STRONTIUM RANELATE 2 G GRANULES FOR ORAL SUSPENSION
Active substance(s): STRONTIUM RANELATE / STRONTIUM RANELATE / STRONTIUM RANELATE
This medicinal product is subject to additional monitoring. This will allow quick
identification of new safety information. Healthcare professionals are asked to report
any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
NAME OF THE MEDICINAL PRODUCT
Strontium ranelate 2 g granules for oral suspension
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each sachet contains 2 g of strontium ranelate.
Excipient with known effect:
Each sachet also contains 20 mg of aspartame (E951).
For the full list of excipients, see section 6.1.
Granules for oral suspension.
White to slightly yellow granules.
Treatment of severe osteoporosis:
- in postmenopausal women,
- in adult men,
at high risk of fracture, for whom treatment with other medicinal products approved
for the treatment of osteoporosis is not possible due to, for example, contraindications
or intolerance. In postmenopausal women, strontium ranelate reduces the risk of
vertebral and hip fractures (see section 5.1).
The decision to prescribe strontium ranelate should be based on an assessment of the
individual patient's overall risks (see sections 4.3 and 4.4).
Posology and method of administration
Treatment should only be initiated by a physician with experience in the treatment of
The recommended dose is one 2 g sachet once daily by oral administration.
Due to the nature of the treated disease, strontium ranelate is intended for long-term
The absorption of strontium ranelate is reduced by food, milk and derivative products
and therefore, Strontium granules for oral suspension should be administered inbetween meals. Given the slow absorption, Strontium granules for oral suspension
should be taken at bedtime, preferably at least two hours after eating (see sections 4.5
Patients treated with strontium ranelate should receive vitamin D and calcium
supplements if dietary intake is inadequate.
The efficacy and safety of strontium ranelate have been established in a broad age
range (up to 100 years at inclusion) of adult men and postmenopausal women with
osteoporosis. No dose adjustment is required in relation to age.
Patients with renal impairment
Strontium ranelate is not recommended for patients with severe renal impairment
(creatinine clearance below 30 ml/min) (see sections 4.4 and 5.2).No dose adjustment
is required in patients with mild-to-moderate renal impairment (30-70 ml/min
creatinine clearance) (see sections 4.4 and 5.2).
Patients with hepatic impairment
No dose adjustment is required in patients with hepatic impairment (see section 5.2).
The safety and efficacy of Strontium granules for oral suspension in children aged
below 18 years have not been established. No data are available.
Method of administration
For oral use.
The granules in the sachets must be taken as a suspension in a glass containing a
minimum of 30 ml (approximately one third of a standard glass) of water.
Although in-use studies have demonstrated that strontium ranelate is stable in
suspension for 24 hours after preparation, the suspension should be drunk
immediately after being prepared.
- Hypersensitivity to the active substance or to any of the excipients listed in section
- Current or previous venous thromboembolic events (VTE), including deep vein
thrombosis and pulmonary embolism.
- Temporary or permanent immobilisation due to e.g. post-surgical recovery or
prolonged bed rest.
- Established, current or past history of ischaemic heart disease, peripheral arterial
disease and/or cerebrovascular disease.
- Uncontrolled hypertension.
Special warnings and precautions for use
Cardiac ischaemic events
In pooled randomised placebo-controlled studies of post-menopausal osteoporotic
patients, a significant increase in myocardial infarction has been observed in
Strontium granules for oral suspension treated patients compared to placebo (see
Before starting treatment, patients should be evaluated with respect to cardiovascular
Patients with significant risk factors for cardiovascular events (e.g. hypertension,
hyperlipidaemia, diabetes mellitus, smoking) should only be treated with strontium
ranelate after careful consideration (see sections 4.3 and 4.8).
During Strontium granules for oral suspension treatment, these cardiovascular risks
should be monitored on a regular basis generally every 6 to 12 months.
Treatment should be stopped if the patient develops ischaemic heart disease,
peripheral arterial disease, cerebrovascular disease or if hypertension is uncontrolled
(see section 4.3).
