Zamadol Melt 50 mg Tablets

1. Name Of The Medicinal Product

Zamadol Melt 50 mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 50 mg of tramadol hydrochloride.

For excipients, see 6.1

3. Pharmaceutical Form

Orodispersible tablets and dispersible tablets.

Round, white, biconcave tablet, engraved 'T' on one side and '50' on the other side, with a characteristic mint flavour.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of moderate to severe pain.

4.2 Posology And Method Of Administration

As with all analgesic drugs, the dose of Zamadol Melt 50 mg Tablets should be adjusted according to the severity of the pain and the clinical response of the individual patient.

Adults and adolescents aged 12 years and over

For oral use:

Acute pain :

An initial dose is 50-100 mg depending on the intensity of pain. This can be followed by doses of 50 or 100 mg not more frequently than 4 hourly, and duration of therapy should be matched to clinical need. A total daily dose of 400 mg should not be exceeded except in special clinical circumstances.

Pain associated with chronic conditions :

Use an initial dose of 50 mg and then titrate dose according to pain severity. The initial dose may be followed if necessary by 50-100 mg every 4 to 6 hours. The recommended doses are intended as a guideline. Patients should always receive the lowest dose that provides effective pain control. A total daily dose of 400 mg should not be exceeded except in special clinical circumstances. The need for continued treatment should be assessed at regular intervals as withdrawal symptoms and dependence have been reported (see section 4.4 Special warnings and special precautions for use).

Elderly :

The usual dosage may be used although it should be noted that in volunteers aged over 75 years the elimination half-life of tramadol was increased following oral administration. An adjustment of the dosage or increasing the dose interval should be considered.

Renal impairment/renal dialysis :

The elimination of tramadol may be prolonged. The usual initial dosage should be used. For patients with creatinine clearance < 30 ml/min, the dosage interval should be increased to 12 hours. Tramadol is not recommended for patients with severe renal impairment (creatinine clearance < 10 ml/min).

As tramadol is only removed very slowly by haemodialysis or haemofiltration, post-dialysis administration to maintain analgesia is not usually necessary.

Hepatic impairment :

The elimination of tramadol may be prolonged. The usual initial dosage should be used but in hepatic impairment the dosage interval should be increased to 12 hours and the dose reduced if necessary. Tramadol is not recommended for patients with severe hepatic impairment.

Children under 12 years :

Not recommended.

The tablet disperses rapidly in the mouth and is then swallowed. Alternatively, the tablet can be dispersed in half a glass of water, stirred and drunk immediately independently of meals.

4.3 Contraindications

Zamadol Melt 50 mg Tablets must not be administered to patients who have previously demonstrated hypersensitivity to the active substance or any of the excipients.

The product must not be administered to patients suffering from acute intoxication or overdose with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs.

In common with other opioid analgesics it must not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal. It must not be administered concomitantly with nalbuphine, buprenorphine or pentazocine (see 4.5, interactions with other medicinal products and other forms of interaction).

Contraindicated in patients suffering from uncontrolled epilepsy.

Tramadol must not be administered during breast-feeding if long term treatment is necessary.

Zamadol Melt 50 mg Tablets is not suitable for children under 12 years of age.

4.4 Special Warnings And Precautions For Use

Warnings :

At therapeutic doses, Zamadol Melt 50 mg Tablets has the potential to cause withdrawal symptoms. Rarely cases of dependence and abuse have been reported. However, Zamadol Melt should only be used for short periods and under strict medical supervision in patients with a tendency of drug abuse or dependence.

At therapeutic doses withdrawal symptoms have been reported at a reporting frequency of 1 in 8,000. Reports of dependence and abuse have been less frequent. Because of this potential the clinical need for continued analgesic treatment should be reviewed regularly. In patients with a tendency to drug abuse or dependence, treatment should be for short periods and under strict medical supervision.

Zamadol Melt is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, it cannot suppress morphine withdrawal symptoms.

Alcohol intake and concomitant use of carbamazepine are not recommended during treatment.

Precautions :

Zamadol Melt should be used with caution in patients with head injury, increased intracranial pressure, impairment of hepatic and renal function, decreased level of consciousness and in patients prone to convulsive disorders or in shock.

Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit. Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons. The risk of convulsions may increase in patients taking tramadol and concomitant medication that can lower the seizure threshold (see section 4.5 Interaction with other medicinal products and other forms of interaction).

At the recommended doses Zamadol Melt is unlikely to produce clinically relevant respiratory depression. However, care should be taken when treating patients with existing respiratory depression, or excessive bronchial secretion and in those patients taking concomitant CNS depressant drugs.

The ingredient aspartame contains a source of phenylalanine which may be harmful to people with phenylketonuria.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of the following is contraindicated:

Patients treated with monoamine oxidase inhibitors within 14 days prior to the administration of the opioid pethidine have experienced life-threatening interactions affecting the central nervous system as well as the respiratory and circulatory centres (risk of serotonergic syndrome – see below). The possibility of similar interactions occurring between monoamine oxidase inhibitors (including the selective MAO A and B inhibitors and linezolid) and tramadol cannot be ruled out.

The combination of mixed agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not recommended because it is theoretically possible that the analgesic effect of a pure agonist is attenuated under these circumstances and that a withdrawal syndrome may occur.

Concomitant use of the following needs to be taken into consideration:

Isolated cases of serotonergic syndrome have been reported with the therapeutic use of tramadol in combination with other serotonergic agents such as selective serotonin re-uptake inhibitors (SSRIs). Signs of serotonergic syndrome may include: confusion, restlessness, agitation, fever, sweat, tachycardia, tremor, ataxia, hyper-reflexia, myoclonus, diarrhoea and possibly coma. Withdrawal of the serotonergic agent produces a rapid improvement.

Concomitant administration of Zamadol Melt with other centrally acting drugs (including other opioid derivatives, benzodiazepines, barbiturates, other anxiolytics, hypnotics, sedative anti-depressants, sedative anti-histamines, neuroleptics, centrally acting anti-hypotensive drugs, baclofen and alcohol) may potentiate CNS depressant effects including respiratory depression.

Simultaneous administration of carbamazepine markedly decreases serum concentrations of tramadol to an extent that a decrease in analgesic effectiveness and a shorter duration of action may occur.

Tramadol may increase the potential for selective serotonin reuptake inhibitors (SSRIs) , tricyclic antidepressants (TCAs), anti-psychotics and other seizure threshold lowering drugs (e.g. bupropion and mefloquine) to cause convulsions (see sections 4.4 Special warnings and special precautions for use and 5.2 Pharmacokinetic properties).

There have been isolated reports of interaction with coumarin anticoagulants resulting in an increased international normalised ratio (INR) and so care should be taken when commencing treatment with tramadol in patients on anticoagulants.

