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CISPLATIN 50

Active substance: CISPLATIN

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with tubular damage, may be first noted during the second week after a dose and is manifested
by an increase in serum creatinine, blood urea nitrogen, serum uric acid and/or a decrease in
creatinine clearance. Renal insufficiency is generally mild to moderate and reversible at the
usual doses of the drug (recovery occurring as a rule within 2-4 weeks); however, high or
repeated Cisplatin doses can increase the severity and duration of renal impairment and may
produce irreversible renal insufficiency (sometimes fatal). Renal failure has been reported also
following intraperitoneal instillation of the drug.
Cisplatin may also cause serious electrolyte disturbances, mainly represented by hypomagnesemia,
hypocalcemia, and hypokalemia, and associated with renal tubular dysfunction. Hypomagnesemia
and/or hypocalcemia may become symptomatic, with muscle irritability or cramps, clonus,
tremor, carpopedal spasm, and/or tetany.
Gastrointestinal toxicity: Nausea and vomiting occur in the majority of Cisplatin-treated patients,
usually starting within 1 hour of treatment and lasting up to 24 hours or longer. These side effects
are only partially relieved by standard antiemetics. The severity of these systems may be reduced
by dividing the total dose per cycle into smaller doses given once daily for five days.
Haematologic toxicity: Myelosuppression often occurs during Cisplatin therapy, but is mostly
mild to moderate and reversible at the usual doses. Leucopenia is dose-related, possibly
cumulative, and usually reversible. The onset of leucopenia occurs usually between days 6 and
26 and the time of recovery ranges from 21 to 45 days. Thrombocytopenia is also a doselimiting effect of Cisplatin but is usually reversible. The onset of thrombocytopenia is usually
from days 10 to 26 and the time of recovery ranges from about 28 to 45 days.
The incidence of Cisplatin-induced anaemia (haemoglobin drop of 2 g/100 ml) ranges from 9%
to 40%, although this is a difficult toxic effect to assess because it may have a complex aetiology
in cancer patients.
There have been rare reports of acute myelogenous leukemias and myelodysplastic syndromes
arising in patients who have been treated with Cisplatin, mostly when given in combination
with other potentially leukomogenic agents.
Ototoxicity: Unilateral or bilateral tinnitus, with or without hearing loss, occurs in about 10%
of Cisplatin-treated patients and is usually reversible. The damage to the hearing system appears to
be dose-related and cumulative, and it is reported more frequently in very young and very old patients.
The overall incidence of audiogram abnormalities is 24%, but large variations exist. These
abnormalities usually appear within 4 days after drug administration and consist of at least a
15 decibel loss in pure tone threshold. The audiogram abnormalities are most common in the
4000-8000 Hz frequencies.
Neurotoxicity: Peripheral neuropathies occur infrequently with usual doses of the drug. These
are generally sensory in nature (e.g. paresthesia of the upper and lower extremities) but can
also include motor difficulties, reduced reflexes and leg weakness. Autonomic neuropathy,
seizures, slurred speech, loss of taste and memory loss have also been reported. These
neuropathies usually appear after prolonged therapy, but have also developed after a single
drug dose. Peripheral neuropathy may be irreversible in some patients; however, it has been
partially or completely reversible in others following discontinuance of Cisplatin therapy.
Hypersensitivity: Anaphylactic and anaphylactic-like reactions, such as flushing, facial oedema,
wheezing, tachycardia and hypotension, have been occasionally reported. These reactions may
occur within a few minutes after intravenous administration. Antihistamine, adrenaline and/or
glucocorticoids control all these reactions. Rarely, urticarial or maculopapular skin rashes have
also been observed.
Ocular toxicity: Optic neuritis, papilloedema, and cortical blindness have been reported rarely
in patients receiving Cisplatin. These events are usually reversible after drug withdrawal.
Hepatotoxicity: Mild and transient elevations of serum AST and ALT levels may occur infrequently.
Other toxicities: Other reported toxicities are:
cardiovascular abnormalities (coronary artery disease, congestive heart failure, arrhythmias,
postural hypotension, thrombotic microangiopathy, etc), hyponatremia / syndrome of
inappropriate antidiuretic hormone (SIADH), mild alopecia, myalgia, pyrexia and gingival platinum
line. Pulmonary toxicity has been reported in patients treated with Cisplatin in combination
with bleomycin or 5-fluorouracil.
Hyperuricaemia: Hyperuricaemia occurring with Cisplatin is more pronounced with doses
greater than 50 mg/m2. Allopurinol effectively reduces uric acid levels.
Hypomagnesemia: Asymptomatic hypomagnesemia has been documented in a certain
number of patients treated with Cisplatin, symptomatic hypomagnesemia has been observed
in a limited number of cases.
Convulsions: Seizures have also been reported with the use of this product.
Cardiotoxicity: Isolated cases of tachycardia and arrhythmia have been reported with Cisplatin
chemotherapy.
Thromboembolism: Cancer patients are generally at an increased risk for thromboembolic
events. Cerebrovascular accidents (e.g. haemorrhagic and ischaemic stroke, amaurosis fugax,
sagittal sinus thrombosis) have been observed in patients receiving Cisplatin therapy.
Local effects such as phlebitis, cellulitis and skin necrosis (following extravasation of the drug)
may also occur.
Cisplatin can affect male fertility. Impairment of spermatogenesis and azoospermia have been
reported. Although the impairment of spermatogenesis can be reversible, males undergoing
Cisplatin treatment should be warned about the possible adverse effects on male fertility.