In phase III placebo-controlled studies, strontium ranelate treatment was associated
with an increase in the annual incidence of venous thromboembolism (VTE),
including pulmonary embolism (see section 4.8). The cause of this finding is
unknown. Strontium granules for oral suspension is contra-indicated in patients with a
past history of venous thromboembolic events (see section 4.3) and should be used
with caution in patients at risk of VTE.
When treating patients over 80 years at risk of VTE, the need for continued treatment
with Strontium granules for oral suspension should be re-evaluated. Strontium
granules for oral suspension should be discontinued as soon as possible in the event
of an illness or a condition leading to immobilisation (see section 4.3) and adequate
preventive measures taken. Therapy should not be restarted until the initiating
condition has resolved and the patient is fully mobile. When a VTE occurs, Strontium
granules for oral suspension should be stopped.
Use in patients with renal impairment
In the absence of bone safety data in patients with severe renal impairment treated
with strontium ranelate, Strontium granules for oral suspension is not recommended
in patients with a creatinine clearance below 30 ml/min (see section 5.2). In
accordance with good medical practice, periodic assessment of renal function is
recommended in patients with chronic renal impairment. Continuation of treatment
with Strontium granules for oral suspension in patients developing severe renal
impairment should be considered on an individual basis.
Life-threatening cutaneous reactions (Stevens-Johnson syndrome (SJS), toxic
epidermal necrolysis (TEN) and drug rash with eosinophilia and systemic symptoms
(DRESS)) have been reported with the use of strontium ranelate.
Patients should be advised of the signs and symptoms and monitored closely for skin
reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of
treatment and usually around
3-6 weeks for DRESS.
If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or
mucosal lesions) or DRESS (e.g. rash, fever, eosinophilia and systemic involvement
(e.g. adenopathy, hepatitis, interstitial nephropathy, interstitial lung disease) are
present, Strontium granules for oral suspension treatment should be discontinued
The best results in managing SJS, TEN or DRESS come from early diagnosis and
immediate discontinuation of any suspect drug. Early withdrawal is associated with a
better prognosis. The outcome of DRESS is favorable in most cases upon
discontinuation of strontium ranelate and after initiation of corticosteroid therapy
when necessary. Recovery could be slow and recurrences of the syndrome have been
reported in some cases after discontinuation of corticosteroid therapy.
If the patient has developed SJS, TEN or DRESS with the use of Strontium granules
for oral suspension, Strontium granules for oral suspension must not be re-started in
this patient at any time.
A higher incidence, although still rare, of hypersensitivity reactions including skin
rash, SJS or TEN in patients of Asian origin has been reported.
Interaction with laboratory test
Strontium interferes with colorimetric methods for the determination of blood and
urinary calcium concentrations. Therefore, in medical practice, inductively coupled
plasma atomic emission spectrometry or atomic absorption spectrometry methods
should be used to ensure an accurate assessment of blood and urinary calcium
Strontium granules for oral suspension contains aspartame, a source of phenylalanine,
which may be harmful for people with phenylketonuria.
Interaction with other medicinal products and other forms of interaction
Food, milk and derivative products, and medicinal products containing calcium may
reduce the bioavailability of strontium ranelate by approximately 60-70%. Therefore,
administration of Strontium granules for oral suspension and such products should be
separated by at least two hours (see sections 4.2 and 5.2).
As divalent cations can form complexes with oral tetracycline (e.g. doxycycline) and
quinolone antibiotics (e.g. ciprofloxacin) at the gastro-intestinal level and thereby
reduce their absorption, simultaneous administration of strontium ranelate with these
medicinal products is not recommended. As a precautionary measure, Strontium
granules for oral suspension treatment should be suspended during treatment with
oral tetracycline or quinolone antibiotics.
An in vivo clinical interaction study showed that the administration of aluminium and
magnesium hydroxides either two hours before or together with strontium ranelate
caused a slight decrease in the absorption of strontium ranelate (20-25% AUC
decrease), while absorption was almost unaffected when the antacid was given two
hours after strontium ranelate. It is therefore preferable to take antacids at least two
hours after Strontium granules for oral suspension. However, when this dosing
regimen is impractical due to the recommended administration of Strontium granules
for oral suspension at bedtime, concomitant intake remains acceptable.
