MIRAPEXIN 0.52 mg prolonged-release tablets

1. Name Of The Medicinal Product

MIRAPEXIN 0.52 mg prolonged-release tablets

2. Qualitative And Quantitative Composition

Each prolonged-release tablet contains 0.75 mg pramipexole dihydrochloride monohydrate equivalent to 0.52 mg pramipexole.

Please note:

Pramipexole doses as published in the literature refer to the salt form.

Therefore, doses will be expressed in terms of both pramipexole base and pramipexole salt (in brackets).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged-release tablet.

The tablets are white to off-white, of round shape, with bevelled edges, and have a code embossed (one side with the code P2, and one side with the Boehringer Ingelheim company symbol).

4. Clinical Particulars

4.1 Therapeutic Indications

MIRAPEXIN is indicated in adults for treatment of the signs and symptoms of idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end of dose or “on off” fluctuations).

4.2 Posology And Method Of Administration

Posology

MIRAPEXIN prolonged-release tablets are a once-a-day oral formulation of pramipexole.

Initial treatment

Doses should be increased gradually from a starting dose of 0.26 mg of base (0.375 mg of salt) per day and then increased every 5 - 7 days. Providing patients do not experience intolerable undesirable effects, the dose should be titrated to achieve a maximal therapeutic effect.

Ascending dose schedule of MIRAPEXIN prolonged-release tablets
Week	Daily dose (mg of base)	Daily dose (mg of salt)
1	0.26	0.375
2	0.52	0.75
3	1.05	1.5

If a further dose increase is necessary the daily dose should be increased by 0.52 mg of base (0.75 mg of salt) at weekly intervals up to a maximum dose of 3.15 mg of base (4.5 mg of salt) per day. However, it should be noted that the incidence of somnolence is increased at doses higher than 1.05 mg of base (1.5 mg of salt) per day (see section 4.8).

Patients already taking MIRAPEXIN tablets may be switched to MIRAPEXIN prolonged-release tablets overnight, at the same daily dose. After switching to MIRAPEXIN prolonged-release tablets, the dose may be adjusted depending on the patient's therapeutic response (see section 5.1).

Maintenance treatment

The individual dose of pramipexole should be in the range of 0.26 mg of base (0.375 mg of salt) to a maximum of 3.15 mg of base (4.5 mg of salt) per day. During dose escalation in pivotal studies, efficacy was observed starting at a daily dose of 1.05 mg of base (1.5 mg of salt). Further dose adjustments should be done based on the clinical response and the occurrence of adverse reactions. In clinical trials approximately 5% of patients were treated at doses below 1.05 mg of base (1.5 mg of salt). In advanced Parkinson's disease, pramipexole doses higher than 1.05 mg of base (1.5 mg of salt) per day can be useful in patients where a reduction of the levodopa therapy is intended. It is recommended that the dose of levodopa is reduced during both the dose escalation and the maintenance treatment with MIRAPEXIN, depending on reactions in individual patients (see section 4.5).

Missed dose

When the intake of a dose is missed, MIRAPEXIN prolonged-release tablets should be taken within 12 hours after the regularly scheduled time. After 12 hours, the missed dose should be left out and the next dose should be taken on the following day at the next regularly scheduled time.

Treatment discontinuation

Abrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic malignant syndrome. Pramipexole should be tapered off at a rate of 0.52 mg of base (0.75 mg of salt) per day until the daily dose has been reduced to 0.52 mg of base (0.75 mg of salt). Thereafter the dose should be reduced by 0.26 mg of base (0.375 mg of salt) per day (see section 4.4).

Dosing in patients with renal impairment

The elimination of pramipexole is dependent on renal function. The following dose schedule is suggested:

Patients with a creatinine clearance above 50 ml/min require no reduction in daily dose or dosing frequency.

In patients with a creatinine clearance between 30 and 50 ml/min, treatment should be started with 0.26 mg MIRAPEXIN prolonged-release tablets every other day. Caution should be exercised and careful assessment of therapeutic response and tolerability should be made before increasing to daily dosing after one week. If a further dose increase is necessary, doses should be increased by 0.26 mg pramipexole base at weekly intervals up to a maximum dose of 1.57 mg pramipexole base (2.25 mg of salt) per day.

The treatment of patients with a creatinine clearance below 30 ml/min with MIRAPEXIN prolonged-release tablets is not recommended as no data are available for this patient population. The use of MIRAPEXIN tablets should be considered.

If renal function declines during maintenance therapy, the recommendations given above should be followed.

Dosing in patients with hepatic impairment

Dose adjustment in patients with hepatic failure is probably not necessary, as approx. 90% of absorbed active substance is excreted through the kidneys. However, the potential influence of hepatic insufficiency on MIRAPEXIN pharmacokinetics has not been investigated.

Paediatric population

The safety and efficacy of MIRAPEXIN in children below 18 years has not been established. There is no relevant use of MIRAPEXIN prolonged-release tablets in the paediatric population in Parkinson's Disease.

Method of administration

The tablets should be swallowed whole with water, and must not be chewed, divided or crushed. The tablets may be taken either with or without food and should be taken each day at about the same time.

4.3 Contraindications

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

4.4 Special Warnings And Precautions For Use

When prescribing MIRAPEXIN in a patient with Parkinson's disease with renal impairment a reduced dose is suggested in line with section 4.2.

Hallucinations

Hallucinations are known as a side effect of treatment with dopamine agonists and levodopa. Patients should be informed that (mostly visual) hallucinations can occur.

Dyskinesia

In advanced Parkinson's disease, in combination treatment with levodopa, dyskinesia can occur during the initial titration of MIRAPEXIN. If they occur, the dose of levodopa should be decreased.

Sudden onset of sleep and somnolence

Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported uncommonly. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with MIRAPEXIN. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a reduction of the dose or termination of therapy may be considered. Because of possible additive effects, caution should be advised when patients are taking other sedating medicinal products or alcohol in combination with pramipexole (see sections 4.5, 4.7 and section 4.8).

Impulse control disorders and compulsive behaviours

Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson's disease, including MIRAPEXIN. Furthermore, patients and caregivers should be aware of the fact that other behavioural symptoms of impulse control disorders and compulsions such as binge eating and compulsive shopping can occur. Dose reduction/tapered discontinuation should be considered.