PHYSICIAN'S LEAFLET

Cisplatin 50
Cisplatin 50 mg

Powder for Injection

1.

NAME OF THE MEDICINAL PRODUCT
Cisplatin 50

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Cisplatin 50.0 mg

3.

PHARMACEUTICAL FORM
Yellowish-white, freeze-dried cake in vials containing 50mg Cisplatin.

4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Cisplatin has antitumour activity either as a single agent or in combination chemotherapy
particularly in the treatment of testicular and metastatic ovarian tumours, also cervical tumours,
lung carcinoma and bladder cancer.
4.2 Posology and method of administration
Route of administration: Intravenous infusion.
Cisplatin should be dissolved in water for injections such that the reconstituted solution contains
1 mg/ml of Cisplatin. This solution should then be diluted in 2 litres of 0.9% saline or a
dextrose/saline solution (to which 37.5 g of mannitol may be added) and administration should
be over a 6-8 hour period.
Adults and children
Single agent therapy
The usual dose regimen given as a single agent is 50 - 120 mg/m2 by infusion once every 3 - 4
weeks or 15 - 20 mg/m2 by infusion daily for 5 consecutive days, every 3 - 4 weeks.
Combination chemotherapy
Dosage may be adjusted if the drug is used in combination with other antitumour chemotherapy.
With multiple drug treatment schedules Cisplatin is usually given in doses 20 mg/m2 upwards
every 3 - 4 weeks.
Dosage should be reduced for patients with renal impairment or depressed bone marrow function.
Pre-treatment hydration with 1 - 2 litres of fluid infused for 8 - 12 hours prior to the Cisplatin
will initiate diuresis. Adequate subsequent hydration should maintain diuresis during the 24
hours following administration.
Aluminium containing equipment should not be used for administration of Cisplatin as it may
interact with metal aluminium to form a black precipitate of platinum.
4.3 Contra-indications
Cisplatin is contra-indicated in patients who have previous allergic reactions to Cisplatin or other
platinum compounds as anaphylactic-like reactions have been reported. Relative contraindications are pre-existing renal impairment, hearing disorders and depressed bone marrow
function which may increase toxicity.
4.4 Special warnings and precautions for use
This agent should only be administered under the direction of physicians experienced in cancer
chemotherapy.
Renal function: Cisplatin produces cumulative nephrotoxicity. Renal function and serum
electrolyte (magnesium, sodium, potassium and calcium) should be evaluated prior to initiating
cisplatin treatment and prior to each subsequent course of therapy.
To maintain urine output and reduce renal toxicity it is recommended that Cisplatin be
administered as an intravenous infusion over 6-8 hours, as indicated in section 4.2 ‘Posology
and method of administration’. Moreover, pre-treatment intravenous hydration with 1-2 litres
of fluid over 8-12 hours followed by adequate hydration for the next 24 hours is recommended.
Repeat courses of Cisplatin should not be given unless levels of serum creatinine are below
1.5 mg/100 ml (100 mcmol/l) or blood urea below 55 mg/100 ml (9 mmol/l) and circulating
blood elements are at an acceptable level.
Special care has to be taken when cisplatin-treated patients are given concomitant therapies
with other potentially nephrotoxic drugs (See also section 4.5 ‘Interaction with other medicinal
products and other forms of Interaction’).
In addition, adequate post-treatment hydration and urinary output should be monitored.
Concomitant use of nephrotoxic drugs may seriously impair kidney function.
Bone marrow function: Peripheral blood counts should be monitored frequently in patients
receiving Cisplatin. Although the haematologic toxicity is usually moderate and reversible,
severe thrombocytopenia and leucopenia may occur. In patients who develop thrombocytopenia
special precautions are recommended: care in performing invasive procedures; search for signs
of bleeding or bruising; test of urine, stools and emesis for occult blood, avoiding aspirin and
other NSAIDs. Patients who develop leucopenia should be observed carefully for signs of
infection and might require antibiotic support and blood product transfusions.
Hearing function: Cisplatin may produce cumulative ototoxicity, which is more likely to occur