No interaction was observed with oral supplementation of vitamin D.
No evidence of clinical interactions or relevant increase of blood strontium levels
with medicinal products expected to be commonly prescribed concomitantly with
strontium ranelate in the target population were found during clinical trials. These
included: nonsteroidal anti-inflammatory agents (including acetylsalicylic acid),
anilides (such as paracetamol), H2 blockers and proton pump inhibitors, diuretics,
digoxin and cardiac glycosides, organic nitrates and other vasodilators for cardiac
diseases, calcium channel blockers, beta blockers, ACE inhibitors, angiotensin II
antagonists, selective beta-2 adrenoceptor agonists, oral anticoagulants, platelet
aggregation inhibitors, statins, fibrates and benzodiazepine derivatives.
Fertility, pregnancy and lactation
There are no data from the use of strontium ranelate in pregnant women.
At high doses, animal studies have shown reversible bone effects in the offspring of
rats and rabbits treated during pregnancy (see section 5.3). If Strontium granules for
oral suspension is used inadvertently during pregnancy, treatment must be stopped.
Physico-chemical data suggest excretion of Strontium ranelate in human milk.
Strontium granules for oral suspension should not be used during breast-feeding.
No effects were observed on males and females fertility in animal studies.
Effects on ability to drive and use machines
Strontium ranelate has no or negligible influence on the ability to drive and use
Summary of the safety profile
Strontium ranelate has been studied in clinical trials involving nearly 8,000
participants. Long-term safety has been evaluated in postmenopausal women with
osteoporosis treated for up to 60 months with strontium ranelate 2 g/day (n=3,352) or
placebo (n=3,317) in phase III studies. Mean age was 75 years at inclusion and 23%
of the patients enrolled were 80 to 100 years of age.
In a pooled analysis of randomised placebo-controlled studies in post-menopausal
osteoporotic patients, the most common adverse reactions consisted of nausea and
diarrhoea, which were generally reported at the beginning of treatment with no
noticeable difference between groups afterwards. Discontinuation of therapy was
mainly due to nausea.
There were no differences in the nature of adverse reactions between treatment
groups regardless of whether patients were aged below or above 80 at inclusion.
Tabulated list of adverse reactions
The following adverse reactions have been reported during clinical studies and/or
post marketing use with strontium ranelate.
Adverse reactions are listed below using the following convention: very common
(≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare
(≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from
the available data).
System Organ Class
Blood and lymphatic Uncommon
Metabolism and nutrition Common
Nervous system disorders Common
Ear and labyrinth disorders Common
Respiratory, thoracic and Common
Skin and subcutaneous Very common
Lymphadenopathy (in association
Bone marrow failure#
Eosinophilia (in association with
hypersensitivity skin reactions)
Disturbances in consciousness
Venous thromboembolism (VTE)
Diarrhoea and Loose stools
Oral mucosal irritation (stomatitis
and/or mouth ulceration)
Serum transaminase increased (in
association with hypersensitivity
Hypersensitivity skin reactions
Drug Reaction with Eosinophilia
and Systemic Symptoms (DRESS)
(see section 4.4)#
Severe cutaneous adverse reactions
and Very common
connective tissue disorders
toxic epidermal necrolysis* (see
Musculoskeletal pain (muscle
spasm, myalgia, bone pain,
arthralgia and pain in extremity)§
Pyrexia (in association with
hypersensitivity skin reactions)
Blood Creatine phosphokinase
§ Frequency in Clinical Trials was similar in the drug and placebo group.
* In Asian countries reported as rare
# For adverse reaction not observed in clinical trials, the upper limit of the 95%
confidence interval is not higher than 3/X with X representing the total sample size
summed up across all relevant clinical trials and studies.
Musculo-skeletal fraction > 3 times the upper limit of the normal range. In most
cases, these values spontaneously reverted to normal without change in treatment.
