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MEDOX 50 MICROGRAMS/ML + 5 MG/ML EYE DROPS SOLUTION.

Active substance(s): LATANOPROST / TIMOLOL MALEATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Medox 50 micrograms/ml + 5 mg/ml eye drops, solution.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml solution contains latanoprost 50 micrograms and timolol maleate 6.8 mg
equivalent to 5 mg timolol.
Excipient: Benzalkonium chloride 0.20 mg/ml.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Eye drops, solution.
The solution is a clear, colourless liquid.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Reduction of intraocular pressure (IOP) in patients with open angle glaucoma and
ocular hypertension who are insufficiently responsive to topical beta-blockers or
prostaglandin analogues.

4.2

Posology and method of administration
Recommended dosage for adults (including older people):
Recommended therapy is one eye drop in the affected eye(s) once daily.
If one dose is missed, treatment should continue with the next dose as planned. The
dose should not exceed one drop in the affected eye(s) daily.
Method of administration:
Contact lenses should be removed before instillation of the eye drops and may be
reinserted after 15 minutes.

When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic
absorption is reduced. This may result in a decrease in systemic side effects and an
increase in local activity.
If more than one topical ophthalmic drug is being used, the drugs should be
administered at least five minutes apart.
Paediatric population:
Safety and effectiveness in children and adolescents has not been established. No data
are available.

4.3

Contraindications
Medox is contraindicated in patients with:
• Hypersensitivity to the active substances or to any of the excipients listed in
section 6.1.
• Reactive airway disease including bronchial asthma or a history of bronchial
asthma, severe chronic obstructive pulmonary disease.
• Sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third
degree atrioventricular block not controlled with pace-maker, overt cardiac
failure, cardiogenic shock.

4.4

Special warnings and precautions for use
Systemic effects:
Like other topically applied ophthalmic agents, Medox is absorbed systemically. Due
to the beta-adrenergic component timolol, the same types of cardiovascular,
pulmonary and other adverse reactions as seen with systemic beta-adrenergic
blocking agents may occur. Incidence of systemic ADRs after topical ophthalmic
administration is lower than for systemic administration. To reduce the systemic
absorption, see 4.2.
Cardiac disorders:
In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's
Angina and cardiac failure) and hypotension therapy with beta-blockers should be
critically assessed and the therapy with other active substances should be considered.
Patients with cardiovascular diseases should be watched for signs of deterioration of
these diseases and of adverse reactions.
Due to its negative effect on conduction time, beta-blockers should only be given
with caution to patients with first degree heart block.
Cardiac reactions, and rarely, death in association with cardiac failure have been
reported following administration of timolol.
Vascular disorders:
Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of
Raynaud's disease or Raynaud's syndrome) should be treated with caution.
Respiratory disorders:
Respiratory reactions, including death due to bronchospasm in patients with asthma
have been reported following administration of some ophthalmic beta-blockers.
Medox should be used with caution, in patients with mild/moderate chronic

obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the
potential risk.
Hypoglycemia/diabetes:
Beta-blockers should be administered with caution in patients subject to spontaneous
hypoglycaemia or to patients with labile diabetes, as beta-blockers may mask the
signs and symptoms of acute hypoglycaemia.
Beta-blockers may also mask the signs of hyperthyroidism.
Surgical anaesthesia:
Beta-blocking ophthalmological preparations may block systemic beta-agonist effects
e.g. of adrenaline. The anaesthesiologist should be informed when the patient is
receiving timolol.
Corneal diseases:
Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases
should be treated with caution.
Other beta-blocking agents:
The effect on intra-ocular pressure or the known effects of systemic beta-blockade
may be potentiated when timolol is given to the patients already receiving a systemic
beta-blocking agent. The response of these patients should be closely observed. The
use of two topical beta-adrenergic blocking agents is not recommended (see section
4.5).
Anaphylactic reactions:
While taking beta-blockers, patients with a history of atopy or a history of severe
anaphylactic reaction to a variety of allergens may be more reactive to repeated
challenge with such allergens and unresponsive to the usual doses of adrenaline used
to treat anaphylactic reactions.
Choroidal detachment:
Choroidal detachment has been reported with administration of aqueous suppressant
therapy (e.g. timolol, acetazolamide) after filtration procedures.
Concomitant therapy:
Timolol may interact with other drugs see 4.5 Interaction with other medicinal
products and other forms of interaction.
The use of two local beta-blockers or two local prostaglandins is not recommended.
Ocular effects:
Latanoprost may gradually change eye colour by increasing the amount of brown
pigment in the iris. Similar to experience with latanoprost eye drops, increased iris
pigmentation was seen in16-20% of all patients treated with Medox for up to one year
(based on photographs). This effect has predominantly been seen in patients with
mixed coloured irides, i.e. green-brown, yellow-brown or blue/grey-brown, and is due
to increased melanin content in the stromal melanocytes of the iris. Typically, the
brown pigmentation around the pupil spreads concentrically towards the periphery in
affected eyes, but the entire iris or parts of it may become more brownish. In patients
with homogeneously blue, grey, green or brown eyes, the change has only rarely been
seen during two years of treatment in clinical trials with latanoprost.
The change in iris colour occurs slowly and may not be noticeable for several months
to years and it has not been associated with any symptom or pathological changes.
No further increase in brown iris pigment has been observed after discontinuation of
treatment, but the resultant colour change may be permanent.
Neither naevi nor freckles of the iris have been affected by the treatment.