with high-dose regimens. Audiometry should be performed prior to initiating therapy, and
repeated audiograms should be performed when auditory symptoms occur or clinical hearing
changes become apparent. Clinically important deterioration of auditive function may require
dosage modifications or discontinuation of therapy.
CNS functions: Cisplatin is known to induce neurotoxicity; therefore, neurologic examination
is warranted in patients receiving a cisplatin-containing treatment. Since neurotoxicity may
result in irreversible damage, it is recommended to discontinue therapy with Cisplatin when
neurologic toxic signs or symptoms become apparent.
Anaphylactic-like reactions to Cisplatin have been observed. These reactions can be controlled
by administration of antihistamines, adrenaline and/or glucocorticoids.
Neurotoxicity secondary to Cisplatin administration has been reported and therefore neurological
examinations are recommended. Cisplatin has been shown to be mutagenic. It may also have
an anti-fertility effect. Other anti-neoplastic substances have been shown to be carcinogenic
and this possibility should be borne in mind in long term use of Cisplatin.
Liver function should also be monitored periodically.
Administration of live or live-attenuated vaccines in patients immunocompromised by
chemotherapeutic agents including cisplatin, may result in serious or fatal infections. Vaccination
with a live vaccine should be avoided in patients receiving cisplatin. Killed or inactivated vaccines
may be administered; however, the response to such vaccines may be diminished.
4.5 Interaction with other medicinal products and other forms of Interaction
Cisplatin is mostly used in combination with antineoplastic drugs having similar cytotoxic effects.
In these circumstances additive toxicity is likely to occur.
Nephrotoxic drugs: Aminoglycoside antibiotics, when given concurrently or within 1-2 weeks
after cisplatin administration, may potentiate its nephrotoxic effects. Concomitant use of other
potentially nephrotoxic drugs (e.g. amphotericin B) is not recommended during Cisplatin therapy.
Ototoxic drugs: Concurrent and/or sequential administration of ototoxic drugs such as
aminoglycoside antibiotics or loop diuretics may increase the potential of Cisplatin to cause
ototoxicity, especially in the presence of renal impairment.
Renally excreted drugs: Literature data suggest that Cisplatin may alter the renal elimination
of bleomycin and methotrexate (possibly as a result of cisplatin-induced nephrotoxicity) and
enhance their toxicity.
Anticonvulsant agents: In patients receiving Cisplatin and phenytoin, serum concentrations
of the latter may be decreased, possibly as a result of decreased absorption and/or increased
metabolism. In these patients, serum levels of phenytoin should be monitored and dosage
adjustments made as necessary.
Antigout agents: Cisplatin may raise the concentration of blood uric acid. Thus, in patients
concurrently receiving antigout agents such as allopurinol, colchicine, probenecid or sulfinpyrazone,
dosage adjustment of these drugs may be necessary to control hyperuricemia and gout.
4.6 Pregnancy and lactation
Cisplatin has been shown to be teratogenic and embryotoxic in animals. The use of the drug
should be avoided in pregnant of nursing women if possible.
4.7 Effects on ability to drive and use machines
There are no known effects of Cisplatin on the ability to drive or operate machinery. However,
the profile of undesirable effects (central nervous system and special sense) may reduce the
patient’s driving skills and abilities to operate machinery.
4.8 Undesirable effects
Nephrotoxicity: Acute renal toxicity, which was highly frequent in the past and represented
the major dose-limiting toxicity of Cisplatin, has been greatly reduced by the use of 6 to 8-hour
infusions as well as by concomitant intravenous hydration and forced diuresis. Cumulative
toxicity, however, remains a problem and may be severe. Renal impairment, which is associated