Description of selected adverse reactions
In phase III studies, the annual incidence of venous thromboembolism (VTE)
observed over 5 years was approximately 0.7%, with a relative risk of 1.4 (95% CI =
[1.0 ; 2.0]) in strontium ranelate treated patients as compared to placebo (see section
In pooled randomised placebo-controlled studies of post-menopausal osteoporotic
patients, a significant increase of myocardial infarction has been observed in
strontium ranelate treated patients as compared to placebo (1.7% versus 1.1 %), with
a relative risk of 1.6 (95% CI = [1.07 ; 2.38]).
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.
Good tolerance was shown in a clinical study investigating the repeated
administration of 4 g strontium ranelate per day over 25 days in healthy
postmenopausal women. Single administration of doses up to 11 g in healthy young
male volunteers did not cause any particular symptoms.
Following episodes of overdoses during clinical trials (up to 4 g/day for a maximal
duration of 147 days), no clinically relevant events were observed.
Administration of milk or antacids may be helpful to reduce the absorption of the
active substance. In the event of substantial overdose, vomiting may be considered to
remove unabsorbed active substance.
Pharmacotherapeutic group: Drugs for the treatment of bone diseases - Other drugs
affecting bone structure and mineralisation, ATC code: M05BX03.
Mechanism of action
In vitro, strontium ranelate:
- increases bone formation in bone tissue culture as well as osteoblast precursor
replication and collagen synthesis in bone cell culture.
- reduces bone resorption by decreasing osteoclast differentiation and resorbing
This results in a rebalance of bone turnover in favour of bone formation.
The activity of strontium ranelate was studied in various non-clinical models. In
particular, in intact rats, strontium ranelate increases trabecular bone mass, trabeculae
number and thickness; this results in an improvement of bone strength.
In bone tissue of treated animals and humans, strontium is mainly adsorbed onto the
crystal surface and only slightly substitutes for calcium in the apatite crystal of newly
formed bone. Strontium ranelate does not modify the bone crystal characteristics. In
iliac crest bone biopsies obtained after up to 60 months of treatment with strontium
ranelate 2 g/day in phase III trials, no deleterious effects on bone quality or
mineralisation were observed.
The combined effects of strontium distribution in bone (see section 5.2) and increased
X-ray absorption of strontium as compared to calcium, leads to an amplification of
bone mineral density (BMD) measurement by dual-photon X-ray absorptiometry
(DXA). Available data indicate that these factors account for approximately 50% of
the measured change in BMD over 3 years of treatment with strontium ranelate 2
g/day. This should be taken into account when interpreting BMD changes during
treatment with strontium ranelate. In phase III studies, which demonstrated the anti-
fracture efficacy of strontium ranelate treatment, measured mean BMD increased
from baseline with strontium ranelate by approximately 4% per year at the lumbar
spine and 2% per year at the femoral neck, reaching 13% to 15% and 5% to 6%
respectively after 3 years, depending on the study.
In phase III studies, as compared to placebo, biochemical markers of bone formation
(bone-specific alkaline phosphatase and C-terminal propeptide of type I procollagen)
increased and those of bone resorption (serum C-telopeptide and urinary Ntelopeptide cross links) decreased from the third month of treatment up to 3 years.
Secondary to the pharmacological effects of strontium ranelate, slight decreases in
calcium and parathyroid hormone (PTH) serum concentrations, increases in blood
phosphorus concentrations and in total alkaline phosphatase activity were observed,
with no observed clinical consequences.
Osteoporosis is defined as BMD of the spine or hip 2.5 SD or more below the mean
value of a normal young population. A number of risk factors are associated with
postmenopausal osteoporosis including low bone mass, low bone mineral density,
early menopause, a history of smoking and a family history of osteoporosis. The
clinical consequence of osteoporosis is fractures. The risk of fractures is increased
with the number of risk factors.