Patients with psychotic disorders

Patients with psychotic disorders should only be treated with dopamine agonists if the potential benefits outweigh the risks. Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see section 4.5).

Ophthalmologic monitoring

Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.

Severe cardiovascular disease

In case of severe cardiovascular disease, care should be taken. It is recommended to monitor blood pressure, especially at the beginning of treatment, due to the general risk of postural hypotension associated with dopaminergic therapy.

Neuroleptic malignant syndrome

Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy (see section 4.2).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Plasma protein binding

Pramipexole is bound to plasma proteins to a very low (< 20%) extent, and little biotransformation is seen in man. Therefore, interactions with other medicinal products affecting plasma protein binding or elimination by biotransformation are unlikely. As anticholinergics are mainly eliminated by biotransformation, the potential for an interaction is limited, although an interaction with anticholinergics has not been investigated. There is no pharmacokinetic interaction with selegiline and levodopa.

Inhibitors/competitors of active renal elimination pathway

Cimetidine reduced the renal clearance of pramipexole by approximately 34%, presumably by inhibition of the cationic secretory transport system of the renal tubules. Therefore, medicinal products that are inhibitors of this active renal elimination pathway or are eliminated by this pathway, such as cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine and procainamide, may interact with pramipexole resulting in reduced clearance of pramipexole. Reduction of the pramipexole dose should be considered when these medicinal products are administered concomitantly with MIRAPEXIN.

Combination with levodopa

When MIRAPEXIN is given in combination with levodopa, it is recommended that the dose of levodopa is reduced and the dose of other anti-parkinsonian medicinal products is kept constant while increasing the dose of MIRAPEXIN.

Because of possible additive effects, caution should be advised when patients are taking other sedating medicinal products or alcohol in combination with pramipexole (see sections 4.4, 4.7 and 4.8).

Antipsychotic medicinal products

Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see section 4.4), e.g. if antagonistic effects can be expected.

4.6 Pregnancy And Lactation

Pregnancy

The effect on pregnancy and lactation has not been investigated in humans. Pramipexole was not teratogenic in rats and rabbits, but was embryotoxic in the rat at maternotoxic doses (see section 5.3). MIRAPEXIN should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

As pramipexole treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected. The excretion of pramipexole into breast milk has not been studied in women. In rats, the concentration of active substance-related radioactivity was higher in breast milk than in plasma.

In the absence of human data, MIRAPEXIN should not be used during breast-feeding. However, if its use is unavoidable, breast-feeding should be discontinued.

Fertility

No studies on the effect on human fertility have been conducted. In animal studies, pramipexole affected oestrous cycles and reduced female fertility as expected for a dopamine agonist. However, these studies did not indicate direct or indirect harmful effects with respect to male fertility.

4.7 Effects On Ability To Drive And Use Machines

MIRAPEXIN can have a major influence on the ability to drive and use machines.

Hallucinations or somnolence can occur.

Patients being treated with MIRAPEXIN and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved (see also sections 4.4, 4.5 and 4.8).

4.8 Undesirable Effects

Expected adverse reactions

The following adverse reactions are expected under the use of MIRAPEXIN: abnormal dreams, amnesia, behavioural symptoms of impulse control disorders and compulsions such as binge eating, compulsive shopping, hypersexuality and pathological gambling; cardiac failure, confusion, constipation, delusion, dizziness, dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia, hypotension, insomnia, libido disorders, nausea, paranoia, peripheral oedema, pneumonia, pruritus, rash and other hypersensitivity; restlessness, somnolence, sudden onset of sleep, syncope, visual impairment including diplopia, vision blurred and visual acuity reduced, vomiting, weight decrease including decreased appetite, weight increase.

Based on the analysis of pooled placebo-controlled trials, comprising a total of 1,778 Parkinson's disease patients on pramipexole and 1,297 patients on placebo, adverse drug reactions were frequently reported for both groups. 67% of patients on pramipexole and 54% of patients on placebo reported at least one adverse drug reaction.

The adverse drug reactions reported in the table below are those events that occurred in 0.1% or more of patients treated with pramipexole and were reported significantly more often in patients taking pramipexole than placebo, or where the event was considered clinically relevant. The majority of adverse drug reactions were mild to moderate, they usually start early in therapy and most tended to disappear even as therapy was continued.

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (

The most commonly (

System Organ Class	Adverse Drug Reaction
Infections and infestations
Uncommon	pneumonia
Psychiatric disorders
Common	abnormal dreams, behavioural symptoms of impulse control disorders and compulsions; confusion, hallucinations, insomnia
Uncommon	binge eating1, compulsive shopping, delusion, hyperphagia1, hypersexuality, libido disorder, paranoia, pathological gambling, restlessness
Nervous system disorders
Very common	dizziness, dyskinesia, somnolence
Common	headache
Uncommon	amnesia, hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Common	visual impairment including diplopia, vision blurred and visual acuity reduced
Cardiac disorders
Uncommon	cardiac failure1
Vascular disorders
Common	hypotension
Respiratory, thoracic, and mediastinal disorders
Uncommon	dyspnoea, hiccups
Gastrointestinal disorders
Very common	nausea
Common	constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon	hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common	fatigue, peripheral oedema
Investigations
Common	weight decrease including decreased appetite
Uncommon	weight increase

¹This side effect has been observed in post-marketing experience. With 95 % certainty, the frequency category is not greater than uncommon, but might be lower. A precise frequency estimation is not possible as the side effect did not occur in a clinical trial database of 2,762 patients with Parkinson's Disease treated with pramipexole.

Somnolence

Pramipexole is commonly associated with somnolence and has been associated uncommonly with excessive daytime somnolence and sudden sleep onset episodes (see also section 4.4).

Libido disorders

Pramipexole may uncommonly be associated with libido disorders (increased or decreased).

Impulse control disorders and compulsive behaviours

Patients treated with dopamine agonists for Parkinson's disease, including MIRAPEXIN, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation. See also section 4.4.

In a cross-sectional, retrospective screening and case-control study including 3,090 Parkinson's disease patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment had symptoms of an impulse control disorder during the past six months. Manifestations observed include pathological gambling, compulsive shopping, binge eating, and compulsive sexual behaviour (hypersexuality). Possible independent risk factors for impulse control disorders included dopaminergic treatments and higher doses of dopaminergic treatment, younger age (

Cardiac failure

In clinical studies and post-marketing experience cardiac failure has been reported in patients with pramipexole. In a pharmacoepidemiological study pramipexole use was associated with an increased risk of cardiac failure compared with non-use of pramipexole (observed risk ratio 1.86; 95% CI, 1.21-2.85).