PAT I E N T

I N F O R M AT I O N

4.9 Overdose
There are no special instructions.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC code: L01XA01
In vitro studies indicate that DNA is the principal target molecule of cis-platinum.
The basis for the selectivity of the cis-isomer may reside in its ability to react in a specifically
defined configuration with DNA.
Modification of the DNA template results in the selective inhibition of DNA synthesis. The drug
is cell cycle non-specific.
5.2 Pharmacokinetic properties
A biphasic plasma-decay pattern occurs in man after bolus administration. The initial plasma
half-life in man is 25 - 49 minutes and the terminal half-life 3 - 4 days. In addition, a third
excretory phase with a longer half-life may be postulated from the high plasma platinum
concentration found after 21 days. During the terminal phase more than 90% of the drug is
bound to plasma proteins.
The urinary elimination of the drug is incomplete: the 5-day recovery of platinum in the urine
being only 27 to 45%.
Studies in man measuring free platinum species have shown a mean terminal half-life of 48
minutes after bolus injection, which probably corresponds to the initial half-life (25 - 49 minutes)
seen when total platinum is monitored and reflects the distribution of the drug. Urinary
excretion of filterable platinum was greater after 6 hours infusion (75%) than after a 15 minute
injection (40%) of the same dose of cis-platinum.
Diuresis induced by high-volume hydration or mannitol infusion was associated with a reduction
in the concentration of platinum excreted in the urine. The reduced concentration of platinum
caused by the high urine volume may play a role in renal protection.
5.3 Preclinical safety data
No further preclinical safety data are available.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipient(s)
Sodium chloride, Mannitol
6.2 Incompatibilities
None known.
6.3 Shelf-life
36 months.
6.4 Special precautions for storage
The unopened vials should be stored at room temperature, protected from light.
The reconstituted solution must not be cooled or refrigerated, as cooling may result in
precipitation. It should be kept at room temperature and protected from light, also during
intravenous infusion. Any unused solution should be discarded.
Keep out of the reach and sight of children.
6.5 Nature and contents of container
Colourless glass vials (Type II) with bromobutyl rubber stoppers and aluminium snap-caps.
6.6 Instructions for use and handling
Cisplatin powder should be dissolved in sterile Water for Injections such that the reconstituted
solution contains 1mg/ml of Cisplatin. The reconstituted solution should be diluted in 2 litres
of 0.9% saline or a dextrose/saline solution (to which 37.5g of mannitol may be added).
Personnel should be trained in good technique for reconstitution and handling. Pregnant staff
should be excluded from working with Cisplatin.
Care should be taken to prevent inhaling particles and exposing the skin to Cisplatin. Adequate
protective clothing should be worn, such as PVC gloves, safety glasses, disposable gowns and masks.
In the event of contact with eyes, wash with water or saline. If the skin comes into contact
with the drug wash thoroughly with water and in both cases seek medical advice. Seek immediate
medical attention if the drug is ingested or inhaled.
All used materials, needles, syringes, vials and other items which have come into contact with
cytotoxic drugs should be incinerated. Contaminated surfaces should be washed with copious
amounts of water.
7.