Treatment of postmenopausal osteoporosis:
The anti-fracture studies program of strontium ranelate was made up of two placebocontrolled phase III studies: SOTI study and TROPOS study. SOTI involved 1,649
postmenopausal women with established osteoporosis (low lumbar BMD and
prevalent vertebral fracture) and a mean age of 70 years. TROPOS involved 5,091
postmenopausal women with osteoporosis (low femoral neck BMD and prevalent
fracture in more than half of them) and a mean age of 77 years. Together, SOTI and
TROPOS enrolled 1,556 patients over 80 years at inclusion (23.1% of the study
population). In addition to their treatment (2 g/day strontium ranelate or placebo), the
patients received adapted calcium and vitamin D supplements throughout both
Strontium ranelate reduced the relative risk of new vertebral fracture by 41% over 3
years in the SOTI study (table 1). The effect was significant from the first year.
Similar benefits were demonstrated in women with multiple fractures at baseline.
With respect to clinical vertebral fractures (defined as fractures associated with back
pain and/or a body height loss of at least 1 cm), the relative risk was reduced by 38%.
Strontium ranelate also decreased the number of patients with a body height loss of at
least 1 cm as compared to placebo. Quality of life assessment on the QUALIOST
specific scale as well as the General Health perception score of the SF-36 general
scale indicated benefit of strontium ranelate, compared with placebo.
Efficacy of strontium ranelate to reduce the risk of new vertebral fracture was
confirmed in the TROPOS study, including for osteoporotic patients without fragility
fracture at baseline.
Table 1: Incidence of patients with vertebral fracture and relative risk reduction
New vertebral fracture over 3 years 32,8%
New vertebral fracture over the 1st 11,8%
New clinical vertebral fracture over 17,4%
New vertebral fracture over 3 years 20,0%
In patients over 80 years of age at inclusion, a pooled analysis of SOTI and TROPOS
studies showed that strontium ranelate reduced the relative risk of experiencing new
vertebral fractures by 32% over 3 years (incidence of 19.1% with strontium ranelate
vs. 26.5% with placebo).
In an a-posteriori analysis of patients from the pooled SOTI and TROPOS studies
with baseline lumbar spine and / or femoral neck BMD in the osteopenic range and
without prevalent fracture but with at least one additional risk factor for fracture
(N=176), strontium ranelate reduced the risk of a first vertebral fracture by 72% over
3 years (incidence of vertebral fracture 3.6% with strontium ranelate vs. 12.0% with
An a-posteriori analysis was performed on a subgroup of patients from the TROPOS
study of particular medical interest and at high-risk of fracture [defined by a femoral
neck BMD T-score ≤ -3 SD (manufacturer’s range corresponding to -2.4 SD using
NHANES III) and an age ≥ 74 years (n=1,977, i.e. 40% of the TROPOS study
population)]. In this group, over 3 years of treatment, strontium ranelate reduced the
risk of hip fracture by 36% relative to the placebo group (table 2).
Table 2: Incidence of patients with hip fracture and relative risk reduction in
patients with BMD ≤ -2.4 SD (NHANES III) and age ≥ 74 years
Hip fracture over 3 6,4%
Treatment of Osteoporosis in men:
The efficacy of strontium ranelate was demonstrated in men with osteoporosis in a 2year, double-blind, placebo-controlled study with a main analysis after one year in
243 patients (Intention to treat population, 161 patients received strontium ranelate) at
high risk of fracture (mean age 72,7 years; mean lumbar BMD T-score value of -2.6;
28% of prevalent vertebral fracture).
All patients received daily supplemental calcium (1000 mg) and vitamin D (800 UI).
Statistically significant increases in BMD were observed as early as 6 months
following initiation of strontium ranelate treatment versus placebo.
Over 12 months, a statistically significant increase in mean lumbar spine BMD, main
efficacy criteria (E (SE) = 5.32% (0.75); 95%CI = [3.86 ; 6.79]; p<0,001), similar to
that observed in the pivotal anti-fracture phase III studies carried-out in postmenopausal women, was observed.
Statistically significant increases in femoral neck BMD and total hip BMD (p<0,001)
were observed after 12 months.