4.9 Overdose

There is no clinical experience with massive overdose. The expected adverse reactions would be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hyperkinesia, hallucinations, agitation and hypotension. There is no established antidote for overdose of a dopamine agonist. If signs of central nervous system stimulation are present, a neuroleptic agent may be indicated. Management of the overdose may require general supportive measures, along with gastric lavage, intravenous fluids, administration of activated charcoal and electrocardiogram monitoring.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: anti-Parkinson drugs, dopamine agonists, ATC code: N04BC05.

Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 subfamily of dopamine receptors of which it has a preferential affinity to D3 receptors, and has full intrinsic activity.

Pramipexole alleviates parkinsonian motor deficits by stimulation of dopamine receptors in the striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release, and turnover.

In human volunteers, a dose-dependent decrease in prolactin was observed. In a clinical trial with healthy volunteers, where MIRAPEXIN prolonged-release tablets were titrated faster (every 3 days) than recommended up to 3.15 mg pramipexole base (4.5 mg of salt) per day, an increase in blood pressure and heart rate was observed. Such effect was not observed in patient studies.

In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson's disease. Placebo-controlled clinical trials included approximately 1,800 patients of Hoehn and Yahr stages I – V treated with pramipexole. Out of these, approximately 1,000 were in more advanced stages, received concomitant levodopa therapy, and suffered from motor complications.

In early and advanced Parkinson's disease, efficacy of pramipexole in controlled clinical trials was maintained for approximately six months. In open continuation trials lasting for more than three years there were no signs of decreasing efficacy.

In a controlled double blind clinical trial of 2 year duration, initial treatment with pramipexole significantly delayed the onset of motor complications, and reduced their occurrence compared to initial treatment with levodopa. This delay in motor complications with pramipexole should be balanced against a greater improvement in motor function with levodopa (as measured by the mean change in UPDRS-score). The overall incidence of hallucinations and somnolence was generally higher in the escalation phase with the pramipexole group. However, there was no significant difference during the maintenance phase. These points should be considered when initiating pramipexole treatment in patients with Parkinson's disease.

The safety and efficacy of MIRAPEXIN prolonged-release tablets in the treatment of Parkinson's disease was evaluated in a multinational drug development program consisting of three randomised, controlled trials. Two trials were conducted in patients with early Parkinson's disease and one trial was conducted in patients with advanced Parkinson's disease.

Superiority of MIRAPEXIN prolonged-release tablets over placebo was demonstrated after 18 weeks of treatment on both the primary (UPDRS Parts II+III score) and the key secondary (CGI-I and PGI-I responder rates) efficacy endpoints in a double-blind placebo-controlled trial including a total of 539 patients with early Parkinson's disease. Maintenance of efficacy was shown in patients treated for 33 weeks. MIRAPEXIN prolonged-release tablets were non-inferior to pramipexole immediate release tablets as assessed on the UPDRS Parts II+III score at week 33.

In a double-blind placebo-controlled trial including a total of 517 patients with advanced Parkinson's disease who were on concomitant levodopa therapy superiority of MIRAPEXIN prolonged-release tablets over placebo was demonstrated after 18 weeks of treatment on both the primary (UPDRS Parts II+III score) and the key secondary (off-time) efficacy endpoints.

The efficacy and tolerability of an overnight switch from MIRAPEXIN tablets to MIRAPEXIN prolonged-release tablets at the same daily dose were evaluated in a double-blind clinical study in patients with early Parkinson's disease.

Efficacy was maintained in 87 of 103 patients switched to MIRAPEXIN prolonged-release tablets. Out of these 87 patients, 82.8% did not change their dose, 13.8% increased and 3.4% decreased their dose.

In half of the 16 patients who did not meet the criterion for maintained efficacy on UPDRS Part II+III score, the change from baseline was considered not clinically relevant.

Only one patient switched to MIRAPEXIN prolonged-release tablets experienced a drug-related adverse event leading to withdrawal.

The European Medicines Agency has waived the obligation to submit the results of studies with MIRAPEXIN in all subsets of the paediatric population in Parkinson's Disease (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic Properties

Pramipexole is completely absorbed following oral administration. The absolute bioavailability is greater than 90%.

In a Phase I trial, where pramipexole immediate release and prolonged-release tablets were assessed in fasted state, the minimum and peak plasma concentration (C_min, C_max) and exposure (AUC) of the same daily dose of MIRAPEXIN prolonged-release tablets given once daily and MIRAPEXIN tablets given three times a day were equivalent.

The once daily administration of MIRAPEXIN prolonged-release tablets causes less frequent fluctuations in the pramipexole plasma concentration over 24 hours compared to the three times daily administration of pramipexole immediate release tablets.

The maximum plasma concentrations occur at about 6 hours after administration of MIRAPEXIN prolonged-release tablets once daily. Steady state of exposure is reached at the latest after 5 days of continuous dosing.

Concomitant administration with food does generally not affect the bioavailability of pramipexole. Intake of a high fat meal induced an increase in peak concentration (C_max) of about 24% after a single dose administration and about 20% after multiple dose administrations and a delay of about 2 hours in time to reach peak concentration in healthy volunteers. Total exposure (AUC) was not affected by concomitant food intake. The increase in C_max is not considered clinically relevant. In the Phase III studies that established safety and efficacy of MIRAPEXIN prolonged-release tablets, patients were instructed to take study medication without regard to food intake.

While body weight has no impact on the AUC, it was found to influence the volume of distribution and therefore the peak concentrations C_max. A decreased body weight by 30 kg results in an increase in C_max of 45%. However, in Phase III trials in Parkinson's disease patients no clinically meaningful influence of body weight on the therapeutic effect and tolerability of MIRAPEXIN prolonged-release tablets was detected.

Pramipexole shows linear kinetics and a small inter-patient variation of plasma levels. In humans, the protein binding of pramipexole is very low (< 20%) and the volume of distribution is large (400 l). High brain tissue concentrations were observed in the rat (approx. 8-fold compared to plasma).

Pramipexole is metabolised in man only to a small extent.

Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of ¹⁴C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately 400 ml/min. The elimination half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.

