ml glass ampoule (hydrolytic type 1) containing 5 mg verapamil. Pack size: 5 × 2 ml ampoules.
2 ml pre-filled glass syringe (borosilicate type 1) with tip cap and butyl rubber stopper and polystyrene plunger. Pack size: 5 × 2 ml syringes.
None.
Abbott Laboratories Ltd
Abbott House,
Vanwall Business Park,
Vanwall Road,
Maidenhead,
Berkshire,
SL6 4XE ,
United Kingdom.
PL 00037/0367
17 June 2003
02nd August 2010
Generic Name: norfloxacin ophthalmic (nor FLOX a sin off THAL mik)
Brand Names: Chibroxin
Norfloxacin ophthalmic is an antibiotic.
Norfloxacin ophthalmic is used to treat bacterial infections of the eyes.
Norfloxacin ophthalmic may also be used for purposes other than those listed in this medication guide.
Apply light pressure to the inside corner of your eye (near your nose) after each drop to prevent the fluid from draining down your tear ducts.
If you wear contact lenses, ask your doctor if you should wear them during treatment. Norfloxacin ophthalmic can cause the development of crystals on contact lenses. After applying this medication, wait at least 15 minutes before inserting contact lenses, unless otherwise directed by your doctor.
Use norfloxacin ophthalmic eye drops exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.
Wash your hands before using the eye drops.
To apply the eye drops:
Shake the drops gently to be sure the medicine is well mixed. Tilt your head back slightly and pull down on your lower eyelid. Position the dropper above your eye. Look up and away from the dropper. Squeeze out a drop and close your eye. Apply gentle pressure to the inside corner of your eye (near your nose) for about 1 minute to prevent the liquid from draining down your tear duct. If you are using more than one drop in the same eye or drops in both eyes, repeat the process with about 5 minutes between drops.
If you are using norfloxacin ophthalmic to treat a corneal ulcer, you may notice a whitish buildup on the ulcer. This means that the medication is working; it is not a harmful development.
Apply the missed dose as soon as you remember. However, if it is almost time for your next regularly scheduled dose, skip the missed dose and apply the next one as directed. Do not use a double dose of this medication.
An overdose of this medication is unlikely to occur. If you do suspect an overdose, wash the eye with water and call an emergency room or poison control center near you. If the drops have been ingested, drink plenty of fluid and call an emergency center for advice.
If you wear contact lenses, ask your doctor if you should wear them during treatment. Norfloxacin ophthalmic can cause the development of crystals on contact lenses. After applying this medication, wait at least 15 minutes before inserting contact lenses, unless otherwise directed by your doctor.
Serious side effects are not expected with this medication.
If you are using norfloxacin ophthalmic to treat a corneal ulcer, you may notice a whitish buildup on the ulcer. This means that the medication is working; it is not a harmful development.
Commonly, some eye burning, stinging, irritation, itching, redness, blurred vision, eyelid itching, eyelid swelling or crusting, a bad taste in your mouth, tearing, or sensitivity to light may occur.
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.
Usual Adult Dose for Conjunctivitis:
Instill 1 or 2 drops to the affected eye(s) 4 times daily for up to 7 days. For severe infections, instill 1 or 2 drops to the affected eye(s) every 2 hours while awake on the first day.
Usual Pediatric Dose for Conjunctivitis:
1 year to 18 years: Instill 1 or 2 drops to the affected eye(s) 4 times daily for up to 7 days. For severe infections, instill 1 or 2 drops to the affected eye(s) every 2 hours while awake on the first day.
Drugs other than those listed here may also interact with norfloxacin ophthalmic. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.
Servitrocin may be available in the countries listed below.
Erythromycin is reported as an ingredient of Servitrocin in the following countries:
Erythromycin ethylsuccinate (a derivative of Erythromycin) is reported as an ingredient of Servitrocin in the following countries:
Erythromycin stearate (a derivative of Erythromycin) is reported as an ingredient of Servitrocin in the following countries:
International Drug Name Search
Hippurin may be available in the countries listed below.
Methenamine hippurate (a derivative of Methenamine) is reported as an ingredient of Hippurin in the following countries:
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Bupiforan may be available in the countries listed below.
Bupivacaine hydrochloride (a derivative of Bupivacaine) is reported as an ingredient of Bupiforan in the following countries:
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Sandoz Metoprolol may be available in the countries listed below.
Metoprolol tartrate (a derivative of Metoprolol) is reported as an ingredient of Sandoz Metoprolol in the following countries:
International Drug Name Search
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. Theolair Tablets contain 125 mg or 250 mg of theophylline anhydrous intended for oral administration. Theolair Tablets also contain: colloidal silicon dioxide, lactose, magnesium stearate, and pregelatinized starch.
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.
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.
Overview Theophylline is rapidly and completely absorbed after oral administration in 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-hr 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).
| 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 † |
| 6 - 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 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 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 sub-therapeutic 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.
(see Table I for mean clearance and half-life values)
Geriatric The 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 39°C (102°F) 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.
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 beta2 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.
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.
Theolair Tablets are contraindicated in patients with a history of hypersensitivity to theophylline or any other components in these products.
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:
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 monitoring of serum theophylline concentrations in patients with the following risk factors:
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.)
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).
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).
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).
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:
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 has 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.
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 μεq/L to 800 μεq/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.
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.
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 Tables II and III are current as of June, 1996. 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.
| 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 P-450 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 P-450 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 unkown. | 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 | Decreases theophylline clearance. (MTX) higher dose MTX may have a greater effect. | 20% increase after low dose MTX, |
| 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; due to phosphodiesterase inhibition. | Larger dose of pancuronium possibly 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. | Serum theophylline and phenytoin concentrations decrease about Theophylline decreases phenytoin 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta2 blocking effect may decre |
Minocycline Actavis may be available in the countries listed below.
Minocycline hydrochloride (a derivative of Minocycline) is reported as an ingredient of Minocycline Actavis in the following countries:
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Preventing infection caused by Haemophilus influenza type b bacteria and/or diphtheria, tetanus, and pertussis.
ActHIB is a vaccine. It works by stimulating the body to produce antibodies against the organism that causes H. influenza infection.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with ActHIB. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with ActHIB. However, no specific interactions with ActHIB are known at this time.
This may not be a complete list of all interactions that may occur. Ask your health care provider if ActHIB may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use ActHIB as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use ActHIB.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Fever; irritability; redness, tenderness, pain, swelling, or a lump at the injection site; sleepiness.
Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); seizures.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
See also: ActHIB side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.
ActHIB is usually handled and stored by a health care provider. If you are using ActHIB at home, store ActHIB as directed by your pharmacist or health care provider. Keep ActHIB out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about ActHIB. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
Mucosol may be available in the countries listed below.
Ambroxol is reported as an ingredient of Mucosol in the following countries:
Carbocisteine is reported as an ingredient of Mucosol in the following countries:
International Drug Name Search
Moxonidine Mylan may be available in the countries listed below.
Moxonidine is reported as an ingredient of Moxonidine Mylan in the following countries:
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