Accumulation of pigment in the trabecular meshwork or elsewhere in the anterior
chamber has not been observed but patients should be examined regularly and,
depending on the clinical situation, treatment may be stopped if increased iris
pigmentation ensues.
Before treatment is instituted patients should be informed of the possibility of a
change in eye colour. Unilateral treatment can result in permanent heterochromia.
There is no documented experience with latanoprost in inflammatory, neovascular,
chronic angle closure or congenital glaucoma, in open angle glaucoma of
pseudophakic patients and in pigmentary glaucoma. Latanoprost has no or little effect
on the pupil but there is no documented experience in acute attacks of closed angle
glaucoma. Therefore it is recommended that Medox should be used with caution in
these conditions until more experience is obtained.
Latanoprost should be used with caution in patients with a history of herpetic
keratitis, and should be avoided in cases of active herpes simplex keratitis and in
patients with a history of recurrent herpetic keratitis specifically associated with
prostaglandin analogues.
Macular oedema, including cystoid macular oedema, has been reported during
treatment with latanoprost. These reports have mainly occurred in aphakic patients, in
pseudophakic patients with a torn posterior lens capsule, or in patients with known
risk factors for macular oedema. Medox should be used with caution in these patients.
Use of contact lenses:
Medox contains benzalkonium chloride, which is commonly used as a preservative in
ophthalmic products. Benzalkonium chloride has been reported to cause punctuate
keratopathy and/or toxic ulcerative keratopathy, may cause eye irritation and is
known to discolour soft contact lenses. Close monitoring is required with frequent or
prolonged use of Medox in dry eye patients, or in conditions where the cornea is
compromised. Contact lenses may absorb benzalkonium chloride and these should be
removed before applying Medox but may be reinserted after 15 minutes (see section
4.2 Posology and Method of Administration).
Paediatric population
Medox is not recommended for use in children or adolescent (see section 4.2)

4.5

Interaction with other medicinal products and other forms of interaction
No specific drug interaction studies have been performed with Medox.
There have been reports of paradoxical elevations in intraocular pressure following
the concomitant ophthalmic administration of two prostaglandin analogues.
Therefore, the use of two or more prostaglandins, prostaglandin analogues, or
prostaglandin derivatives is not recommended.
There is a potential for additive effects resulting in hypotension and/or marked
bradycardia when ophthalmic beta-blockers solution is administered concomitantly
with oral calcium channel blockers, beta-adrenergic blocking agents, antiarrhythmics
(including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine.
Potentiated systemic beta blockade (e.g., decreased heart rate, depression) has been
reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine,
fluoxetine, paroxetine) and timolol.
The effect on intraocular pressure or the known effects of systemic beta-blockade
may be potentiated when Medox is given to patients already receiving an oral betaadrenergic blocking agent, and the use of two or more topical beta-adrenergic
blocking agents is not recommended.
Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline
(epinephrine) has been reported occasionally.

The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when
taking beta-blockers.
Beta-blockers may increase the hypoglycaemic effect of anti-diabetic agents. Betablockers can mask the signs and symptoms of hypoglycaemia (see 4.4 Special
warnings and special precautions for use).
Paediatric population
No interaction studies have been reported.