5.3 Preclinical Safety Data

Repeated dose toxicity studies showed that pramipexole exerted functional effects, mainly involving the CNS and female reproductive system, and probably resulting from an exaggerated pharmacodynamic effect of pramipexole.

Decreases in diastolic and systolic pressure and heart rate were noted in the minipig, and a tendency to a hypotensive effect was discerned in the monkey.

The potential effects of pramipexole on reproductive function have been investigated in rats and rabbits. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in the rat at maternally toxic doses. Due to the selection of animal species and the limited parameters investigated, the adverse effects of pramipexole on pregnancy and male fertility have not been fully elucidated.

A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats. The relevance for humans is unknown.

Pramipexole was not genotoxic. In a carcinogenicity study, male rats developed Leydig cell hyperplasia and adenomas, explained by the prolactin-inhibiting effect of pramipexole. This finding is not clinically relevant to man. The same study also showed that, at doses of 2 mg/kg (of salt) and higher, pramipexole was associated with retinal degeneration in albino rats. The latter finding was not observed in pigmented rats, nor in a 2-year albino mouse carcinogenicity study or in any other species investigated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Hypromellose 2208

Maize starch

Carbomer 941

Colloidal anhydrous silica

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Store in the original package in order to protect from moisture.

This medicinal product does not require any special temperature storage conditions.

6.5 Nature And Contents Of Container

OPA/aluminium/PVC-aluminium blisters.

Each blister strip contains 10 prolonged-release tablets.

Cartons containing 1, 3 or 10 blister strips (10, 30 or 100 prolonged-release tablets).

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Boehringer Ingelheim International GmbH

Binger Strasse 173

D-55216 Ingelheim am Rhein

Germany

8. Marketing Authorisation Number(S)

EU/1/97/051/016-018

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 23 February 1998

Date of latest renewal: 23 February 2008

10. Date Of Revision Of The Text

17 June 2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Methamphetamine Hydrochloride

Class: Amphetamines
VA Class: CN801
CAS Number: 537-46-2
Brands: Desoxyn

• Abuse Potential


• 
  

  High potential for abuse.^{a c}

  
  


• 
  

  Administration of amphetamines for prolonged periods of time may lead to drug dependence and must be avoided.^{a b c}

  
  


• 
  

  Particular attention should be paid to the possibility of individuals obtaining methamphetamine for nontherapeutic use or distribution to others, and the drug should be prescribed or dispensed sparingly.^{a c}

  
  

• Sudden Death and Serious Cardiovascular Events


• 
  

  Possible sudden death and serious cardiovascular events (e.g., fatal cardiorespiratory arrest), particularly in individuals who abuse methamphetamine.^{a c d} (See Sudden Death and Serious Cardiovascular Events under Cautions.)

  
  

Introduction

Dextrorotatory isomer of phenylmethylamine;^a sympathomimetic amine with CNS-stimulating activity.^c

Uses for Methamphetamine Hydrochloride

Attention Deficit Hyperactivity Disorder

Used as an adjunct to psychological, educational, social, and other remedial measures in the treatment of attention deficit hyperactivity disorder (ADHD) (hyperkinetic disorder, hyperkinetic syndrome of childhood, minimal brain dysfunction).^{a c e}

Almost all studies comparing behavioral therapy versus stimulants alone have shown a much stronger therapeutic effect from stimulants than from behavioral therapy, and stimulants (e.g., amphetamines, methylphenidate) remain the drugs of choice for the management of ADHD.

Drug therapy is not indicated in all patients with ADHD, and such therapy should be considered only after a complete evaluation, including medical history, has been performed.^{a c}

Use should depend on age and the clinician’s assessment of the severity and duration of symptoms and should not depend solely on one or more behavioral characteristics.^{a c}

Not recommended for ADHD symptoms associated with acute stress reactions.^{a c}

Exogenous Obesity

Has been used as an adjunct to caloric restriction in the short-term (i.e., a few weeks) treatment of exogenous obesity.^{a c} However, because of limited efficacy (short-lived), such use no longer is recommended.

The anorexigenic effect appears to be temporary, seldom lasting more than a few weeks, and tolerance may occur.^{a b c}

Obesity usually is a chronic disease, and short-term or intermittent therapy with anorexigenic drugs is unlikely to maintain long-term benefit.

Misuse and Abuse

Misuse and abuse have experienced a resurgence, in large part, due to the relative ease with which methamphetamine can be synthesized clandestinely from readily available chemicals such as ephedrine, phenylpropanolamine (no longer commercially available in the US), or pseudoephedrine. Recent restrictions (including enactment of the Comprehensive Methamphetamine Control Act of 1996, the Methamphetamine Anti-Proliferation Act [MAPA] of 2000, and the Combat Methamphetamine Epidemic Act [CMEA] of 2005) on the availability of these compounds are hoped to reverse this resurgence in misuse and abuse.

Methamphetamine Hydrochloride Dosage and Administration

Administration

Oral Administration

Administer orally.^{a c}

When used as an anorexigenic agent, administer 30 minutes before each meal.^c

Because of potential for insomnia, avoid administering doses in the late evening.^{a c}

Dosage

Available as methamphetamine hydrochloride; dosage expressed in terms of the salt.^c

Adjust dosage according to individual response and tolerance; the smallest dose required to produce the desired response should always be used.^{a c}

When possible, therapy should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued treatment.^{a c}

If tolerance to anorectic effect occurs, manufacturer suggests not to exceed recommended dosage (in an attempt to increase effect), but rather to discontinue therapy.^c

Pediatric Patients

Exogenous Obesity

Oral

Children ≥12 years of age: 5 mg given 30 minutes before each meal recommended by manufacturer.^c Treatment should not exceed a few weeks.^{a c}

Attention Deficit Hyperactivity Disorder

Oral

Children ≥6 years of age: Initially, 5 mg once or twice daily; daily dosage is increased in 5-mg increments at weekly intervals until the optimum response is attained.^{a c}

Usual dosage is 20–25 mg daily, given in 2 divided doses.^{a c}

Adults

Exogenous Obesity

Oral

5 mg given 30 minutes before each meal recommended by manufacturer.^c Treatment should not exceed a few weeks.^{a c}