4.6 Pregnancy And Lactation

Pregnancy :

In humans, there are no sufficient data to assess malformative effect of tramadol when given during the first trimester of pregnancy. Animal studies have not shown any teratogenic effects, but at high doses, foetotoxicity due to maternotoxicity appeared (See 5.3 Preclinical data).

Tramadol crosses the placenta, therefore as with other opioid analgesics, chronic use of tramadol during the third trimester may induce a withdrawal syndrome in new-born. At the end of pregnancy, high dosages, even for short term treatment, may induce respiratory depression in new-born. There is inadequate evidence available on the safety of tramadol in human pregnancy, therefore Zamadol Melt should not be used in pregnant woman.

Lactation :

Tramadol and its metabolites are found in small amounts in human breast milk. An infant could ingest 0.1 % of the dose given to the mother. Zamadol Melt should not be administered during breast feeding.

4.7 Effects On Ability To Drive And Use Machines

Zamadol Melt may cause drowsiness and this effect may be potentiated by alcohol and other CNS depressants. Ambulant patients should be warned not to drive or operate machinery if affected.

4.8 Undesirable Effects

The table below presents possible adverse drug reactions in system organ class order and sorted by frequency.

Organ System	Frequency	Adverse drug reaction
Immune system disorders	Rare (>1/10.000, <1/1.000)	- allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.
Metabolism and Nutritional disorders	Rare (>1/10.000, <1/1.000)	- changes in appetite.
Psychiatric disorders	Rare (>1/10.000, <1/1.000)	The following may vary in nature and intensity depending on the individual (see below): - changes in mood (e.g. elation, dysphoria) - changes in activity (e.g. suppression, increase) - change in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders) - hallucinations - confusion - sleep disturbances - nightmares   - dependency (see below)
Nervous system disorders	Very Common (>1/10)	- dizziness
Common (>1/100, <1/10)	- headache - drowsiness
Rare (>1/10.000, <1/1.000)	- epileptiform convulsions (see below) - paraesthesia - tremor.
Very rare (including isolated cases) (<1/10.000)	- vertigo
Eye disorders	Rare (>1/10.000, <1/1.000	- blurred vision
Cardiac disorders	Uncommon (>1/1000, <1/100)	- cardiovascular regulation (e.g. palpitation, tachycardia, postural hypotension, cardiovascular collapse). These effects may occur especially on intravenous administration and in patients who are physically stressed.
Rare (>1/10.000, <1/1.000)	- bradycardia, increase in blood pressure
Vascular disorders	Very rare (including isolated cases) (<1/10.000)	- flushing
Respiratory, thoracic and mediastinal disorders	Very rare (including isolated cases) (<1/10.000)	- worsening of asthma, respiratory depression (see below)
Gastrointestinal disorders	Very Common (>1/10)	- vomiting, nausea
Common (>1/100, <1/10)	- constipation, dry mouth
Uncommon (>1/1000, <1/100)	- retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating)
Hepato-biliary disorders	Very rare (including isolated cases) (<1/10.000)	- increase in liver enzyme values (a few isolated cases have been reported)
Skin and subcutaneous tissue disorders	Common (>1/100 <1/10)	- sweating
Uncommon (>1/1000, <1/100)	- dermal reactions (e.g. pruritus, rash, urticaria)
Musculoskeletal, connective tissue and bone disorders	Rare (>1/10.000, <1/1.000)	- motorial weakness
Renal and urinary system disorders	Rare (>1/10.000, <1/1.000)	- micturition disorders (difficulty in passing urine and urinary retention)
General disorders	Common (>1/100, <1/10)	- fatigue

Psychic side-effects may occur following administration of tramadol which vary individually in intensity and nature (depending on personality and duration of medication). These include changes in mood (usually elation, occasionally dysphoria), changes in activity (usually suppression, occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders), hallucinations, confusion, sleep disturbances and nightmares.

Prolonged administration of Zamadol Melt may lead to dependence (see section 4.4). Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms.

Epileptiform convulsions are rare and occur mainly after administration of high doses of tramadol or after concomitant treatment with drugs which can lower the seizure threshold or themselves induce cerebral convulsions (e.g. antidepressants or anti-psychotics, see section 4.5 "Interaction with other medicinal products and other forms of interaction".

Worsening of asthma has also been reported, though a causal relationship has not been established. Respiratory depression has been reported. If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (see section 4.5 "Interaction with other medicinal products and other forms of interaction") respiratory depression may occur.

4.9 Overdose

Symptoms of overdose are typical of other opioid analgesics, and include miosis, vomiting, hypotension, cardiovascular collapse, sedation and coma, epileptic seizures and respiratory depression. Respiratory failure may also occur.

Supportive measures such as maintaining the patency of the airway and maintaining cardiovascular function should be instituted; naloxone should be used to reverse respiratory depression; fits can be controlled with diazepam. Naloxone administration may increase the risk of seizures. The use of benzodiazepines (intravenously) should be considered for patients with seizures.

Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with Zamadol Melt with haemodialysis or haemofiltration alone is not suitable for detoxification.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Analgesic, Other opioids, ATC code: N02AX02

Tramadol is a centrally acting analgesic. It is a non selective pure agonist at mu, delta and kappa opioid receptors with a higher affinity for the mu receptor. Other mechanisms which may contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release.

Tramadol has antitussive properties. Unlike morphine, tramadol does not depress breathing over a wide range of analgesic doses. The effects of tramadol on the cardiovascular system are comparatively small. The potency of tramadol is 1/10 to 1/6 that of morphine.

5.2 Pharmacokinetic Properties

Absorption

After oral administration, tramadol is almost completely absorbed. Mean absolute bioavailability is approximately 70% following a single dose and increases to approximately 90% at steady state.

Following a single oral dose administration of tramadol 100 mg to young healthy volunteers, plasma concentrations were detectable within approximately 15-45 minutes with a mean Cmax of 280 to 308 ng/ml and Tmax of 1.6 to 2 hours.

In a specific study of comparing the Orodispersible tablets with Immediate Release capsules, the administration of a single dose of 50 mg Zamadol Melt in healthy volunteers produced a mean AUC 1102 + 357 ng.h/ml, a mean Cmax 141 + 39 ng/ml; and a mean Tmax 1.5 hours. This demonstrated bioequivalence to 50 mg immediate release capsules (AUC 1008 + 285 ng.h/ml; Cmax 139 + 37 ng/ml; Tmax 1.5 hours).

Distribution

Plasma protein binding of tramadol is approximately 20%. It is independent of the plasma concentration of the drug within the therapeutic range.

Tramadol crosses the blood-brain barrier and the placental barrier. Tramadol and its metabolite O-desmethyltramadol are detectable in breast milk in very small amounts (0.1% and 0.02% of the administered doses, respectively).

Tramadol has a high tissue affinity, with an apparent volume of distribution of 3 to 4 l/kg.