MARKETING AUTHORISATION HOLDER
Pharmacia Limited - Ramsgate Road - Sandwich - Kent - CT13 9NJ - United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)
PL 00032/0334

9.

DATE OF FIRST AUTHORISATION / RENEWAL OF AUTHORISATION
25 March 2002

10. DATE OF REVISION OF THE TEXT
February 2010
11. LEGAL CATEGORY
POM


L E A F L E T

Cisplatin 50
Cisplatin 50mg

Powder for Injection

In this leaflet:
1. What CISPLATIN is and what it is used for
2. Before you are given CISPLATIN
3. How CISPLATIN is given to you
4. Possible side effects
5. How to store CISPLATIN
6. Further information





❖ Driving and using machinery:
Cisplatin may cause certain side effects, e.g. effects on your vision or nervous
system that may reduce your driving skills and abilities to operate machinery,
therefore caution should be taken following treatment with CISPLATIN.

3. How CISPLATIN is given to you
• CISPLATIN will be given to you by infusion into a vein (through a ‘drip’) under
the direction of specialists in the hospital. The powder is dissolved to make a
solution. The solution is then added to a salt solution or to a sugar and salt
solution, which is then given into the blood stream over a period of 6 to 8
hours.
• Your doctor will decide the dose suitable for you. It will be calculated based on
your body surface area. The usual dose (single) is 20mg for each square metre
of your body surface area every 3 to 4 weeks.
• A lower dose will be given if you suffer from kidney disease or decreased bone
marrow function (not enough blood cells are being made).
• You will receive between 1 and 2 litres of fluid by infusion for 8 to 12 hours
before you receive your CISPLATIN , to increase both the amount of urine you
produce and how often you pass it. This is called diuresis. Enough fluid will be
given to maintain diuresis during the 24 hours after receiving CISPLATIN.

4. Possible side effects

Important things that you SHOULD know about your medicine:
• CISPLATIN will only be given by specialist staff in hospital, as you will need
to be carefully monitored during and after treatment. In particular your
blood, kidney and liver function will be monitored and you will be given
fluids to keep you hydrated.
• CISPLATIN can cause allergic symptoms such as flushing, wheezing, rash and
swelling of the face, decreased blood pressure and increased heart rate.
Contact your doctor immediately if you get these symptoms.
• Tell your doctor if you are taking or have taken any other medicines, including
medicines without prescription, for example aspirin.
• CISPLATIN can cause blood problems which might make you more susceptible
to infection and bleeding and usually occurs between days 6 and 26 after
your treatment.
• CISPLATIN can affect male fertility. Please contact your doctor for more
information.
Please read the rest of this leaflet. It includes other important information on
the safe and effective use of this medicine that might be especially important
to you.

1. What CISPLATIN is and what it is used for
• CISPLATIN is used in adults and children. The active ingredient is cisplatin.
• CISPLATIN belongs to one of a group of medicines called cytotoxics, which are
used to kill cancer cells in tumours.
• CISPLATIN is used to treat a wide range of tumours, in particular, testicular,
cervical, lung and bladder cancer and ovarian cancer that has the potential to
spread to other parts of the body. Cisplatin can be given alone or in combination
with other medicines.

2. Before you are given CISPLATIN
❖ Do not take CISPLATIN if you:

• Have ever had a reaction to CISPLATIN or other similar medicines containing
platinum or to any of the inactive ingredients of the medicine – see Section 6
for details.

❖ Take special care with CISPLATIN:
Tell your doctor if:

• You have a disease affecting the kidneys, or have ever had a disease which
affects the kidneys.
• You suffer from decreased bone marrow function (not enough blood cells are
being made)
• You have or have ever had a disorder which affects your hearing
• Previous use of CISPLATIN caused you to suffer a nervous disorder.
• You have had or are due to have any vaccination.
This will help your Doctor decide that CISPLATIN is suitable for you. He may arrange
for your liver to be monitored regularly during the course of your treatment.

Taking other medicines:
There are some medicines that may interact with CISPLATIN. Make sure your doctor
knows if you are taking any of the following:
• any one of a group of antibiotics known as aminoglycosides, cephaloridine (Also
an antibiotic) or any diuretics (drugs which gets rid of excess water from the
body), for example furosemide
• any drugs potentially toxic to kidneys, for example amphotericin B
• aspirin or NSAIDS (Non-Steroidal Anti-Inflammatory Drugs)
• antiepileptic medicines such as phenytoin
• medicines used for treating acute arthritis (gout) such as allopurinol, probenecid
or sulfinpyrazone (dosage adjustment of these drugs may be necessary)
• other anti-tumour drugs such as Bleomycin and/or Methotrexate
Please tell your doctor if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.

Like all medicines, CISPLATIN can cause side effects but not everyone gets them.
CISPLATIN can cause allergic symptoms such as flushing, wheezing, rash and
swelling of the face, decreased blood pressure and increased heart rate. Contact
your doctor immediately if you get these symptoms.
CISPLATIN can affect male fertility. Please contact your doctor for more information.
Other side effects include:
• Effects on your mouth, stomach and intestines: Nausea, (feeling
sick), vomiting and loss of appetite are common with CISPLATIN treatment.
Your doctor can give you other medicines called ‘anti-emetics’ to help if the
nausea and vomiting is very bad. You may also have loss of taste or changes
to your gums.
• Effects on your kidneys and bladder: CISPLATIN can damage your
kidneys resulting in reduced function. Blood tests will be done by your doctor
for raised blood levels of substances called urea, creatinine and uric acid to
check your kidneys are working properly.
• Effects on your liver: Increased blood levels of substances that will show
how well your liver is working.
• Effects on your blood and lymph system: Blood problems such as
decreased number of formed white and red blood cells and anaemia. This
might make you more susceptible to infection and bleeding and usually occurs
between days 6 and 26 after your treatment with CISPLATIN. Blood tests will
be done by your doctor to check for any problems.
• Effects on your ears: Hearing problems including tinnitus (ringing in the
ears) and some loss of hearing. The “ringing” in the ears usually disappears after
a while.
• Effects on your nervous system: Tingling, pins and needles or loss of
feeling in the arms and legs. It can also cause shaking, convulsions, seizures,
and/or slurred speech.
• Effects on eyes and vision: Some loss of vision, blurring of vision, change
in colour perception which returns when CISPLATIN treatment is stopped.
• Effects on your nutrition and metabolism: You may have decreased
levels of the mineral magnesium and/or sodium in your blood. The drug may
cause raised blood levels of uric acid. You may be given a drug called allopurinol
to counteract this.
• Effects on your heart and circulation: You may notice that the rate
that your heart beats changes. You may get low blood pressure. Cancer patients,
including those receiving CISPLATIN are generally at an increased risk for
thromboembolic events (blood clots), including stroke.
• Effects on muscles and skin: Mild hair loss, muscle aches, inflammation
at the site of injection.

If you get any of the above side effects, or notice any other
unusual side effects not listed in this leaflet, tell your doctor at
once.

5. How to store CISPLATIN
• The unopened vials should be stored at room temperature protected from
light.
• Keep out of the reach and sight of children.
• CISPLATIN should not be used after the expiry date printed on the box and on
the vial. The pharmacist will check this when your medicine is prepared for you.

6. Further information
What Cisplatin contains and contents of the pack
CISPLATIN is a yellow-white freeze dried cake and is available in single vials containing
50mg Cisplatin powder for injection.
The powder also contains sodium chloride and mannitol.

Marketing Authorisation Holder:
Pharmacia Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom

Manufacturer:
Actavis Italy S.p.A., Viale Pasteur, 10, 20014 Nerviano, Milan, Italy

Company contact address:

Do not take CISPLATIN if you are pregnant planning to become pregnant or if
you are breast-feeding.

Pfizer Limited, Walton Oaks, Dorking Road, Tadworth, Surrey, KT20 7NS
Telephone 01304 616161
Leaflet last updated: February 2010
Ref: CS 8_0

N. 400004381.4

N. 400004381.4

❖ Pregnancy and breast-feeding:

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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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