Prescribing Limits

Pediatric Patients

Exogenous Obesity

Oral

Children ≥12 years of age: Treatment should not exceed a few weeks.^c

Adults

Exogenous Obesity

Oral

Treatment should not exceed a few weeks.^c

Special Populations

Hepatic Impairment

No specific hepatic dosage recommendations.^c

Renal Impairment

No specific renal dosage recommendations.^c

Geriatric Patients

Select dosage with caution, usually starting at the low end of the dosage range, because of age-related decreases in hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.^{a c}

Cautions for Methamphetamine Hydrochloride

Contraindications

• 
  

  Contraindicated in patients with hypersensitivity or idiosyncrasy to sympathomimetic amines; in patients with^{a c} symptomatic cardiovascular disease,^{a c} hyperthyroidism,^{a c} moderate to severe hypertension,^{a c} glaucoma,^{a c} or advanced arteriosclerosis;^{a c} within 14 days of MAO inhibitor therapy;^{a c} and in agitated patients.^{a c}

  
  


• 
  

  Although amphetamines generally should not be used in patients with a history of drug abuse,^{a c} some experts state that this is not an absolute contraindication, provided the patient can be monitored more carefully than would otherwise be indicated.

  
  

Warnings/Precautions

Warnings

Sudden Death and Serious Cardiovascular Events

Sudden unexplained death, stroke, or MI reported in patients with or without structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of stimulants.^{c d f}

Epidemiologic data suggest a possible association between use of stimulants and sudden unexplained death in healthy children and adolescents.^{g h i} FDA unable to conclude that these data affect evaluation of overall risk and benefit of stimulants used to treat ADHD in children and adolescents.^g FDA is conducting an ongoing safety review of amphetamines and other stimulants to evaluate possible link between use of these agents and sudden death in children.^{g h i} Pediatric patients with ADHD and their parents should avoid discontinuing the child’s use of such stimulants before consulting a clinician.^g

Thoroughly review medical history (including evaluation for family history of sudden death or ventricular arrhythmia) and perform physical examination in all children, adolescents, and adults being considered for stimulant therapy;^{c d} if initial findings suggest presence of cardiac disease, perform further cardiac evaluation (e.g., ECG, echocardiogram).^c

In general, avoid use of CNS stimulants in adults or children with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, CAD, or other serious cardiac conditions.^c (See Contraindications under Cautions.)

Patients who develop exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.^c

Effects on BP and Heart Rate

Possible modest increases in average BP (i.e., by about 2–4 mm Hg) and heart rate (i.e., by about 3–6 bpm); larger increases may occur.^c Modest increases not expected to have short-term sequelae; however, monitor all patients for larger changes in BP and heart rate.^c

Caution advised in patients with underlying medical conditions that might be affected by increases in BP or heart rate (e.g., hypertension, heart failure, recent MI, ventricular arrhythmia).^c

Exacerbation or Precipitation of Psychotic Symptoms

May exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorder.^c

Psychotic symptoms (e.g., hallucinations, delusional thinking) may occur with usual dosages in children and adolescents without prior history of psychotic illness.^{c d} If psychotic symptoms occur, consider causal relationship to stimulants, and discontinue therapy as appropriate.^c

Precipitation of Manic Symptoms

May precipitate mixed or manic episodes in ADHD patients with comorbid bipolar disorder; use with caution in these patients.^{c d} Prior to initiating therapy, carefully screen patients with ADHD and comorbid depressive symptoms to identify risk for bipolar disorder; screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, or depression).^c

Manic symptoms may occur with usual dosages in children and adolescents without prior history of mania.^c If manic symptoms occur, consider causal relationship to stimulants, and discontinue therapy as appropriate.^c

Aggression

Aggressive behavior and hostility (frequently observed in children and adolescents with ADHD) reported in patients receiving drug therapy for ADHD.^c No systematic evidence that stimulants cause these adverse effects; however, monitor patients beginning treatment for ADHD for onset or worsening of aggressive behavior or hostility.^c

Growth Suppression

Long-term (i.e., >14 months) administration expected to cause at least a temporary suppression of normal weight and/or height patterns in some children and adolescents.^c

Manufacturer recommends monitoring growth during treatment; patients not growing or gaining weight as expected may require temporary discontinuance of treatment.^c However, AAP states that studies of stimulants in children found little or no decrease in expected height, with any decrease in growth early in treatment being compensated for later on.

Seizures

Possible lowering of seizure threshold in patients with history of seizures, in those with prior EEG abnormalities but no history of seizures, and, very rarely, in those without history of seizures and with no prior EEG abnormalities.^c If seizures occur, discontinue therapy.^c

Visual Effects

Visual disturbances (difficulty with accommodation, blurred vision) reported with stimulants.^{a c}

General Precautions

Least amount of methamphetamine feasible should be prescribed or dispensed at one time in order to minimize possible overdosage.^c

Do not use to combat fatigue/exhaustion or to replace rest/sleep in normal persons.^{a c}

Hypertension

Use with caution in patients with mild hypertension.^{a c} Contraindicated in those with moderate or severe hypertension.^c (See Contraindications under Cautions.)

Nervous System Effects

Use with caution, if at all, in patients with hyperexcitability states or in those receiving drugs that may produce this effect.^a Also use with caution in asthenic patients or in those with psychopathic personalities or history of suicidal or homicidal tendencies.^a

Tics

Amphetamines reported to exacerbate motor and phonic tics and Tourette’s syndrome.^c However, a history of tics or their development during therapy is not an absolute contraindication to continued use. Several controlled studies have not found stimulants to worsen or precipitate tics or Tourette’s syndrome. Nevertheless, evaluate for presence of tics and Tourette’s syndrome in children and their families prior to initiating stimulant therapy.^c

Fetal/Neonatal Morbidity and Mortality

Teratogenicity and embryolethality demonstrated in animals receiving high multiples of the human dose.^c

Specific Populations

Pregnancy

Category C.^c (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Risk of prematurity, low birth weight, and withdrawal symptoms (e.g., dysphoria, lassitude, agitation) in infants born to dependent women.^c

Lactation

Amphetamines are distributed into milk.^{a c} Discontinue nursing or the drug.^{a c}

Pediatric Use

Not recommended for treatment of ADHD in pediatric patients <6 years of age.^f

Not recommended for management of exogenous obesity in pediatric patients <12 years of age.^{a b c}

Aggressive behavior, hostility, and psychotic (e.g., hallucinations, delusional thinking) or manic symptoms reported in children and adolescents receiving stimulants for management of ADHD.^{b c} (See Warnings under Cautions.)