Metabolism

Tramadol is metabolised by cytochrome P450 isoenzyme CYP2D6. It undergoes biotransformation to a number of metabolites mainly by means of N- and O-demethylation. O-desmethyl tramadol appears to be the most pharmacologically active metabolite, showing analgesic activity in rodents. It is 2 to 4 times more active than tramadol.

As humans excrete a higher percentage of unchanged tramadol than animals it is believed that the contribution made by this metabolite to analgesic activity is likely to be less in humans than animals. In humans the plasma concentration of this metabolite is about 25% that of unchanged tramadol.

The inhibition of one or both cytochrome P450 isoenzymes, CYP3A4 and CYP2D6 involved in the metabolism of tramadol, may affect the plasma concentration of tramadol or its active metabolite. The clinical consequences of any such interactions are not known.

Elimination

For tramadol, the terminal elimination half-life (t½β) was 6.0 ± 1.5 hours in young volunteers. For O-desmethyltramadol, t½β (6 healthy volunteers) was 7.9 hours (range 5.4 – 9.6 hours).

When C14 labelled tramadol was administered to humans, approximately 90% was excreted via the kidneys with the remaining 10% appearing in the faeces.

Tramadol pharmacokinetics show little age dependence in volunteers up to the age of 75 years. In volunteers aged over 75 years, t½β was 7.0 ± 1.6 hours on oral administration.

Since tramadol is eliminated both metabolically and renally, the terminal half-life t½β may be prolonged in impaired hepatic or renal function. However, the increase in the t½β values is relatively low if at least one of these organs is functioning normally. In patients with liver cirrhosis t½β tramadol was a mean of 13.3 ± 4.9 hours ; in patients with renal insufficiency (creatinine clearance

PK/PD

Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.

The PK/PD relation is dose-dependent, but varies within a wide range. Generally, a serum concentration between 100 and 300 ng/ml is effective.

5.3 Preclinical Safety Data

In single and repeat-dose toxicity studies (rodents and dogs) exposure to tramadol 10 times that expected in man is required before toxicity (hepatotoxicity) is observed. Symptoms of toxicity are typical of opioids and include restlessness, ataxia, vomiting, tremor, dyspnoea and convulsions.

Exposure to tramadol (>that expected in man), in lifetime toxicity studies in rodents did not reveal any evidence of carcinogenic hazard, and a battery of in-vitro and in-vivo mutagenicity tests were negative.

No teratogenic effects have been observed in animal tests (rat and rabbit: the dosage of Tramadol given has been up to seven times higher than the dosage given to humans). Minimal embryo toxic effects (delayed ossification) were observed in the tests. No effect was observed on the fertility or the development of the offspring in the tests.

6. Pharmaceutical Particulars

6.1 List Of Excipients

ethylcellulose,

copovidone,

silicon dioxide,

mannitol (E421),

crospovidone,

aspartame (E951),

mint rootbeer flavouring,

magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage precautions

6.5 Nature And Contents Of Container

Tablets in blisters composed of two sheets:

- a complex of polyamide/ aluminium/poly(vinyl chloride)

- a sheet of aluminium.

Pack sizes: 10, 20, 28, 30, 40, 50, 56, 60 and 100 tablets.

'Not all pack sizes may be marketed.'

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Meda Pharmaceuticals Ltd

249 West George Street

Glasgow

G2 4RB

Trading as:

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

UK

8. Marketing Authorisation Number(S)

PL 15142/0128

9. Date Of First Authorisation/Renewal Of The Authorisation

1st November 2009

10. Date Of Revision Of The Text

1^st November 2009

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Ipratropium and Albuterol

Dosage Form: inhalation solution
IPRATROPIUM BROMIDE and ALBUTEROL SULFATE INHALATION SOLUTION

Rx only

Ipratropium and Albuterol Description

The active components in ipratropium bromide and albuterol sulfate inhalation solution are albuterol sulfate and iprotrium bromide.

Albuterol sulfate, is a salt of racemic albuterol and a relatively selective β2-adrenergic bronchodilator chemically described as α1-[(tert-butylamino)methyl]-4-hydroxy-m-xylene-α,α'-diol sulfate (2:1) (salt). It is a white crystalline powder, soluble in water and slightly soluble in ethanol. The World Health Organization recommended name for albuterol base is salbutamol. It has the following structural formula:

(C13H21NO3)2•H2SO4                                                        M.W. 576.7

Ipratropium bromide is an anticholinergic bronchodilator chemically described as 8-azoniabicyclo [3.2.1]-octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8methyl-8-(1-methylethyl)-, bromide, monohydrate (endo, syn)-, (±)-; a synthetic quaternary ammonium compound, chemically related to atropine. It is a white crystalline substance, freely soluble in water and lower alcohols, and insoluble in lipophilic solvents such as ether, chloroform, and fluorocarbons. It has the following structural formula:

C20H30BrNO3•H2O                                                                     M.W. 430.4

Each 3 mL vial of ipratropium bromide and albuterol sulfate inhalation solution contains 3 mg (0.1%) of albuterol sulfate (equivalent to 2.5 mg (0.083%) of albuterol base) and 0.5 mg (0.017%) of ipratropium bromide in an isotonic, sterile, aqueous solution containing disodium edetate dihydrate, hydrochloric acid, sodium chloride, and water for injection.

Ipratropium bromide and albuterol sulfate inhalation solution is a clear, colorless solution. It does not require dilution prior to administration by nebulization. For ipratropium bromide and albuterol sulfate inhalation solution, like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the jet nebulizer utilized, and compressor performance. Using the nebulizer (with face mask or mouth piece) connected to a compressor system, under in vitro conditions, the mean delivered dose from the mouthpiece (% nominal dose) was approximately 46% of albuterol and 42% of ipratropium bromide at a mean flow rate of 3.6 L/min. The mean nebulization time was 15 minutes or less. Ipratropium bromide and albuterol sulfate inhalation solution should be administered from jet nebulizers at adequate flow rates, via face masks or mouthpieces (see DOSAGE AND ADMINISTRATION).

Ipratropium and Albuterol - Clinical Pharmacology

Ipratropium bromide and albuterol sulfate inhalation solution is a combination of the β2-adrenergic bronchodilator, albuterol sulfate, and the anticholinergic bronchodilator, ipratropium bromide.

Albuterol Sulfate

Mechanism of Action

The prime action of β-adrenergic drugs is to stimulate adenyl cyclase, the enzyme that catalyzes the formation of cyclic-3',5'-adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). The cAMP thus formed mediates the cellular responses. In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on β2-adrenergic receptors compared with isoproterenol. While it is recognized that β2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, recent data indicated that 10% to 50% of the β-receptors in the human heart may be β2-receptors. The precise function of these receptors, however, is not yet established. Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other β-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients.