4.6

Fertility, pregnancy and lactation
Fertility
Neither latanoprost nor timolol have been found to have any effect on male or female
fertility in animal studies.
Pregnancy
Latanoprost:
There are no adequate data from the use of latanoprost in pregnant women. Studies in
animals have shown reproductive toxicity (see 5.3). The potential risk for humans is
unknown.
Timolol:
There are no adequate data for the use of timolol in pregnant women. Timolol should
not be used during pregnancy unless clearly necessary. To reduce the systemic
absorption, see 4.2.
Epidemiological studies have not revealed malformative effects but show a risk for
intra uterine growth retardation when betablockers are administered by the oral route.
In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension,
respiratory distress and hypoglycaemia) have been observed in the neonate when
beta-blockers have been administered until delivery. If Medox is administered until
delivery, the neonate should be carefully monitored during the first days of life.
Consequently Medox should not be used during pregnancy (see 5.3).
Lactation
Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in
eye drops it is not likely that sufficient amounts would be present in breast milk to
produce clinical symptoms of beta-blockade in the infant. To reduce the systemic
absorption, see 4.2.
Latanoprost and its metabolites may pass into breast milk. Medox should therefore
not be used in women who are breast feeding.

4.7

Effects on ability to drive and use machines
Instillation of eye drops may cause transient blurring of vision. Until this has
resolved, patients should not drive or use machines

4.8

Undesirable effects
Like other topically applied ophthalmic drugs, timolol is absorbed into the systemic
circulation. This may cause similar undesirable effects as seen with systemic beta
blocking agents. Incidence of systemic ADRs after topical ophthalmic administration
is lower than for systemic administration. Listed adverse reactions include reactions
seen within the class of ophthalmic beta-blockers.

For latanoprost, the majority of adverse events relate to the ocular system. In data
from the extension phase of the Medox eye drops pivotal trials, 16 - 20% of patients
developed increased iris pigmentation, which may be permanent. In an open 5 year
latanoprost safety study, 33% of patients developed iris pigmentation (see 4.4). Other
ocular adverse events are generally transient and occur on dose administration. For
timolol, the most serious adverse events are systemic in nature, including
bradycardia, arrhythmia, congestive heart failure, bronchospasm and allergic
reactions.
Treatment related adverse events seen in clinical trials with Medox are listed below.
Adverse events are categorized by frequency as follows: very common (≥1/10),
common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), rare (≥ 1/10,000 to
<1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the
available data).
Nervous System Disorders
Uncommon: Headache.
Eye Disorders
Very common: Increased iris pigmentation.
Common: Eye irritation (including stinging, burning and itching), Eye pain
Uncommon: Eye hyperaemia, Conjunctivitis, Vision blurred, Lacrimation increased,
Blepharitis, Corneal disorders
Skin and Subcutaneous Tissue Disorders
Uncommon: Skin rash, Pruritus
Additional adverse events have been reported specific to the use of the individual
components of Medox either in clinical studies, spontaneous reports or in the
available literature.
For latanoprost, these are:
Infections and Infestations:
Herpetic Keratitis
Nervous System Disorders:
Dizziness.
Eye Disorders:
Eyelash and vellus hair changes (increased length, thickness, pigmentation, and
number), punctate epithelial erosions, periorbital oedema, iritis/uveitis, macular
oedema (in aphakic, pseudophakic patients with torn posterior lens capsules or in
patients with known risk factors for macular oedema). Dry eye, keratitis, corneal
oedema and erosions, misdirected eyelashes sometimes resulting in eye irritation,
iris cyst, photophobia, periorbital and lid changes resulting in deepening of the eyelid
sulcus.
Cardiac Disorders:
Aggravation of angina in patients with pre-existing disease, palpitations.
Respiratory, Thoracic and Mediastinal Disorders:
Asthma, asthma aggravation, dyspnoea.

Skin and Subcutaneous Tissue Disorders:
Darkening of palpebral skin.
Musculoskeletal and Connective Tissue Disorders:
Joint pain, muscle pain.
General disorders and Administration Site Conditions:
Chest pain
For timolol, these are:
Immune System Disorders:
Systemic allergic reactions including angioedema, urticaria, localized and generalized
rash, pruritus, anaphylactic reaction.
Metabolism and nutrition disorders:
Hypoglycaemia.
Psychiatric Disorders:
Insomnia, depression, nightmares, memory loss.
Nervous System Disorders:
Syncope, cerebrovascular accident, cerebral ischaemia, increase in signs and
symptoms of myasthenia gravis, dizziness, paresthesia, and headache.
Eye Disorders:
Signs and symptoms of ocular irritation (e.g., burning, stinging, itching, tearing,
redness), blepharitis, keratitis, blurred vision and choroidal detachment following
filtration surgery (see 4.4 Special warnings and special precautions for use).
Decreased corneal sensitivity, dry eyes, corneal erosion ptosis, diplopia.
Ear and Labyrinth Disorders:
Tinnitus.
Cardiac Disorders:
Bradycardia, chest pain, palpitations, oedema, arrhythmia, congestive heart failure,
atrioventricular block, cardiac arrest, cardiac failure.
Vascular Disorders:
Hypotension, Raynaud's phenomenon, cold hands and feet.
Respiratory, Thoracic and Mediastinal Disorders:
Bronchospasm (predominately in patients with pre-existing bronchospastic disease),
dyspnoea, cough.
Gastrointestinal Disorders:
Dysgeusia, nausea, dyspepsia, diarrhoea, dry mouth, abdominal pain, vomiting.
Skin and Subcutaneous Tissue Disorders:
Alopecia, psoriasis form rash or exacerbation of psoriasis, skin rash.
Musculoskeletal and connective tissue disorders:
Myalgia.
Reproductive system and breast disorders:

Sexual dysfunction, decreased libido.
General disorders and administration site conditions:
Asthenia/fatigue.
Cases of corneal calcification have been reported very rarely in association with the
use of phosphate containing eye drops in some patients with significantly damaged
corneas.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at:www.mhra.gov.uk/yellowcard.

4.9

Overdose
No data are available in humans with regard to overdose with Medox.
Symptoms of systemic timolol overdose are: bradycardia, hypotension, bronchospasm
and cardiac arrest. If such symptoms occur the treatment should be symptomatic and
supportive. Studies have shown that timolol does not dialyse readily.
Apart from ocular irritation and conjunctival hyperaemia, no other ocular or systemic
side effects are known if latanoprost is overdosed.
If latanoprost is accidentally ingested orally the following information may be useful:
Treatment: Gastric lavage if needed. Symptomatic treatment. Latanoprost is
extensively metabolised during the first pass through the liver. Intravenous infusion
of 3 micrograms/kg in healthy volunteers induced no symptoms, but a dose of 5.5-10
micrograms/kg caused nausea, abdominal pain, dizziness, fatigue, hot flushes and
sweating. These events were mild to moderate in severity and resolved without
treatment, within 4 hours after terminating the infusion.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Ophthalmological-betablocking agents - timolol,
combinations
ATC code: S01ED51
Mechanism of action
Medox consists of two components: latanoprost and timolol maleate. These two
components decrease elevated intraocular pressure (IOP) by different mechanisms of
action and the combined effect results in additional IOP reduction compared to either
compound administered alone.
Latanoprost, a prostaglandin F2alpha analogue, is a selective prostanoid FP receptor
agonist that reduces the IOP by increasing the outflow of aqueous humour. The main
mechanism of action is increased uveoscleral outflow. Additionally, some increase in
outflow facility (decrease in trabecular outflow resistance) has been reported in man.
Latanoprost has no significant effect on the production of aqueous humour, the bloodaqueous barrier or the intraocular blood circulation. Chronic treatment
with latanoprost in monkey eyes, which had undergone extracapsular lens extraction
did not affect the retinal blood vessels as determined by fluorescein angiography.

Latanoprost has not induced fluorescein leakage in the posterior segment of
pseudophakic human eyes during short term treatment.
Timolol is a beta-1 and beta-2 (non-selective) adrenergic receptor blocking agent that
has no significant intrinsic sympathomimetic, direct myocardial depressant or
membrane-stabilising activity. Timolol lowers IOP by decreasing the formation of
aqueous in the ciliary epithelium.
The precise mechanism of action is not clearly established, but inhibition of the
increased cyclic AMP synthesis caused by endogenous beta-adrenergic stimulation is
probable. Timolol has not been found to significantly affect the permeability of the
blood-aqueous barrier to plasma proteins. In rabbits, timolol was without effect on the
regional ocular blood flow after chronic treatment.
Pharmacodynamic effects
Clinical effects
In dose finding studies, Medox produced significantly greater decreases in mean
diurnal IOP compared to latanoprost and timolol administered once daily as
monotherapy. In two well controlled, double masked six-month clinical studies the
IOP reducing effect of Medox was compared with latanoprost and timolol
monotherapy in patients with an IOP of at least 25 mm Hg or greater. Following a 2-4
week run-in with timolol (mean decrease in IOP from enrollment of 5 mm Hg),
additional decreases in mean diurnal IOP of 3.1, 2.0 and 0.6 mm Hg were observed
after 6 months of treatment for Medox, latanoprost and timolol (twice daily),
respectively. The IOP lowering effect of Medox was maintained in 6-month open
label extension of these studies.
Existing data suggest that evening dosing may be more effective in IOP lowering than
morning dosing. However, when considering a recommendation of either morning or
evening dosing, sufficient consideration should be given to the lifestyle of the patient
and their likely compliance.
It should be kept in mind that in case of insufficient efficacy of the fixed combination,
results from studies indicate that the use of unfixed administration of timolol bid and
latanoprost once a day might be still efficient.
Onset of action of Medox is within one hour and maximal effect occurs within six to
eight hours. Adequate IOP reducing effect has been shown to be present up to 24
hours post dosage after multiple treatments.