Sudden death reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of stimulants.^c Epidemiologic data also suggest a possible association between use of stimulants and sudden death in healthy children and adolescents.^{g h i} (See Sudden Death and Serious Cardiovascular Events under Cautions.)

Long-term administration expected to cause at least a temporary suppression of normal weight and/or height patterns in some children and adolescents.^{a c} (See Growth Suppression under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.^{a c} Other clinical experience has not identified differences in responses between geriatric and younger patients.^{a c}

Use with caution in geriatric or debilitated patients.^a Select dosage with caution.^{a c} (See Geriatric Patients under Dosage and Administration.)

Common Adverse Effects

Elevation of BP,^c tachycardia,^{a c} palpitations,^{a c} dizziness,^{a c} dysphoria,^{a c} overstimulation,^c insomnia,^{a c} tremor,^{a c} restlessness,^{a c} headache,^{a c} diarrhea,^{a c} constipation,^{a c} dry mouth,^{a c} unpleasant taste,^{a c} urticaria,^{a c} impotence,^{a c} changes in libido.^{a c}

Interactions for Methamphetamine Hydrochloride

Specific Drugs and Laboratory Tests

Drug or Test	Interaction	Comments
Anesthetics, general (cyclopropane, halothane)	Possible increased sensitivity of heart to arrhythmic action of sympathomimetic aminesa	Avoid concomitant usea
Antidepressants, tricyclic		Use concomitantly under close supervision; adjust dosage carefullya c
Insulin	Possible altered insulin requirements in patients with diabetes mellitusa c	Use concomitantly with caution in patients with diabetes mellitusa
MAO inhibitors	Possible hypertensive crisisc	Contraindicated in patients currently or recently (within 14 days) receiving MAO inhibitora c
Phenothiazines	Possible antagonism of CNS stimulant action of amphetaminesa c
Test for plasma corticosteroids	Amphetamines may substantially increase plasma corticosteroid concentrationsa c

Methamphetamine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Readily and rapidly absorbed from the GI tract.^{a c}

Duration

Therapeutic effects persist for 6–12 hours; effects may continue up to 24 hours following administration of large doses.^a

Distribution

Extent

Amphetamines apparently cross the placenta since withdrawal manifestations have occurred in neonates.^c (See Pregnancy under Cautions.)

Amphetamines are distributed into milk.^{a c}

Elimination

Metabolism

Metabolized in the liver by aromatic hydroxylation, N-dealkylation, and deamination.^{a c}

Elimination Route

Excreted principally in urine.^a With normal urinary pH, approximately 62% of the dose is excreted in urine within the first 24 hours as unchanged drug (about (1/3)) and metabolites (about (2/3)).^{a c}

Excretion is enhanced in acidic urine.^{a c}

Half-life

4–5 hours.^{a c} Alkaline urine substantially increases half-life.^c

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at <30°C.^{a c f}

ActionsActions

• 
  

  Pharmacologic actions of methamphetamine are qualitatively similar to those of amphetamine and ephedrine and include CNS and respiratory stimulation and sympathomimetic activity including pressor response, mydriasis, bronchodilation, and contraction of the urinary bladder sphincter.^a

  
  


• 
  

  CNS stimulating effect is approximately equal to or greater than that of amphetamine but less than that of dextroamphetamine; pressor effect is less than that of amphetamine but greater than that of ephedrine.^a

  
  


• 
  

  Theories of dysfunction in ADHD focus on the prefrontal cortex, which controls many executive functions (e.g., planning, impulse control). Stimulants have putative effects on central dopamine and norepinephrine pathways that are crucial in frontal lobe function.

  
  


• 
  

  Produces an anorexigenic effect, leading to loss of weight.^{a c} No primary effect on appetite has been demonstrated and it has been postulated that anorexigenic effects are secondary to increased sympathetic activity resulting from release of norepinephrine and dopamine.

  
  


• 
  

  Depresses motility of GI tract.^a

  
  

Advice to Patients

• 
  

  Provide patient or caregiver with a copy of the manufacturer’s patient information (medication guide); discuss and answer questions about its contents as needed.^{a c d} Instruct patient or caregiver to read and understand contents of medication guide before initiating therapy and each time the prescription is refilled.^{a c d f}

  
  


• 
  

  Advise parents with concerns about long-term effects (e.g., effects on weight) and the need for continued therapy that drug holidays can be considered in consultation with the patient’s clinician. However, the benefits versus risks of such interruptions in therapy have not been established.

  
  


• 
  

  Advise not to increase or decrease dosage unless instructed by their clinician.^c

  
  


• 
  

  Advise that abrupt discontinuance following prolonged administration of high dosages may result in extreme fatigue and mental depression.^c

  
  


• 
  

  Question about possible substance abuse, including in family members (since they may abuse the patient’s medication supply).^f

  
  


• 
  

  Advise patients to inform clinician immediately if adverse cardiovascular (e.g., chest pain, shortness of breath, fainting) or psychiatric effects (e.g., hallucinations, delusional thinking, mania) occur.^f

  
  


• 
  

  Instruct about the potential for methamphetamine to impair patient’s ability to perform potentially hazardous activities, such as driving a vehicle or operating heavy machinery.^{a c f}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary supplements, and herbal products, as well as any concomitant illnesses/conditions (e.g., cardiac/cardiovascular disease, thyroid disease, glaucoma, suicidal ideation or behaviors, mental/psychiatric disorder).^{c f}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{c f}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^c (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug.^{a c}

Methamphetamine Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	5 mg	Desoxyn ( C-II)	Ovation

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

a. AHFS drug information 2007. McEvoy GK, ed. Methamphetamine. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2476-7.

b. AHFS drug information 2007. McEvoy GK, ed. Amphetamines general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2468-72.

c. Ovation Pharmaceuticals, Inc. Desoxyn (methamphetamine hydrochloride) tablets prescribing information. Deerfield, IL; 2007 May.

d. US Food and Drug Administration. FDA news: FDA directs ADHD drug manufacturers to notify patients about cardiovascular adverse events and psychiatric adverse events. Rockville, MD; 2007 Feb 21. From FDA website.

e. Ovation Pharmaceuticals, Inc., Deerfield, IL: Personal communication.

f. Ovation Pharmaceuticals, Inc. Desoxyn (methamphetamine hydrochloride) medication guide. Deerfield, IL; 2007 May.