Strontium ranelate is made up of 2 atoms of stable strontium and 1 molecule of
ranelic acid, the organic part permitting the best compromise in terms of molecular
weight, pharmacokinetics and acceptability of the medicinal product. The
pharmacokinetics of strontium and ranelic acid have been assessed in healthy young
men and healthy postmenopausal women, as well as during long-term exposure in
men with osteoporosis and postmenopausal osteoporotic women including elderly
Due to its high polarity, the absorption, distribution and binding to plasma proteins of
ranelic acid are low. There is no accumulation of ranelic acid and no evidence of
metabolism in animals and humans. Absorbed ranelic acid is rapidly eliminated
unchanged via the kidneys.
The absolute bioavailability of strontium is about 25% (range 19-27%) after an oral
dose of 2 g strontium ranelate. Maximum plasma concentrations are reached 3-5
hours after a single dose of 2 g. Steady state is reached after 2 weeks of treatment.
Intake of strontium ranelate with calcium or food reduces the bioavailability of
strontium by approximately 60-70%, compared with administration 3 hours after a
meal. Due to the relatively slow absorption of strontium, food and calcium intake
should be avoided both before and after administration of Strontium granules for oral
suspension. Oral supplementation with vitamin D has no effect on strontium
Strontium has a volume of distribution of about 1 l/kg. The binding of strontium to
human plasma proteins is low (25%) and strontium has a high affinity for bone tissue.
Measurement of strontium concentration in iliac crest bone biopsies from patients
treated for up to 60 months with strontium ranelate 2 g/day indicate that bone
strontium concentrations may reach a plateau after about 3 years of treatment. There
are no data in patients to demonstrate elimination kinetics of strontium from bone offtherapy.
As a divalent cation, strontium is not metabolised. Strontium ranelate does not inhibit
cytochrome P450 enzymes.
The elimination of strontium is time and dose independent. The effective half-life of
strontium is about 60 hours. Strontium excretion occurs via the kidneys and the
gastrointestinal tract. Its plasma clearance is about 12 ml/min (CV 22%) and its renal
clearance about 7 ml/min (CV 28%).
Pharmacokinetics in special populations
Population pharmacokinetic data showed no relationship between age and apparent
clearance of strontium in the target population.
In patients with mild-to-moderate renal impairment (30-70 ml/min creatinine
clearance), strontium clearance decreases as creatinine clearance decreases
(approximately 30% decrease over the creatinine clearance range 30 to 70 ml/min)
and thereby induces an increase in strontium plasma levels. In phase III studies, 85%
of the patients had a creatinine clearance between 30 and 70 ml/min and 6% below 30
ml/min at inclusion, and the mean creatinine clearance was about 50 ml/min. No
dosage adjustment is therefore required in patients with mild-to-moderate renal
There is no pharmacokinetic data in patients with severe renal impairment (creatinine
clearance below 30 ml/min).
There is no pharmacokinetic data in patients with hepatic impairment. Due to the
pharmacokinetic properties of strontium, no effect is expected.
Preclinical safety data
Non-clinical data revealed no special hazard for humans based on conventional
studies of safety pharmacology, genotoxicity and carcinogenic potential.
Chronic oral administration of strontium ranelate at high doses in rodents induced
bone and tooth abnormalities, mainly consisting of spontaneous fractures and delayed
mineralisation that were reversible after cessation of treatment. These effects were
reported at bone strontium levels 2-3 times higher than bone strontium levels in
humans up to 3 years of treatment. The data on skeletal strontium ranelate
accumulation in longer term exposure is limited.
Developmental toxicity studies in rats and rabbits resulted in bone and tooth
abnormalities (e.g. bent long bones and wavy ribs) in the offspring. In rats, these
effects were reversible 8 weeks after cessation of treatment.
Environmental Risk Assessment (ERA)
The environmental risk assessment of strontium ranelate has been conducted in
accordance to European guidelines on ERA.
Strontium ranelate does not present a risk for the environment.
List of excipients
- 2 years.
- Once reconstituted in water, the suspension is stable for 24 hours. However, it is
recommended to drink the suspension immediately after preparation (see section 4.2)
Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
Nature and contents of container
Boxes containing 28 sachets.
Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.
MARKETING AUTHORISATION HOLDER
Rivopharm UK Ltd.
40 Bank Street
MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
DATE OF REVISION OF THE TEXT
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.