5.2

Pharmacokinetic properties
Latanoprost
Latanoprost is an isopropyl ester prodrug, which per se is inactive but after hydrolysis
by esterases in the cornea to the acid of latanoprost, becomes biologically active. The
prodrug is well absorbed through the cornea and all drug that enters the aqueous
humor is hydrolysed during the passage through the cornea. Studies in man indicate
that the maximum concentration in the aqueous humour, approximately 15-30 ng/ml,
is reached about 2 hours after topical administration of latanoprost alone. After
topical application in monkeys latanoprost is distributed primarily in the anterior
segment, the conjunctiva and the eye lids.
The acid of latanoprost has a plasma clearance of 0.40 l/h/kg and a small volume of
distribution, 0.16 l/kg, resulting in a rapid half life in plasma, 17 minutes. After
topical ocular administration the systemic bioavailability of the acid of latanoprost is
45%.
The acid of latanoprost has a plasma protein binding of 87%.

There is practically no metabolism of the acid of latanoprost in the eye. The main
metabolism occurs in the liver. The main metabolites, the 1,2-dinor and 1,2,3,4tetranor metabolites, exert no or only weak biological activity in animal studies and
are excreted primarily in the urine.
Timolol
The maximum concentration of timolol in the aqueous humour is reached about 1
hour after topical administration of eye drops.
Part of the dose is absorbed systemically and a maximum plasma concentration of 1
ng/ml is reached 10-20 minutes after topical administration of one eye drop to each
eye once daily (300 micrograms/day). The half life of timolol in plasma is about 6
hours. Timolol is extensively metabolised in the liver. The metabolites are excreted in
the urine together with some unchanged timolol.
Medox
No pharmacokinetic interactions between latanoprost and timolol were observed,
although there was an approximate 2-fold increased concentration of the acid of
latanoprost in aqueous humour 1-4 hours after administration of Medox compared to
monotherapy.
Paediatric population
The safety and effectiveness of Medox in children and adolescents from birth to 18
years of age has not been established.

5.3

Preclinical safety data
The ocular and systemic safety profile of the individual components is well
established. No adverse ocular or systemic effects were seen in rabbits treated
topically with the fixed combination or with concomitantly administered latanoprost
and timolol ophthalmic solutions. Safety pharmacology, genotoxicity and
carcinogenicity studies with each of the components revealed no special hazards for
humans. Latanoprost did not affect corneal wound healing in the rabbit eye, whereas
timolol inhibited the process in the rabbit and the monkey eye when administered
more frequently than once a day.
For latanoprost, no effects on male and female fertility in rats and no teratogenic
potential in rats and rabbits have been established. No embryotoxicity was observed
in rats after intravenous doses of up to 250 micrograms/kg/day. However, latanoprost
caused embryofetal toxicity, characterised by increased incidence of late resorption
and abortion and by reduced foetal weight, in rabbits at intravenous doses of 5
micrograms/kg/day (approximately 100 times the clinical dose) and above.

Timolol showed no effects on male and female fertility in rats or teratogenic
potential in mice, rats and rabbits.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sodium chloride
Benzalkonium chloride (50% solution)
Sodium dihydrogen phosphate monohydrate
Disodium phosphate anhydrous
Hydrochloric acid solution (for pH adjustment)
Sodium hydroxide solution (for pH adjustment)

Water for injections

6.2

Incompatibilities
In vitro studies have shown that precipitation occurs when eye drops containing
thiomersal are mixed with latanoprost and timolol eye drops. If such drugs are used
concomitantly with Medox, the eye drops should be administered with an interval of
at least five minutes.

6.3

Shelf life
3 years
After opening of container: 4 weeks

6.4

Special precautions for storage
Store in a refrigerator (2°C – 8°C)
Opened bottle: Do not store above 25°C.
Keep the bottle in the outer carton in order to protect from light.

6.5

Nature and contents of container
LDPE bottle (5 ml) and dropper applicator (dropper tip), PP screw cap, tamper
evident LDPE overcap.
Each bottle contains 2.5 ml eye drop solution.
Pack sizes:
1 × 2.5 ml
3 × 2.5 ml
6 × 2.5 ml
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements

7

MARKETING AUTHORISATION HOLDER
MEDICOM HEALTHCARE LTD
235 Hunts Pond Road, Titchfield Common, PO14 4PJ
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 18956/0020

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
05/05/2017

10

DATE OF REVISION OF THE TEXT
09/08/2017

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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