g. Food and Drug Administration. FDA Alert: Information for healthcare professionals: Communication about an ongoing safety review of stimulant medications [dexmethylphenidate (marketed as Focalin, Focalin XR), dextroamphetamine (marketed as Dexedrine, Dexedrine Spansules, Dextrostat, and generics), lisdexamfetamine (marketed as Vyvanse), methamphetamine (marketed as Desoxyn), methylphenidate (marketed as Concerta, Daytrana, Metadate CD, Metadate ER, Methylin, Methylin ER, Ritalin, Ritalin-LA, and Ritalin-SR), mixed salts amphetamine (marketed as Adderall and Adderall XR), and pemoline (marketed as Cylert and generics)] used in children with attention-deficit/hyperactivity disorder (ADHD). Rockville, MD; 2009 Jun 23. From the FDA website.

h. Gould MS, Walsh BT, Munfakh JL et al. Sudden death and use of stimulant medications in youths. Am J Psychiatry. 2009; 166:992-1001. [PubMed 19528194]

i. Vitiello B, Towbin K. Stimulant treatment of ADHD and risk of sudden death in children. Am J Psychiatry. 2009; 166:955-7. [PubMed 19528196]

j. US Food and Drug Administration. AHRQ and FDA to collaborate in largest study ever of possible heart risks with ADHD medications. FDA News September 17, 2007. From FDA web site.

More Methamphetamine Hydrochloride resources

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

• Methamphetamine Prescribing Information (FDA)


• Desoxyn Prescribing Information (FDA)


• Desoxyn Concise Consumer Information (Cerner Multum)


• Desoxyn Advanced Consumer (Micromedex) - Includes Dosage Information


• Desoxyn MedFacts Consumer Leaflet (Wolters Kluwer)

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International Apex Dobutamine

International Apex Dobutamine may be available in the countries listed below.

Ingredient matches for International Apex Dobutamine

Dobutamine

Dobutamine hydrochloride (a derivative of Dobutamine) is reported as an ingredient of International Apex Dobutamine in the following countries:

• Philippines

International Drug Name Search

Liquifilm Tears

1. Name Of The Medicinal Product

Liquifilm Tears 1.4% w/v eye drops, solution

2. Qualitative And Quantitative Composition

Polyvinyl alcohol 1.4% w/v

Excipient: Benzalkonium chloride 0.005% w/v

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Eye drops, solution

A clear, colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

As an ocular lubricant for the relief of dry eye and dry eye symptoms.

4.2 Posology And Method Of Administration

Dosage schedule: One to two drops as required or directed for all ages.

Route of administration: Topical instillation into conjunctival sac.

4.3 Contraindications

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

Not for use with soft contact lenses.

4.4 Special Warnings And Precautions For Use

If irritation, pain, redness and changes in vision occur or worsen or persist for more than 72 hours, treatment should be discontinued and a new assessment considered.

To avoid contamination, the dropper tip should not be allowed to touch the eye or any other surface.

Contact lenses should be removed before each application and may be reinserted after 15 minutes.

Liquifilm Tears contain benzalkonium chloride which is irritant to the eye and could cause discolouration of soft lenses. Avoid contact with soft contact lenses. Remove contact lenses before Liquifilm Tears is used and wait for at least 15 minutes before reinsertion.

Concomitant ocular medication should be administered 15 minutes prior to the instillation of Liquifilm Tears.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

4.6 Pregnancy And Lactation

The constituents of Liquifilm Tears have been used as pharmaceutical agents for many years with no untoward effects. No special precautions are necessary for the use of Liquifilm Tears in pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

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

Based upon the information available, Liquifilm Tears has no or negligible influence on the ability to drive and use machines. However, it may cause transient blurring of vision. Do not drive or use hazardous machinery unless vision is clear.

4.8 Undesirable Effects

The following undesirable effects have been reported since Liquifilm Tears was marketed.

Frequency:

Not known: the incidence cannot be determined from available information.

Eye disorders:

Not known: Eye irritation, eye pain, ocular hyperaemia, lacrimation increased, foreign body sensation, eye pruritus.

Immune system disorders:

Not known: hypersensitivity

4.9 Overdose

No case of overdose has been reported.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Artificial tears and other indifferent preparations, ATC code: S01AX20.

Not applicable. Liquifilm Tears contains no pharmacologically active ingredient.

5.2 Pharmacokinetic Properties

Not applicable. Liquifilm Tears contains no pharmacologically active ingredient.

5.3 Preclinical Safety Data

The constituents of Liquifilm Tears have been used safely in pharmaceutical products for many years. Topical administration in animal studies showed no untoward effects.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride

Sodium phosphate dibasic

Sodium phosphate monobasic

Benzalkonium chloride

Edetate disodium

Hydrochloric acid or sodium hydroxide (to adjust pH)

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months unopened.

Discard 28 days after opening.

6.4 Special Precautions For Storage

Do not store above 25°C. Do not refrigerate or freeze.

6.5 Nature And Contents Of Container

Low density polyethylene (LDPE) bottle and tip and medium impact polystyrene (MIPS) screw cap. Safety seal to ensure integrity of the container.

Liquifilm Tears is available in 15ml bottles.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Allergan Ltd

Marlow International

The Parkway

Marlow

Bucks

SL7 1YL

UK

8. Marketing Authorisation Number(S)

PL 00426/0009R

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 19^th September 1974

Date of latest renewal: 10^th October 2005

10. Date Of Revision Of The Text

15 July 2009

Prednisolone Sodium Phosphate Ophthalmic Solution

Dosage Form: ophthalmic solution
Prednisolone Sodium Phosphate

Ophthalmic Solution USP, 1% (Sterile)

Rx only

DESCRIPTION:

Prednisolone Sodium Phosphate Ophthalmic Solution, 1%, is a sterile solution for ophthalmic administration having the following composition:

Each mL Contains:

ACTIVE: Prednisolone Sodium Phosphate 10 mg (1%) [equivalent to 9.1 mg/mL prednisolone phosphate] in a buffered isotonic solution containing INACTIVES: Hypromellose, Monobasic and Dibasic Sodium Phosphate, Sodium Chloride, Edetate Disodium and Purified Water. Sodium Hydroxide and/or Hydrochloric Acid may be added to adjust the pH (6.2 - 8.2).

PRESERVATIVE ADDED: Benzalkonium Chloride 0.01%.