Pharmacokinetics

Albuterol sulfate is longer acting than isoproterenol in most patients by any route of administration, because it is not a substrate for the cellular uptake processes for catecholamine nor for the metabolism of catechol-O-methyl transferase. Instead the drug is conjugatively metabolized to albuterol 4'-O-sulfate.

Animal Pharmacology/Toxicology

Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5% of plasma concentrations. In structures outside of the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those found in whole brain.

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrythmias and sudden death (with histological evidence of myocardial necrosis) when beta-agonists and methyl-xanthines are administered concurrently. The clinical significance of these findings is unknown.

Ipratropium Bromide

Mechanism of Action

Ipratropium bromide is an anticholinergic (parasympatholytic) agent, which blocks the muscarinic receptors of acetylcholine, and, based on animal studies, appears to inhibit vagally mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increases in intracellular concentration of cyclic guanosine monophosphate (cGMP), resulting from the interaction of acetylcholine with the muscarinic receptors of bronchial smooth muscle.

Pharmacokinetics

The bronchodilation following inhalation of ipratropium is primarily a local, site-specific effect, not a systemic one. Much of an inhaled dose is swallowed as shown by fecal excretion studies. Following nebulization of a 1-mg dose to healthy volunteers, a mean of 4% of the dose was excreted unchanged in the urine.

Ipratropium bromide is minimally (0% to 9% in vitro) bound to plasma albumin and α1-acid glycoproteins. It is partially metabolized to inactive ester hydrolysis products. Following intravenous administration, approximately one-half is excreted unchanged in the urine. The half-life of elimination is about 1.6 hours after intravenous administration. Ipratropium bromide that reaches the systemic circulation is reportedly removed by the kidneys rapidly at a rate that exceeds the glomerular filtration rate. The pharmacokinetics of ipratropium bromide and albuterol sulfate inhalation solution or ipratropium bromide have not been studied in the elderly and in patients with hepatic or renal insufficiency (see PRECAUTIONS).

Animal Pharmacology/Toxicology

Autoradiographic studies in rats have shown that ipratropium does not penetrate the blood-brain barrier.

Ipratropium Bromide and Albuterol Sulfate Inhalation Solution

Mechanism of Action

Ipratropium bromide and albuterol sulfate inhalation solution is expected to maximize the response to treatment in patients with chronic obstructive pulmonary disease (COPD) by reducing bronchospasm through two distinctly different mechanisms: sympathomimetic (albuterol sulfate) and anticholinergic/parasympatholytic (ipratropium bromide). Simultaneous administration of both an anticholinergic and a β2-sympathomimetic is designed to produce greater bronchodilation effects than when either drug is utilized alone at its recommended dosage.

Animal Pharmacology/Toxicology

In 30-day studies in Sprague-Dawley rats and Beagle dogs, subcutaneous doses of up to 205.5 mcg/kg of ipratropium administered with up to 1000 mcg/kg albuterol in rats and 3.16 mcg/kg ipratropium and 15 mcg/kg albuterol in dogs (less than the maximum recommended daily inhalation dose for adults on a mg/m2 basis) did not cause death or potentiation of the cardiotoxicity induced by albuterol administered alone.

Pharmacokinetics

In a double blind, double period, crossover study, 15 male and female subjects were administered single doses of ipratropium bromide and albuterol sulfate inhalation solution or albuterol sulfate inhalation solution at two times the recommended single doses as two inhalations separated by 15 minutes. The total nebulized dose of albuterol sulfate from both treatments was 6 mg and the total dose of ipratropium bromide from ipratropium bromide and albuterol sulfate inhalation solution was 1 mg. Peak albuterol plasma concentrations occurred at 0.8 hours after dosing for both treatments. The mean peak albuterol concentration following administration of albuterol sulfate alone was 4.86 (± 2.65) mg/mL and it was 4.65 (± 2.92) mg/mL for ipratropium bromide and albuterol sulfate inhalation solution. Mean AUC values for the two treatments were 26.6 (± 15.2) ng•hr/mL (albuterol sulfate alone) versus 24.2 (± 14.5) ng•hr/mL (ipratropium bromide and albuterol sulfate inhalation solution). The mean t1/2 values were 7.2 (± 1.3) hours (albuterol sulfate alone) and 6.7 (± 1.7) hours (ipratropium bromide and albuterol sulfate inhalation solution). A mean of 8.4 (± 8.9)% of the albuterol dose was excreted unchanged in urine following administration of two vials of ipratropium bromide and albuterol sulfate inhalation solution which is similar to 8.8 (± 7.3)% that was obtained from albuterol sulfate inhalation solution. There were no statistically significant differences in the pharmacokinetics of albuterol between the two treatments. For ipratropium, a mean of 3.9 (± 5.1)% of the ipratropium bromide dose was excreted unchanged in urine following two vials of ipratropium bromide and albuterol sulfate inhalation solution, which is comparable with previously reported data.

Clinical Trials

In a 12 week, randomized, double-blind, positive-control, crossover study of albuterol sulfate, ipratropium bromide, and ipratropium bromide and albuterol sulfate inhalation solution, 863 COPD patients were evaluated for bronchodilator efficacy comparing ipratropium bromide and albuterol sulfate inhalation solution with albuterol sulfate and ipratropium bromide alone.

Ipratropium bromide and albuterol sulfate inhalation solution demonstrated significantly better changes in FEV1, as measured from baseline to peak response, when compared with either albuterol sulfate or ipratropium bromide. Ipratropium bromide and albuterol sulfate inhalation solution was also shown to have the rapid onset associated with albuterol sulfate, with a mean time to peak FEV1 of 1.5 hours, and the extended duration associated with ipratropium bromide with a duration of 15% response in FEV1 of 4.3 hours.

Figure 3. 1-3. Mean Change in FEV1 - Measured on Day 14

This study demonstrated that each component of ipratropium bromide and albuterol sulfate inhalation solution contributed to the improvement in pulmonary function, especially during the first 4 to 5 hours after dosing, and that ipratropium bromide and albuterol sulfate inhalation solution was significantly more effective than albuterol sulfate or ipratropium bromide alone.

Indications and Usage for Ipratropium and Albuterol

Ipratropium bromide and albuterol sulfate inhalation solution is indicated for the treatment of bronchospasm associated with COPD in patients requiring more than one bronchodilator.

Contraindications

Ipratropium bromide and albuterol sulfate inhalation solution is contraindicated in patients with a history of hypersensitivity to any of its components, or to atropine and its derivatives.

Warnings

Paradoxical Bronchospasm

In the clinical study of ipratropium bromide and albuterol sulfate inhalation solution, paradoxical bronchospasm was not observed. However, paradoxical bronchospasm has been observed with both inhaled ipratropium bromide and albuterol products and can be life-threatening. If this occurs, ipratropium bromide and albuterol sulfate inhalation solution should be discontinued immediately and alternative therapy instituted.

Do Not Exceed Recommended Dose

Fatalities have been reported in association with excessive use of inhaled products containing sympathomimetic amines and with the home use of nebulizers.

Cardiovascular Effect

Ipratropium bromide and albuterol sulfate inhalation solution, like other beta adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon for ipratropium bromide and albuterol sulfate inhalation solution at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta agonists have been reported to produce ECG changes, such as flattening of the T-wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, ipratropium bromide and albuterol sulfate inhalation solution, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions to albuterol and/or ipratropium bromide may occur after the administration of ipratropium bromide and albuterol sulfate inhalation solution as demonstrated by rare cases of urticaria, angioedema, rash, pruritus, oropharyngeal edema, bronchospasm, and anaphylaxis.

Precautions

General

1. Effects Seen with Sympathomimetic Drugs: As with all products containing sympathomimetic amines, ipratropium bromide and albuterol sulfate inhalation solution should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Large doses of intravenous albuterol have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis. Additionally, β-agonists may cause a decrease in serum potassium in some patients, possibly through intracellular shunting. The decrease is usually transient, not requiring supplementation.

2. Effects Seen with Anticholinergic Drugs: Due to the presence of ipratropium bromide in ipratropium bromide and albuterol sulfate inhalation solution, it should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, or bladder-neck obstruction.

3. Use in Hepatic or Renal Disease: Ipratropium bromide and albuterol sulfate inhalation solution has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in these patient populations.

Information for Patients

The action of ipratropium bromide and albuterol sulfate inhalation solution should last up to 5 hours. Ipratropium bromide and albuterol sulfate inhalation solution should not be used more frequently than recommended. Patients should be instructed not to increase the dose or frequency of ipratropium bromide and albuterol sulfate inhalation solution without consulting their healthcare provider. If symptoms worsen, patients should be instructed to seek medical consultation.

Patients must avoid exposing their eyes to this product as temporary papillary dilation, blurred vision, eye pain, or precipitation or worsening of narrow-angle glaucoma may occur, and therefore proper nebulizer technique should be assured, particularly if a mask is used.

If a patient becomes pregnant or begins nursing while on ipratropium bromide and albuterol sulfate inhalation solution, they should contact their healthcare provider about use of ipratropium bromide and albuterol sulfate inhalation solution.

See the illustrated Patient's Instruction for Use in the product package insert.

Drug Interactions

Anticholinergic agents

Although ipratropium bromide is minimally absorbed into the systemic circulation, there is some potential for an additive interaction with concomitantly used anticholinergic medications. Caution is, therefore, advised in the co-administration of ipratropium bromide and albuterol sulfate inhalation solution with other drugs having anticholinergic properties.

ß-adrenergic agents

Caution is advised in the co-administration of ipratropium bromide and albuterol sulfate inhalation solution and other sympathomimetic agents due to the increased risk of adverse cardiovascular effects.

ß-receptor blocking agents

These agents and albuterol sulfate inhibit the effect of each other. β-receptor blocking agents should be used with caution in patients with hyperreactive airways, and if used, relatively selective β1 selective agents are recommended.

Diuretics

The electrocardiogram (ECG) changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by β-agonists, especially when the recommended dose of the β-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of β-agonist-containing drugs, such as ipratropium bromide and albuterol sulfate inhalation solution, with non-potassium sparing diuretics.

Monoamine oxidase inhibitors or tricyclic antidepressants

Ipratropium bromide and albuterol sulfate inhalation solution should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents because the action of albuterol sulfate on the cardiovascular system may be potentiated.

Albuterol Sulfate

Carcinogenesis, Mutagenesis, Impairment of Fertility

Albuterol sulfate

In a 2-year study in Sprague-Dawley rats, albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at and above dietary doses of 2 mg/kg (approximately equal to the maximum recommended daily inhalation dose for adults on a mg/m2 basis). In another study, this effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist.

In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 500 mg/kg (approximately 140 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). In a 22-month study in Golden hamsters, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg (approximately 20 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).

Albuterol sulfate was not mutagenic in the Ames test or a mutation test in yeast. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleous assay.

Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses of albuterol sulfate up to 50 mg/kg (approximately 25 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).

Ipratropium bromide

In 2-year studies in Sprague-Dawley rats and CD-1 mice, ipratropium bromide showed no evidence of tumorigenicity at oral doses up to 6 mg/kg (approximately 15 times and 8 times the maximum recommended daily inhalation dose for adults in rats and mice respectively, on a mg/m2 basis).

Ipratropium bromide was not mutagenic in the Ames test and mouse dominant lethal test. Ipratropium bromide was not clastogenic in a mouse micronucleous assay.

A reproduction study in rats demonstrated decreased conception and increased resorptions when ipratropium bromide was administered orally at a dose of 90 mg/kg (approximately 240 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). These effects were not seen with a dose of 50 mg/kg (approximately 140 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).

Pregnancy

Teratogenic Effects

Pregnancy Category C

Albuterol sulfate: Pregnancy Category C.

Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice given albuterol sulfate subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m2 basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately equal to the maximum recommended daily inhalation dose for adults on a mg/m2 basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m2 basis). Cleft palate formation also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with 2.5 mg/kg isoproterenol (positive control).

A reproduction study in Stride rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol was administered orally at a dose of 50 mg/kg (approximately 55 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).

A study in which pregnant rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.

During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. Because no consistent pattern of defects can be discerned, a relationship between albuterol use and congenital anomalies has not been established.

Ipratropium bromide: Pregnancy Category B.

Reproduction studies in CD-1 mice, Sprague-Dawley rats and New Zealand rabbits demonstrated no evidence of teratogenicity at oral doses up to 10, 100, and 125 mg/kg, respectively (approximately 15, 270, and 680 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). Reproduction studies in rats and rabbits demonstrated no evidence of teratogenicity at inhalation doses up to 1.5 and 1.8 mg/kg, respectively (approximately 4 and 10 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). There are no adequate and well-controlled studies of the use of ipratropium bromide and albuterol sulfate inhalation solution, albuterol sulfate, or ipratropium bromide in pregnant women. Ipratropium bromide and albuterol sulfate inhalation solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

Oral albuterol sulfate has been shown to delay preterm labor in some reports. Because of the potential of albuterol to interfere with uterine contractility, use of ipratropium bromide and albuterol sulfate inhalation solution during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Nursing Mothers

It is not known whether the components of ipratropium bromide and albuterol sulfate inhalation solution are excreted in human milk. Although lipid-insoluble quaternary bases pass into breast milk, it is unlikely that ipratropium bromide would reach the infant to an important extent, especially when taken as a nebulized solution. Because of the potential for tumorigenicity shown for albuterol sulfate in some animals, a decision should be made whether to discontinue nursing or discontinue ipratropium bromide and albuterol sulfate inhalation solution, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of ipratropium bromide and albuterol sulfate inhalation solution in patients below 18 years of age have not been established.

Geriatric Use

Of the total number of subjects in clinical studies of ipratropium bromide and albuterol sulfate inhalation solution, 62 percent were 65 and over, while 19 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Adverse Reactions

Adverse reaction information concerning ipratropium bromide and albuterol sulfate inhalation solution was derived from the 12-week controlled clinical trial.

ADVERSE EVENTS OCCURRING IN ≥ 1% OF ≥ 1 TREATMENT GROUP(S) AND WHERE THE COMBINATION TREATMENT SHOWED THE HIGHEST PERCENTAGE

Body System	Albuterol	Ipratropium	Ipratropium Bromide and Albuterol Sulfate Inhalation Solution
COSTART Term	n (%)	n (%)	n (%)
NUMBER OF PATIENTS	761	754	765
N (%) Patients with AE	327 (43.0)	329 (43.6)	367 (48.0)
BODY AS A WHOLE
Pain	8 (1.1)	4 (0.5)	10 (1.3)
Pain chest	11 (1.4)	14 (1.9)	20 (2.6)
DIGESTIVE
Diarrhea	5 (0.7)	9 (1.2)	14 (1.8)
Dyspepsia	7 (0.9)	8 (1.1)	10 (1.3)
Nausea	7 (0.9)	6 (0.8)	11 (1.4)
MUSCULO-SKELETAL
Cramps leg	8 (1.1)	6 (0.8)	11 (1.4)
RESPIRATORY
Bronchitis	11 (1.4)	13 (1.7)	13 (1.7)
Lung Disease	36 (4.7)	34 (4.5)	49 (6.4)
Pharyngitis	27 (3.5)	27 (3.6)	34 (4.4)
Pneumonia	7 (0.9)	8 (1.1)	10 (1.3)
UROGENITAL
Infection urinary tract	3 (0.4)	9 (1.2)	12 (1.6)

Additional adverse reactions reported in more than 1% of patients treated with ipratropium bromide and albuterol sulfate inhalation solution included constipation and voice alterations.

In the clinical trial, there was a 0.3% incidence of possible allergic-type reactions, including skin rash, pruritus, and urticaria.

Additional information derived from the published literature on the use of albuterol sulfate and ipratropium bromide singly or in combination includes precipitation or worsening of narrow-angle glaucoma, acute eye pain, blurred vision, paradoxical bronchospasm, wheezing, exacerbation of COPD symptoms, drowsiness, aching, flushing, upper respiratory tract infection, palpitations, taste perversion, elevated heart rate, sinusitis, back pain, sore throat, and metabolic acidosis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Overdosage

The effects of overdosage with ipratropium bromide and albuterol sulfate inhalation solution are expected to be related primarily to albuterol sulfate, since ipratropium bromide is not well-absorbed systemically after oral or aerosol administration. The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of symptoms such as seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmia, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, and exaggeration of pharmacological effects listed in ADVERSE REACTIONS. Hypokalemia may also occur. As with all sympathomimetic aerosol medications, cardiac arrest and even death may be associated with abuse of ipratropium bromide and albuterol sulfate inhalation solution. Treatment consists of discontinuation of ipratropium bromide and albuterol sulfate inhalation solution together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of ipratropium bromide and albuterol sulfate inhalation solution.

The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately 540 times the maximum recommended daily inhalation dose of ipratropium bromide and albuterol sulfate inhalation solution on a mg/m2 basis). The subcutaneous median lethal dose of albuterol sulfate in mature rats and small young rats is approximately 450 and 2000 mg/kg respectively (approximately 240 and 1100 times the maximum recommended daily inhalation dose of ipratropium bromide and albuterol sulfate inhalation solution on a mg/m2 basis, respectively). The inhalation median lethal dose has not been determined in animals. The oral median lethal dose of ipratropium bromide in mice, rats and dogs is greater than 1000 mg/kg, approximately 1700 mg/kg and approximately 400 mg/kg, respectively (approximately 1400, 4600, and 3600 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis, respectively).

Ipratropium and Albuterol Dosage and Administration

The recommended dose of ipratropium bromide and albuterol sulfate inhalation solution is one 3 mL vial administered 4 times per day via nebulization with up to 2 additional 3 mL doses allowed per day, if needed. Safety and efficacy of additional doses or increased frequency of administration of ipratropium bromide and albuterol sulfate inhalation solution beyond these guidelines has not been studied and the safety and efficacy of extra doses of albuterol sulfate or ipratropium bromide in addition to the recommended doses of ipratropium bromide and albuterol sulfate inhalation solution have not been studied.

The use of ipratropium bromide and albuterol sulfate inhalation solution can be continued as medically indicated to control recurring bouts of bronchospasm. If a previously effective regimen fails to provide the usual relief, medical advice should be sought immediately, as this is often a sign of worsening COPD, which would require reassessment of therapy.

A nebulizer (with face mask or mouthpiece) connected to a compressor was used to deliver ipratropium bromide and albuterol sulfate inhalation solution to each patient in one U.S. clinical study. The safety and efficacy of ipratropium bromide and albuterol sulfate inhalation solution delivered by other nebulizers and compressors have not been established.

Ipratropium bromide and albuterol sulfate inhalation solution should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask.

How is Ipratropium and Albuterol Supplied

Ipratropium Bromide 0.5 mg and Albuterol Sulfate 3 mg* Inhalation Solution is supplied as a 3 mL sterile solution for nebulization in sterile low-density polyethylene unit-dose vials. Store in pouch until time of use. Cards of five vials are placed into a foil pouch. Supplied in unit-dose boxes of 30 vials and unit-dose boxes of 60 vials (2 x 30).

NDC 0093-6723-73 30 vials per carton/5 vials per foil pouch

NDC 0093-6723-74 60 vials per carton/5 vials per foil pouch

Store at 2°C to 25°C (36°F to 77°F). Protect from light.

*Equivalent to 2.5 mg albuterol base

Manufactured In England By:

IVAX PHARMACEUTICALS UK

Runcorn, Cheshire WA7 3FA England

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. B 9/2011

 

 Ipratropium Bromide 0.5 mg and Albuterol Sulfate 3 mg* Inhalation Solution

*Equivalent to 2.5 mg albuterol base

Patient's Instructions for Use

Read this patient information completely every time your prescription is filled as information may have changed. Keep these instructions with your medication as you may want to read them again.

Ipratropium bromide and albuterol sulfate inhalation solution should only be used under the direction of a physician. Your physician and pharmacist have more information about ipratropium bromide and albuterol sulfate inhalation solution and the condition for which it has been prescribed. Contact them if you have additional questions.

Storing your Medicine

Store ipratropium bromide and albuterol sulfate inhalation solution between 2°C and 25°C (36°F and 77°F). Vials should be protected from light before use, therefore, keep unused vials in the foil pouch or carton. Do not use after the expiration (EXP) date printed on the carton.

Dose

Ipratropium bromide and albuterol sulfate inhalation solution is supplied as a single-dose, ready-to-use vial containing 3 mL of solution. No mixing or dilution is needed. Use one new vial for each nebulizer treatment.

FOLLOW THESE DIRECTIONS FOR USE OF YOUR NEBULIZER/COMPRESSOR OR THE DIRECTIONS GIVEN BY YOUR HEALTHCARE PROVIDER. A TYPICAL EXAMPLE IS SHOWN BELOW.

Instructions for Use

1. Remove one vial from the foil pouch. Place remaining vials back into pouch for storage.

2. Twist the cap completely off the vial and squeeze the contents into the nebulizer reservoir (Figure 1).

3. Connect the nebulizer to the mouthpiece or face mask (Figure 2).

4. Connect the nebulizer to the compressor.

5. Sit in a comfortable, upright position; place the mouthpiece in your mouth (Figure 3) or put on the face mask (Figure 4); and turn on the compressor.

6. Breathe as calmly, deeply and evenly as possible through your mouth until no more mist is formed in the nebulizer chamber (about 5-15 minutes). At this point, the treatment is finished.

7. Clean the nebulizer (see manufacturer's instructions).

Manufactured In England By:

IVAX PHARMACEUTICALS UK

Runcorn, Cheshire WA7 3FA England

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. B 9/2011

Steri-Neb™ is a trademark of Norton Healthcare Limited.

IPRATROPIUM BROMIDE and ALBUTEROL SULFATE INHALATION SOLUTION

ADDITIONAL INSTRUCTIONS

____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Patient Information

Ipratropium Bromide 0.5 mg/Albuterol Sulfate 3 mg* Inhalation Solution

*Equivalent to 2.5 mg albuterol base

Prescription Only.

Read the patient information that comes with ipratropium bromide and albuterol sulfate inhalation solution before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

What is ipratropium bromide and albuterol sulfate inhalation solution?

Ipratropium bromide and albuterol sulfate inhalation solution is a combination of two medicines called bronchodilators. Ipratropium bromide and albuterol sulfate inhalation solution contains albuterol sulfate, which is a beta-adrenergic agonist, and ipratropium bromide, which is an anticholinergic. These two medicines work together to help open the airways in your lungs. Ipratropium bromide and albuterol sulfate inhalation solution is used to help treat airway narrowing (bronchospasm) that happens with chronic obstructive pulmonary disease (COPD) in adult patients who need to use more than one bronchodilator medicine.

Who should not use ipratropium bromide and albuterol sulfate inhalation solution?

Do not use ipratropium bromide and albuterol sulfate inhalation solution if you: Are allergic to any of the ingredients in ipratropium bromide and albuterol sulfate inhalation solution or to atropine. The active ingredients are albuterol sulfate and ipratropium bromide. See the end of this leaflet for a complete list of ingredients in ipratropium bromide and albuterol sulfate inhalation solution.

Ipratropium bromide and albuterol sulfate inhalation solution has not been studied in patients younger than 18 years of age.

What should I tell my doctor before I start using ipratropium bromide and albuterol sulfate inhalation solution?

Tell your doctor about all of your conditions, including if you:

• Have heart problems. This includes coronary artery disease and heart rhythm problems.


• Have high blood pressure


• Have diabetes


• Have or had seizures


• Have a thyroid problem called hyperthyroidism


• Have an eye problem called narrow-angle glaucoma


• Have liver or kidney problems


• Have problems urinating due to bladder-neck blockage or an enlarged prostate (men)


• Are pregnant or planning to become pregnant. It is not known if ipratropium bromide and albuterol sulfate inhalation solution can harm your unborn baby. You and your doctor will have to decide if ipratropium bromide and albuterol sulfate inhalation solution is right for you during a pregnancy.


• Are breastfeeding. It is not known if ipratropium bromide and/or albuterol sulfate pass into your milk or if they can harm your baby. You and your doctor should decide whether you should take ipratropium bromide and albuterol sulfate inhalation solution or breastfeed, but not both.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Ipratropium bromide and albuterol sulfate inhalation solution and other medicines can interact. This may cause serious side effects. Especially tell your doctor if you take:

• Other medicines that contain anticholinergics such as ipratropium bromide. This also includes medicines used for Parkinson's disease.


• Other medicines that contain beta-agonists such as albuterol sulfate. These are usually used to treat airway narrowing (bronchospasm).


• Medicines called beta-blockers. These are usually used for high blood pressure or heart problems.


• Medicines called "water pills" (diuretics)


• Medicines for depression called monoamine oxidase inhibitors (MAOIs) or tricyclic antidepressants.

Ask your doctor or pharmacist if you are not sure if you take any of these types of medicines. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacists when you get a new medicine.

How should I use ipratropium bromide and albuterol sulfate inhalation solution?

• Read the Patient's Instructions for Use that you get with your prescription. Talk to your doctor or pharmacist if you have any questions.


• Take ipratropium bromide and albuterol sulfate inhalation solution exactly as prescribed by your doctor. Do not change your dose or how often you use ipratropium bromide and albuterol sulfate inhalation solution without talking to your doctor. Inhale ipratropium bromide and albuterol sulfate inhalation solution through your mouth and into your lungs using a machine called a nebulizer.


• Ipratropium bromide and albuterol sulfate inhalation solution may h

Zantac 300

See also: Generic Zantac, Generic Zantac 150

Zantac 300 is a brand name of ranitidine, approved by the FDA in the following formulation(s):

ZANTAC 300 (ranitidine hydrochloride - tablet; oral)

• 
  Manufacturer: GLAXOSMITHKLINE
  
  Approval date: December 9, 1985
  
  Strength(s): EQ 300MG BASE ^[RLD][AB]

Has a generic version of Zantac 300 been approved?

Yes. The following products are equivalent to Zantac 300:

ranitidine hydrochloride tablet; oral

• 
  Manufacturer: AMNEAL PHARMS NY
  
  Approval date: October 13, 2006
  
  Strength(s): EQ 300MG BASE ^[AB]


• 
  Manufacturer: APOTEX
  
  Approval date: September 12, 1997
  
  Strength(s): EQ 300MG BASE ^[AB]


• 
  Manufacturer: DR REDDYS LABS INC
  
  Approval date: July 27, 2005
  
  Strength(s): EQ 300MG BASE ^[AB]


• 
  Manufacturer: GLENMARK GENERICS
  
  Approval date: November 19, 2008
  
  Strength(s): EQ 300MG BASE ^[AB]


• 
  Manufacturer: IVAX SUB TEVA PHARMS
  
  Approval date: September 30, 1998
  
  Strength(s): EQ 300MG BASE ^[AB]


• 
  Manufacturer: MYLAN
  
  Approval date: August 22, 1997
  
  Strength(s): EQ 300MG BASE ^[AB]


• 
  Manufacturer: PAR PHARM
  
  Approval date: January 28, 1999
  
  Strength(s): EQ 300MG BASE ^[AB]


• 
  Manufacturer: SANDOZ
  
  Approval date: August 29, 1997
  
  Strength(s): EQ 300MG BASE ^[AB]


• 
  Manufacturer: TEVA
  
  Approval date: July 31, 1997
  
  Strength(s): EQ 300MG BASE ^[AB]


• 
  Manufacturer: WATSON LABS
  
  Approval date: October 20, 1997
  
  Strength(s): EQ 300MG BASE ^[AB]


• 
  Manufacturer: WATSON LABS
  
  Approval date: December 19, 2005
  
  Strength(s): EQ 300MG BASE ^[AB]


• 
  Manufacturer: WOCKHARDT
  
  Approval date: December 17, 1998
  
  Strength(s): EQ 300MG BASE ^[AB]


• 
  Manufacturer: WOCKHARDT
  
  Approval date: December 11, 2009
  
  Strength(s): EQ 300MG BASE ^[AB]

Note: Fraudulent online pharmacies may attempt to sell an illegal generic version of Zantac 300. These medications may be counterfeit and potentially unsafe. If you purchase medications online, be sure you are buying from a reputable and valid online pharmacy. Ask your health care provider for advice if you are unsure about the online purchase of any medication.

See also: About generic drugs.

Related Patents

There are no current U.S. patents associated with Zantac 300.

See also...

• Zantac 300 Consumer Information (Cerner Multum)
• Ranitidine Consumer Information (Drugs.com)
• Ranitidine Consumer Information (Wolters Kluwer)
• Ranitidine Effervescent Tablets Consumer Information (Wolters Kluwer)
• Ranitidine Syrup Consumer Information (Wolters Kluwer)
• Ranitidine Tablets Consumer Information (Wolters Kluwer)
• Ranitidine Consumer Information (Cerner Multum)
• Ranitidine Hydrochloride AHFS DI Monographs (ASHP)

Ethamolin

Ethamolin is a brand name of ethanolamine oleate, approved by the FDA in the following formulation(s):

ETHAMOLIN (ethanolamine oleate - injectable; injection)

• 
  Manufacturer: QOL MEDCL
  
  Approval date: December 22, 1988
  
  Strength(s): 50MG/ML ^[RLD]

Has a generic version of Ethamolin been approved?

No. There is currently no therapeutically equivalent version of Ethamolin available.

Note: Fraudulent online pharmacies may attempt to sell an illegal generic version of Ethamolin. These medications may be counterfeit and potentially unsafe. If you purchase medications online, be sure you are buying from a reputable and valid online pharmacy. Ask your health care provider for advice if you are unsure about the online purchase of any medication.

See also: About generic drugs.

Related Patents

There are no current U.S. patents associated with Ethamolin.

See also...

• Ethamolin Consumer Information (Cerner Multum)
• Ethanolamine oleate Consumer Information (Cerner Multum)

Neoptic

Generic Name: gramicidin, neomycin, and polymyxin B ophthalmic (gram i SYE din, NEE oh MYE sin, POL ee MIX in B off THAL mik)

Brand Names: Neosporin Ophthalmic, Ocu-Spore-G

What is Neoptic (gramicidin, neomycin, and polymyxin B ophthalmic)?

Gramicidin, neomycin, and polymyxin B are all antibiotics. They are used to treat bacterial infections.

The ophthalmic form of gramicidin, neomycin, and polymyxin B is used to treat bacterial infections of the eyes.

Gramicidin, neomycin, and polymyxin B ophthalmic may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Neoptic (gramicidin, neomycin, and polymyxin B ophthalmic)?

Contact your doctor if your symptoms begin to get worse or if you do not see any improvement in your condition after a few days.

Do not touch the dropper to any surface, including your eyes or hands. The dropper is sterile. If it becomes contaminated, it could cause an infection in your eye.

Apply light pressure to the inside corner of your eye (near your nose) after each drop to prevent the liquid from draining down your tear duct.

Who should not use Neoptic (gramicidin, neomycin, and polymyxin B ophthalmic)?

Do not use gramicidin, neomycin, and polymyxin B ophthalmic if you have a viral or fungal infection in your eye. It is used to treat infections caused by bacteria only. It is not known whether gramicidin, neomycin, and polymyxin B ophthalmic will harm an unborn baby. Do not use this medication without first talking to your doctor if you are pregnant. It is not known whether gramicidin, neomycin, and polymyxin B ophthalmic passes into breast milk. Do not use this medication without first talking to your doctor if you are breast-feeding a baby.

How should I use Neoptic (gramicidin, neomycin, and polymyxin B ophthalmic)?

Use gramicidin, neomycin, and polymyxin B eyedrops 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 and after using your eyedrops.

To apply the eyedrops:

• 
  

  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.

  
  

Do not touch the dropper to any surface, including your eyes or hands. The dropper is sterile. If it becomes contaminated, it could cause an infection in your eye. Do not use any eyedrop that is discolored or has particles in it. Store gramicidin, neomycin, and polymyxin B ophthalmic at room temperature away from moisture and heat. Keep the bottle properly capped.

What happens if I miss a dose?

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.

What happens if I overdose?

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.

What should I avoid while using Neoptic (gramicidin, neomycin, and polymyxin B ophthalmic)?

Do not touch the dropper to any surface, including your eyes or hands. The dropper is sterile. If it becomes contaminated, it could cause an infection in your eye. Use caution when driving, operating machinery, or performing other hazardous activities. Gramicidin, neomycin, and polymyxin B ophthalmic may cause blurred vision. If you experience blurred vision, avoid these activities.

Use caution with contact lenses. Wear them only if your doctor approves. After applying this medication, wait at least 15 minutes before inserting contact lenses.

Avoid other eye medications unless your doctor approves.

Neoptic (gramicidin, neomycin, and polymyxin B ophthalmic) side effects

Serious side effects are not expected with this medication.

Commonly, some burning, stinging, irritation, itching, redness, blurred vision, eyelid itching, eyelid swelling or crusting, 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.

What other drugs will affect Neoptic (gramicidin, neomycin, and polymyxin B ophthalmic)?

Avoid other eye medications unless they are approved by your doctor.

Drugs other than those listed here may also interact with gramicidin, neomycin, and polymyxin B ophthalmic. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.

More Neoptic resources

• Neoptic Use in Pregnancy & Breastfeeding
• Neoptic Support Group
• 0 Reviews for Neoptic - Add your own review/rating

• Neocidin Prescribing Information (FDA)


• Neocidin Advanced Consumer (Micromedex) - Includes Dosage Information

Compare Neoptic with other medications

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Where can I get more information?

• Your pharmacist has additional information about gramicidin, neomycin, and polymyxin B written for health professionals that you may read.