The chemical name for prednisolone sodium phosphate is Pregna-1, 4-diene - 3, 20-dione, 11, 17-dihydroxy-21-(phosphonooxy)-, disodium salt, (11 β) -, which has the following structural formula:

Molecular formula: C21H27Na2O8P

Molecular Weight: 484.39

CLINICAL PHARMACOLOGY:

Prednisolone sodium phosphate causes inhibition of inflammatory response to inciting agents of mechanical, chemical, or immunological nature. No generally accepted explanation of this steroid property has been advanced.

INDICATIONS AND USAGE:

Prednisolone Sodium Phosphate Ophthalmic Solution 1% or 1/8% is for the treatment of steroid responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis when the inherent hazard of steroid use is accepted to obtain an advisable diminution in edema and inflammation, corneal injury from chemical, radiation, or thermal burns, or penetration of foreign bodies.

Prednisolone Sodium Phosphate Ophthalmic Solution, 1%, is recommended for moderate to severe inflammations, particularly when unusually rapid control is desired. In stubborn cases of anterior segment eye disease, systemic adrenocortical hormone therapy may be required. When deeper ocular structures are involved, systemic therapy is necessary.

CONTRAINDICATIONS:

The use of this preparation is contraindicated in the presence of:

1] Acute superficial herpes simplex keratitis.

2] Fungal diseases of ocular structures.

3] Acute infectious stages of vaccinia, varicella and most other viral diseases of the cornea and conjunctiva.

4] Tuberculosis of the eye.

5] Hypersensitivity to a component of this medication.

The use of this preparation is always contraindicated after uncomplicated removal of a superficial corneal foreign body.

WARNINGS:

NOT FOR INJECTION INTO EYE - FOR TOPICAL USE ONLY

Employment of steroid medication in the treatment of herpes simplex keratitis involving the stroma requires great caution; frequent slit-lamp microscopy is mandatory.

Prolonged use may result in elevated intraocular pressure and/or glaucoma, damage to the optic nerve, defects in visual acuity and fields of vision, posterior subcapsular cataract formation, or may aid in the establishment of secondary ocular infections from pathogens liberated from ocular tissues. In those diseases causing thinning of the cornea or sclera, perforation has been known to occur with the use of topical steroids. Acute purulent untreated infection of the eye may be masked or activity enhanced by presence of steroid medication. Viral, bacterial, and fungal infections of the cornea may be exacerbated by the application of steroids.

This drug is not effective in mustard gas keratitis and Sjögren’s keratoconjuncitivitis.

If irritation persists or develops, the patient should be advised to discontinue use and consult prescribing physician.

Precautions

General:

As fungal infections of the cornea are particularly prone to develop coincidentally with long-term steroid applications, fungus invasion must be suspected in any persistent corneal ulceration where a steroid has been used or is in use.

Intraocular pressure should be checked frequently.

Information for Patients:

Do not touch dropper tip to any surface as this may contaminate the solution.

Usage in Pregnancy:

Pregnancy Category C: Animal reproductive studies have not been conducted with prednisolone sodium phosphate. It is also not known whether prednisolone sodium phosphate can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Prednisolone sodium phosphate should be given to a pregnant woman only if clearly needed.

The effect of prednisolone sodium phosphate on the later growth, development and functional maturation of the child is unknown.

Nursing Mothers:

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when prednisolone sodium phosphate is administered to a nursing woman.

Pediatric Use:

Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS:

Glaucoma with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infections from pathogens including herpes simplex and fungi, and perforation of the globe.

Rarely, filtering blebs have been reported when topical steroids have been used following cataract surgery.

Rarely, stinging, or burning may occur.

DOSAGE AND ADMINISTRATION:

Depending on the severity of inflammation, instill one or two drops of solution into the conjunctival sac up to every hour during the day and every two hours during the night as necessary as initial therapy.

When a favorable response is observed, reduce dosage to one drop every four hours.

Later, further reduction in dosage to one drop three to four times daily may suffice to control symptoms.

The duration of treatment will vary with the type of lesion and may extend from a few days to several weeks, according to therapeutic response. Relapses, more common in chronic active lesions than in self-limited conditions, usually respond to retreatment.

HOW SUPPLIED:

Prednisolone Sodium Phosphate Ophthalmic Solution USP, 1% is supplied in a plastic squeeze bottle with a controlled drop tip in the following sizes:

5 mL bottle - Prod. No. 04307

10 mL bottle - Prod. No. 04309

15 mL bottle - Prod. No. 04311

Storage:

Store between 15° - 30° C (59° - 86° F).

Protect from light. Keep tightly closed.

DO NOT USE IF IMPRINTED NECKBAND IS NOT INTACT.

KEEP OUT OF REACH OF CHILDREN.

Bausch & Lomb Incorporated

Tampa, FL 33637

©Bausch & Lomb Incorporated

9101401 (Folded)

9101501 (Flat)

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

NDC 11695-1431-5

Prednisolone Sodium Phosphate Ophthalmic Solution USP, 1%

Rx only

STERILE

5mL

Reorder No. 029897

Distributed Exclusively by:

Butler AHS Dublin, OH 43017

OPHTHIMAL

PREDNISOLONE SODIUM PHOSPHATE  prednisolone sodium phosphate  solution/ drops

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 11695-1431 Route of Administration OPHTHALMIC DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PREDNISOLONE SODIUM PHOSPHATE (PREDNISOLONE) PREDNISOLONE SODIUM PHOSPHATE 10 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength BENZALKONIUM CHLORIDE   SODIUM PHOSPHATE, DIBASIC   EDETATE DISODIUM   HYDROCHLORIC ACID   HYPROMELLOSES   SODIUM PHOSPHATE, MONOBASIC   WATER   SODIUM CHLORIDE   SODIUM HYDROXIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 11695-1431-5 1 BOTTLE In 1 CARTON contains a BOTTLE, DROPPER 1 5 mL In 1 BOTTLE, DROPPER This package is contained within the CARTON (11695-1431-5)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA040070	07/29/1994

Labeler - Butler Animal Health Supply (017880659)

Registrant - Bausch & Lomb Incorporated (196603781)

Establishment
Name	Address	ID/FEI	Operations
Bausch & Lomb Incorporated		807927397	MANUFACTURE

Revised: 11/2010Butler Animal Health Supply

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Drug List: