Cisplatin
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification Numbers |
| 1.4.1 CAS |
| 1.4.2 Other Numbers |
| 1.5 Brand Names, Trade Names |
| 1.6 Manufacturers, Importers |
| 1.7 Presentation, Formulation |
| 2. SUMMARY |
| 2.1 Main Risks and Target Organs |
| 2.2 Summary of Clinical Effects |
| 2.3 Diagnosis |
| 2.4 First aid measures and management practices |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the Substance |
| 3.2 Chemical Structure |
| 3.3 Physical Properties |
| 3.3.1 Properties of the Substance |
| 3.3.1.1 Colour |
| 3.3.1.2 State/Form |
| 3.3.1.2 Description |
| 3.3.2 Properties of the locally available formulation(s) |
| 3.4 Other Characteristics |
| 3.4.1 Shelf-Life of the Substance |
| 3.4.2 Shelf-life of the locally available formulation |
| 3.4.3 Storage Conditions |
| 3.4.4 Bioavailability |
| 3.4.5 Specific properties and composition |
| 4. USES |
| 4.1 Indications |
| 4.2 Therapeutic Doses |
| 4.3 Contraindications |
| 5. ROUTES OF ENTRY |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Others |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination by route of exposure |
| 7. PHARMACOLOGY AND TOXICOLOGY |
| 7.1 Mode of Action |
| 7.1.1 Toxicodynamics |
| 7.1.2 Pharmacodynamics |
| 7.2 Toxicity |
| 7.2.1 Human Data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Animal Data |
| 7.2.3 In-vitro data |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 7.7 Main Adverse Effects |
| 8. PHARMACOLOGICAL, TOXICOLOGICAL AND OTHER ANALYSES |
| 8.1 Sample |
| 8.1.1 Collection |
| 8.1.2 Storage |
| 8.1.3 Transport |
| 8.2 Toxicological Analytical Methods |
| 8.2.1 Tests for active ingredient |
| 8.2.2 Tests for biological sample |
| 8.3 Other Laboratory analyses |
| 8.3.1 Biochemical Investigations |
| 8.3.1.1 Blood |
| 8.3.1.2 Urine |
| 8.3.1.3 Other |
| 8.3.2 Arterial Blood Gas Analysis |
| 8.3.3 Haematological or Haemostasiological Investigations |
| 8.3.4 Other Relevant Biomedical Analyses |
| 8.4 Interpretation |
| 9. CLINICAL EFFECTS |
| 9.1 Acute Poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin Exposure |
| 9.1.4 Eye Contact |
| 9.1.5 Parenteral Exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin data |
| 9.2.4 Eye Contact |
| 9.2.5 Parenteral Exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis and cause of death |
| 9.4 Systemic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 Central Nervous System (CNS) |
| 9.4.3.2 Peripheral Nervous System |
| 9.4.3.3 Autonomic Nervous System |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Others |
| 9.4.7 Endocrine and Reproductive Systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, Ear, Nose, Throat: Local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid Base disturbances |
| 9.4.12.2 Fluid and Electrolyte Disturbances |
| 9.4.12.3 Other |
| 9.4.13 Allergic Reactions |
| 9.4.14 Other Clinical Effects |
| 9.4.15 Special risks |
| 10. MANAGEMENT |
| 10.1 General Principles |
| 10.2 Relevant laboratory analyses and other investigations |
| 10.2.1 Sample Collection |
| 10.2.2 Biomedical analysis |
| 10.2.3 Toxicological analysis |
| 10.2.4 Other Investigations |
| 10.3 Life Supportive procedures and symptomatic treatment |
| 10.4 Decontamination |
| 10.5 Elimination |
| 10.6 Antidote |
| 10.6.1 Adults |
| 10.6.2 Children |
| 10.7 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from the Literature |
| 11.2 Internally extracted data on cases |
| 11.3 Internal Cases |
| 12. ADDITIONAL INFORMATION |
| 12.1 Availability of Antidotes |
| 12.2 Specific Preventative Measures |
| 12.3 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S), COMPLETE ADDRESS(ES) |
1. NAME
1.1 Substance
Cisplatin (INN)
(WHO,1992)
1.2 Group
ATC Classification Index
Antineoplastic and immunomodulating agents (L)/
Other Cytostatics (L01XA).
(WHO, 1992)
1.3 Synonyms
CACP
CDDP
Cisplatino (Spanish)
CPDC
CPDD
Cis-Diamminedichloro platinum (II)
Cis-Dichlorodiammine platinum (II)
Cis-platin
Cis-platinous diammine dichloride
Cis-platinum
Cis-platinum II
Cis-platinum II Diamine dichloride
Cis PT II
DDP
Neoplatin
NSC-119875
Peyrone's Salt
Peyrone's Chloride
Platinol
Platinum diamminodichloride
1.4 Identification Numbers
1.4.1 CAS
15663-27-1
1.4.2 Other Numbers
RTECS
TP 2450000
Laboratory Code
NSC 119875
Wiswesser Line Notation
Z&2 PT-G2
1.5 Brand Names, Trade Names
Cisplatyl, Cytoplatino, Neoplatin, Placis, Platiblastin,
Platinex, Platinol, Platistil, Platistin, Platosin.
(Reynolds, 1989)
Australia
Cisplatin (David Bull)
Platamine (Farmitalia)
Platinol (Bristol)
(Thomas, 1991; David Bull, 1992)
1.6 Manufacturers, Importers
David Bull: Australia
Bull: UK
Bellon: France
Rhône Poulenc: Sweden, Italy
Bristol Italiana Sud: Italy
Bristol-Meyers: Spain, Australia, Denmark, Luxembourg
Bristol-Meyer Oncology: USA
Bristol-Meyers Pharmaceuticals: UK
Bristol: Germany, Belgium, Canada, Switzerland, Norway, South
Africa, Sweden
Wusserman: Spain
Farmitalia Carlo Erba: South Africa, Sweden, UK
Farmitalia: Germany, Spain, Denmark, Norway
Nordic: UK
Lederle: UK
(Reynolds 1989)
1.7 Presentation, Formulation
Australia
Cisplatin
Vials containing 10 mg, 25 mg, 50 mg of cisplatin as a
lyophilised powder for reconstitution in packs of 1 and 10
vials.
Cisplatin Solution
Vials containing cisplatin as a solution in a concentration
of 1 mg/ml: 10 mg in 10 ml vial, 50 mg in 50 ml vial, 100 mg
in 100 ml vial.
Platamine (Farmitalia)
Vials containing cisplatin in lyophilised powder for
reconstitution: 10 mg in 20 ml vials, 25 mg in 50 ml vials
and 50 mg in 100 ml vials in packs of 1 vial.
Platinol (Bristol)
Vials containing cisplatin as a lyophilised powder for
reconstitution: 10 mg in 20 ml vials and 50 mg in 100 ml
vials
Vials containing cisplatin as a solution in a concentration
of 0.5 mg/ml; 10 mg in 20 ml vial, 25 mg in 50 ml vial and 50
mg in 100 ml vial.
(Thomas, 1991;David Bull, 1992)
2. SUMMARY
2.1 Main Risks and Target Organs
The main risks experienced during cisplatin therapy and
overdosage include nephrotoxicity, electrolyte disturbances,
myelosuppression, neurotoxicity, anaphylactic reactions,
ototoxicity. Nausea and vomiting can be severe.
Rarer risks include cardiovascular effects, ocular effects,
and hepatic effects.
Most effects of overdosage are not usually seen immediately,
but occur several days to months after the event.
The causes of death from an overdose from cisplatin include
myelosuppression, renal failure and tetany.
2.2 Summary of Clinical Effects
Renal toxicity is cumulative and seen usually after several
courses of cisplatin or after overdose (see Section 11).
Disturbances in electrolytes can be a long term manifestation
due to the cisplatin induced renal tubular dysfunction.
Hypomagnesaemia, hypocalcaemia and hypokalaemia are commonly
seen in cisplatin induced renal toxicity and can persist for
months after termination of therapy.
Haematological effects of cisplatin (myelosuppression and
anaemia) are cumulative and in overdosage the haematopoietic
system must be supported to prevent complications of
infection.
Cisplatin induces marked nausea and vomiting in almost all
patients.
Anaphylactoid reactions have occurred during normal therapy
with cisplatin and must be treated vigorously. Cisplatin
causes electrolyte disturbances which are a direct result of
cisplatin induced renal tubular dysfunction. Cisplatin
causes marked excretion of calcium, magnesium and potassium
and to a lesser extent zinc, copper and amino acids. These
disturbances must be corrected to prevent complications.
2.3 Diagnosis
Clinical features
Renal toxicity is manifested by an increase in serum
creatinine, BUN, serum uric acid and/or a decrease in
creatinine clearance and glomerular filtration rate.
The renal impairment is a direct result of cisplatin induced
renal tubular damage leading ultimately to renal failure.
Disturbances have been seen in serum electrolytes
due principally to cisplatin induced renal tubular
dysfunction. Patients subsequently develop hypomagnesaemia,
hypocalcaemia and hypokalaemia and to a lesser extent
hypophosphatemia and hyponatremia.
Cisplatin produces marked nausea and vomiting in
almost all patients to the extent that some patients
experience anticipatory nausea and vomiting. Diarrhoea has
also occurred but with less frequency than nausea and
vomiting.
Ototoxicity develops in various degrees on cisplatin
therapy. In larger and prolonged dosing with cisplatin the
ototoxicity can be irreversible.
Myelosuppression is a common problem seen as
leucopenia, thrombocytopenia and anaemia and if severe enough
can cause the death of the patient.
Myelosuppression can be cumulative.
Anaphylactoid reactions can occur when cisplatin is
given.
Cardiovascular effects are rare but include
bradycardia, left bundle branch block and congestive heart
failure.
Hepatic enzyme concentrations in the sera become
elevated including AST (SGOT) and ALT (SGPT).
Laboratory analyses
Serum electrolyte concentration should be ascertained
throughout treatment including magnesium, potassium, calcium
as well as other renal function tests. These values give an
indication of the renal damage caused by cisplatin.
Peripheral blood counts should also be monitored as these
give an indication of the degree of myelosuppression and
anaemia.
Liver function tests should also be performed regularly.
Visual and auditory tests should be performed throughout as
some of the effects are reversible and it gives an indication
of the severity of toxicity.
ECG and other cardiac monitoring tests should be employed to
recognize electrolyte and cardiac disturbances.
(Gilman et al., 1985; NDIS, 1985; McEvoy, 1992; David Bull,
1992; Fassoulaki & Pavlov, 1989; Reynolds, 1989; Schiller et
al., 1989)
2.4 First aid measures and management practices
Treatment is supportive and symptomatic.
Patients should be monitored for 3 to 4 weeks post
administration to determine the severity of toxicity as
effects are delayed.
There is no specific antidote to use in cisplatin toxicity.
Treatment must involve hydration with 3 to 6 litres of
intravenous fluids per day together with intravenous
mannitol, both of which increase urinary volume and output
and decrease the effective urinary concentration of platinum.
Decontaminate skin or eyes if route of exposure to cisplatin
was in this manner. Copious amounts of water (or appropriate
irrigation fluid) should be used.
Emesis, gastric lavage, charcoal therapy are not appropriate
(but if an overdose occurred orally, these measures would be
used appropriately) as cisplatin is not usually administered
in this manner. The overdoses to date in the literature have
been administered intravenously.
(Schiller et al., 1989; Fassoulaki & Pavlov, 1989; McEvoy,
1992; NDIS, 1985)
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the Substance
Synthetic
3.2 Chemical Structure
Structural formula
Cl NH3
Pt
Cl NH3
Molecular Weight
300.05
Molecular Formula
Cl2H6N2Pt or (NH3)2PtCl2
Structural name(s)
cis - Diamminedichloroplatinum
3.3 Physical Properties
3.3.1 Properties of the Substance
3.3.1.1 Colour
Deep yellow solid.
3.3.1.2 State/Form
Solid.
3.3.1.2 Description
Decomposes at 270 °C
Soluble in water, 0.253 g/100 g at 25 °C,
1 mg/mL in 0.9% sodium chloride
Slowly changes from the cis to the trans form
in aqueous solution.
Soluble in dimethylformamide.
Insoluble in most common solvents.
(McEvoy, 1992; Budavari, 1989)
3.3.2 Properties of the locally available formulation(s)
To be completed by the Centre.
3.4 Other Characteristics
3.4.1 Shelf-Life of the Substance
Cisplatin lyophilised powder - unopened vials of the
dry powder must be kept under refrigeration (2 to 5°C)
and are stable for 25 months from date of manufacture.
(David Bull, 1992)
3.4.2 Shelf-life of the locally available formulation
To be completed by the centre, according to local data,
e.g.
Cisplatin solution (Platinol-Bristol) - unopened vials
of solution must be kept at temperatures above freezing
and below 25°C and are stable for 24 months from the
date of manufacture. (Australia)
Cisplatin Solution (DBL) - unopened vials of solution
must be kept at temperatures between 15° and 25°C and
are stable for 24 months from date of manufacture.
(Australia)
(David Bull, 1992, Thomas, 1991).
3.4.3 Storage Conditions
Store each product as recommended by the manufacturer.
Cisplatin lyophilised powder - Store under
refrigeration (2-8°C) and protect from light.
Cisplatin solution (Platinol-Bristol) - Store above
freezing and below 25°C. Protect from light.
Cisplatin Solution (DBL) - Store between 15 and 25°C,
and protect from light.
The stability of reconstituted solutions:
22 hrs-Cisplatin (David Bull)
24 hrs-Platinamine (Farmitalia)
20 hrs-Platinol (Bristol)
The reconstituted solution should be stored at room
temperature and protected from light. (If stored at
refrigerator temperatures a crystalline precipitate
forms).
Aluminium-containing intravenous sets, needles,
catheters and syringes etc should be avoided due to an
interaction resulting in a precipitation of platinum.
(Thomas, 1991, David Bull, 1992)
3.4.4 Bioavailability
Lyophilised powder dissolves readily in intravenous
fluids containing chloride ions (0.9% sodium chloride,
5% dextrose with 0.18% sodium chloride).
3.4.5 Specific properties and composition
Commercially available cisplatin powder for injection
is a lyophilised powder and contains sodium chloride,
mannitol and hydrochloric acid (to adjust the pH).
Solutions containing 1 mg/mL of cisplatin are clear and
colourless and have a pH of 3.5 to 5.5.
Commercially available cisplatin injection is a clear
and colourless solution and contains sodium chloride,
hydrochloric acid and/or sodium hydroxide to adjust the
pH. The pH is in the range 3.7 to 6, an osmolality of
about 285 to 286 Osm/kg and contains 0.9% sodium
chloride. Depending on the manufacturer, the injection
does or does not contain mannitol.
4. USES
4.1 Indications
Cisplatin is indicated for the following conditions:
- single agent for the treatment of transitional cell bladder
carcinoma that is no longer amenable to local treatment such
as surgery and/or radiation therapy.
- locally advanced or metastatic transitional cell carcinoma
involving the renal pelvis, ureter, bladder and/or
urethra.
- in combination with radiation treatment to treat bilharzial
bladder cancer and together with doxorubicin and
cyclophosphamide to treat locally advanced bladder
cancer.
- the palliative treatment of recurrent or metastatic
squamous cell carcinomas of the head or neck.
- treatment of lung cancer, principally as a component of
various chemotherapeutic regimens in the treatment of non-
small cell lung carcinomas. It is often combined with other
agents such as etoposide, vinblastine or vindesine to obtain
a better response rate in lung cancer. Its use alone has
some value but in combination the results are more
rewarding.**
- in the palliative treatment of recurrent or advanced
squamous cell carcinoma of the cervix and metastatic
testicular carcinoma.
- other types of carcinomas in which cisplatin has been tried
included the following: osteogenic sarcoma, neuroblastoma and
recurrent brain tumours in children, advanced oesophageal
carcinoma and advanced prostatic carcinoma.
** In combination with agents such as bleomycin,
methotrexate, vincristine or vinblastine, fluorouracil in
various regimes (all together or singularly depending on the
protocol and the carcinoma type). Combinations of these
agents have been reported to have a better response rate than
if cisplatin were used alone.
4.2 Therapeutic Doses
Adults
Dosage of cisplatin depends on the clinical, renal,
haematological and otic response and tolerance of the patient
in order to obtain optimal responses.
Dosage of cisplatin depends also on the carcinoma being
treated, the combination with other cancer chemotherapy
agents and/or radiation and published protocol chosen for
that carcinoma.
Cisplatin is administered by the intravenous route. At the
usual dosage, courses of cisplatin therapy should not be
given more frequently that once every 3 to 4 weeks. A repeat
course of cisplatin should not be administered until the
patient's renal, haematological and otic functions are within
acceptable limits and precautions should always be taken to
treat any anaphylactic reactions that may occur.
Cisplatin should only be used by physicians experienced in
administration of cytotoxic agents and in the management of
potential side effects in particular nephrotoxicity and
myelosuppression.
Some dosage schemes are as follows:
Single Agent Therapy
2 to 3 mg/kg every 3 to 4 weeks
20 mg/m2/day for 5 days every 3 to 4 weeks
100 mg-120 mg/m2 every 3 to 4 weeks
80 mg/m2 (24 hour infusion) every 3 to 4 weeks
Some examples of disease states protocols are as follows:
Testicular Neoplasms
For remission induction (in combination with bleomycin and
vinblastine):
20 mg/m2 intravenously daily for 5 consecutive days
every 3 weeks for three to four courses; or 120 mg/m2
every 3 to 4 weeks for three courses.
Ovarian Neoplasms
Dosage of cisplatin in combination chemotherapy regimens
(e.g. Doxorubicin): 50 mg/m2 once every 3 to 4 weeks.
As a single agent: 100 mg/m2 intravenously once every four
weeks (doses of 30 to 120 mg/m2 intravenously once every 3 to
4 weeks have also been used).
Bladder Cancer
Cisplatin 50 to 70 mg/m2 intravenously once every 3 to 4
weeks. The dose depends on prior chemotherapy and/or
radiation treatment.
Head and Neck Cancer
Cisplatin alone
80 to 120 mg/m2 intravenously once every 3 weeks; or
50 mg/m2 intravenously on the first and eighth days
every four weeks.
Combined therapy
80 to 120 mg/m2 - the frequency is determined by
the protocol.
Cervical Carcinoma
Dosages of 50 mg or 100 mg/m2 intravenously once every three
weeks have been used (the lower dose is just as effective as
the higher dose with less side effects).
The dose to treat cervical carcinoma therefore have yet to be
established.
Non-small Cell Lung Carcinoma
Cisplatin alone
75 to 120 mg/m2 intravenously once every 3 to 6 weeks.
Also 50 mg/m2 intravenously on days 1 and 8 of a four-
week course.
In combination with other agents
40 mg-120 mg/m2 intravenously every 3 to 6 weeks has
been employed (e.g. 120 mg/m2 on days 1 and 28 or 29,
then once every 6 weeks).
All appear effective.
Intra-Arterial Dosage
When cisplatin is given intra-arterially a dose of 75 to 150
mg/m2 2 to 5 weekly for at least 1 to 4 courses is used.
This is used in regionally confined malignancies, e.g.
advanced bladder cancer, malignant melanoma and osteogenic
sarcomas.
Intraperitoneal Dosage
The management of intraperitoneal tumours, where the tumour
is confined to the peritoneal cavity and/or associated with
malignant ascites, includes the use of cisplatin.
Dosage
60 to 90 mg/m2 intraperitoneally with intravenous sodium
thiosulphate (e.g. 7.5 g/m2 loading dose followed by
2.13 g/m2 /hour for 12 hours).
Doses of up to 270 mg/m2 intraperitoneally have been used
with or without sodium thiosulphate.
Both these dosage regimens have been repeated every 3 weeks.
Combination Therapy
Cisplatin is commonly used in combination therapy with the
following cytotoxic agents:
a) Testicular Cancer: Vinblastine, Bleomycin,
Actinomycin D
b) Ovarian Cancer: Cyclophosphamide, Doxorubicin,
Hexamethylmelamine, 5-Fluorouracil
c) Head and Neck Cancer: Bleomycin, Methotrexate.
Pretreatment hydration with 2 litres of 5% Glucose and 1/2 to
1/3 normal saline infused over a 2 to 4 hour period prior to
cisplatin therapy is recommended.
Post treatment hydration and urinary output must be maintained
during the following 24 hours.
(McEvoy, 1992; Gilman et al., 1985; NDIS, 1985)
Children
Paediatric dosage of cisplatin has not been fully established.
Osteogenic sarcoma or neuroblastoma
Cisplatin been used in the treatment of the above in doses
of 90 mg/m2 intravenously once every 3 weeks or 30 mg/m2
intravenously once weekly.
Recurrent brain tumours
Doses of 60 mg/m2 intravenously daily for two consecutive
days every 3 to 4 weeks have been used.
Renal Impairment
It has not been clearly determined whether dosage should
routinely be reduced in patients with renal impairment.
Some dosages that have been tried are 75% of the usual dose
when creatinine clearances of 10 to 50 mL/min are present.
Similarly, creatinine clearances of less than 10 mL/min
should be 50% of usual dose.
There is an argument that by reducing doses this might result
in suboptimal therapy.
(McEvoy, 1992; Gilman et al., 1985; NDIS, 1985)
4.3 Contraindications
Absolute
A history of hypersensitivity to cisplatin or other platinum
containing compounds.
Relative
Cumulative and dose related renal insufficiency is the major
dose limiting toxicity of cisplatin. Incidence and severity
increases with total dose and duration of treatment.
Myelosuppression
During treatment, the platelet and leucocyte circulating
concentrations are at their lowest between days 18 and 32
(range 7.3 to 45) and most patients start recovery by day 39
(range 13 to 62).
Leucopenia and thrombocytopenia are more pronounced after
using doses of greater than 50 mg/m2.
Subsequent doses of cisplatin should not be commenced until
the platelet count is greater than 100,000/cubic mm and white
cells are greater than 4000/cubic mm.
Nausea and vomiting
Cisplatin produces marked nausea and vomiting in almost all
patients, which can usually be controlled with anti-emetics.
However, if it is severe or persistent, a reduction or
discontinuation of the treatment may be necessary.
Ototoxicity
Cisplatin can cause ototoxicity; tinnitus and decreased
ability to hear normal conversation may be used as
indicators. Children are particularly sensitive.
Ototoxicity, as induced by cisplatin, is cumulative so
therapy is contraindicated in patients with pre-existing
hearing impairments. Patients with moderate degrees of
hearing loss should have their doses altered if therapy were
continued (Huang & Schacht, 1991).
Hypomagnesaemia and Hypocalcaemia
As cisplatin can cause hypomagnesaemia and hypocalcaemia,
these should be corrected prior to the start of therapy.
Anaemia
Cisplatin can cause a decrease of greater than 2 g per cent
haemoglobin during repeated courses of therapy; treatment
should proceed with extreme caution.
Neurotoxicity
Peripheral neuropathies can occur during cisplatin therapy
and are usually sensory and reversible. In some cases they
become progressive and irreversible. This latter type is
seen generally after prolonged therapy (4 to 7 months) and
cessation of therapy is generally recommended.
Anaphylaxis
Patients with a family or personal history of atopy are at
particular risk. People who have pre-existing asthma or
related conditions should be treated with care.
Precautions
Extreme care should be taken by persons preparing and
administering cisplatin and those handling the urine of
treated patients.
Preparation of cisplatin infusions etc. should be done only
in an approved biological safety cabinet using protective
clothing.
Cisplatin is carcinogenic in animals. Care must be
exercised in regards to handling cisplatin.
5. ROUTES OF ENTRY
5.1 Oral
Cisplatin is not effective when administered orally (Gilman
et al., 1985).
5.2 Inhalation
No data available.
5.3 Dermal
Cisplatin is not administered dermally. Avoid dermal contact
and absorption during administration.
5.4 Eye
Eye contamination may be a possible source of poisoning during
intravenous administration of cisplatin.
5.5 Parenteral
Cisplatin is only available in the injectable form. The
parenteral routes, intravenous, intra-arterial and
intraperitoneal, have all been used in cisplatin therapy and
poisoning would most likely occur by these three routes.
5.6 Others
No data available.
6. KINETICS
6.1 Absorption by route of exposure
Intravenous
Totally absorbed after intravenous use.
Rapid intravenous injection of cisplatin over 1 to 5 minutes
or rapid intravenous infusion over 15 minutes or one hour,
results in peak plasma concentrations immediately.
When cisplatin is administered by intravenous infusion over 6
to 24 hours the plasma concentrations of total platinum
increase gradually during the infusion and reach peak
concentrations immediately following the end of the
infusions.
When mannitol is given at the same time as cisplatin, the
peak plasma concentrations of non protein-bound platinum
appears to be increased.
Intra-arterial
When cisplatin is administered by intra-arterial infusion,
the local tumour exposure of the drug is increased as
compared with intravenous administration.
Intraperitoneal
Cisplatin is rapidly and well absorbed systemically following
intraperitoneal administration. This route gives 50 to 100%
plasma concentration in comparison with intravenous route.
Intraperitoneal fluid concentration of the drug is greatly
increased as compared with intravenous administration
(McEvoy, 1992).
6.2 Distribution by route of exposure
Following the intravenous administration of Cisplatin, the
drug is widely distributed into body fluids and tissues. The
highest concentrations can be seen in the kidneys, liver and
intestines, and can persist for up to 2 to 4 weeks. However,
concentrations can also be found in the muscles, bladder,
testes, prostate, pancreas and spleen.
Cisplatin has also been found in the following tissues; small
and large intestines, adrenals, heart, lungs, lymph nodes,
thyroid, gall bladder, thymus, cerebrum, cerebellum, ovaries
and uterus.
Platinum appears to accumulate in body tissues following
administration of cisplatin and has been detected in many of
these tissues for up to 6 months after the last dose of the
drug. Platinum also has been found in leucocytes and
erythrocytes.
The volume of distribution: 41 L/m2 (range 20 to 80 L/m2)
(McEvoy, 1992).
Cisplatin and any platinum-containing products are rapidly
and extensively bound to tissue and plasma proteins,
including albumin, gamma-globulins and transferrin.
Binding to tissue and plasma proteins appears to be
essentially irreversible with the bound platinum remaining in
plasma during the lifespan of the albumin molecule. Protein
binding increases with time and less than 2 to 10% of
platinum in blood remains unbound several hours after
intravenous administration of cisplatin.
The extent of protein binding is about 90% and this occurs
essentially within the first two hours after a dose (McEvoy,
1992; Speight, 1987; NDIS, 1985).
Penetration into the central nervous system (CNS) does not
occur readily. The resultant levels are low in the CNS, but
significant amounts of cisplatin can be detected in
intracerebral tumour tissue and oedematous brain tissue
adjacent to the tumour. In healthy brain tissue levels
appear to be low (McEvoy, 1992; NDIS, 1985).
6.3 Biological half-life by route of exposure
The distribution half life: 8 to 10 minutes (NDIS, 1985).
The elimination half life: 40 to 45 minutes (NDIS, 1985).
Monophasic elimination half life: 0.3 to 0.5 hours (NDIS,
1985; Speight, 1987)
Terminal half life of total platinum in a patient with severe
renal failure: 1 to 240 hours (NDIS, 1985; Speight, 1987).
Total platinum (adults with normal renal function): 8.1 to 49
minutes (initial phase); 30.5 to 107 hours (or longer) in
terminal phase (McEvoy, 1992).
Non protein bound platinum: 2.7 to 30 minutes in the initial
phase and 32 to 53.5 minutes in the terminal phase.
After a 6-hour intravenous infusion in patients with normal
renal function the terminal plasma elimination half life for
the total platinum is 73 to 290 hours (McEvoy, 1992).
In acute oliguric renal failure requiring haemodialysis the
terminal plasma half life of total platinum was approximately
10 days (McEvoy, 1992).
In children with normal renal function, the serum elimination
half lives of total platinum averages about 25 minutes in the
initial phase and 44 hours in the terminal phase. The serum
elimination half-life of non protein bound platinum averages
1.3 hours.
6.4 Metabolism
The metabolic fate of cisplatin has not been completely
elucidated. There is little evidence to date that the drug
undergoes enzymatic biotransformation. The cisplatin molecule
has chloride ligands on it and it is believed that these are
displaced by water thus forming positively charged platinum
complexes that react with nucleophilic sites. Their rate and
extent depends on the strength, concentration and
accessibility of the nucleophiles. The chemical identities
of the metabolites of cisplatin have been found but have yet
to be identified. There is a strong possibility that
cisplatin and its metabolites undergo enterohepatic
circulation (McEvoy, 1992).
6.5 Elimination by route of exposure
Intact cisplatin and its metabolites are excreted principally
in urine. It occurs predominantly via glomerular filtration
but there is some evidence that secretion and reabsorption of
cisplatin and its metabolites also occurs.
Initially renal clearance of total platinum equals creatinine
clearance and represents elimination of non-protein bound
platinum molecules including intact cisplatin.
As extensive protein binding occurs then clearance declines
rapidly, resulting in a prolonged excretory phase.
The ultimate rate of fall of total plasma platinum
concentration is governed by the rate of degradation of
plasma proteins bearing bound platinum.
A small amount of cisplatin is excreted via the bile and
saliva (McEvoy, 1992).
After a dose of cisplatin:
15 to 30% of the dose is excreted in the urine in the first 2
to 4 hours (of which 90% is intact cisplatin)
20 to 80% of the dose is recovered in the first 24 hours
(NDIS, 1985).
Elimination half-life of cisplatin (Adults) (Speight, 1987)
Normal renal function: 2 to 72 hrs
Endstage renal disease: 1 to 240 hrs
Percent excreted unchanged: 25 to 75%
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of Action
7.1.1 Toxicodynamics
Cisplatin appears to be cycle-phase nonspecific and
will cause cell death in all cells. It is in those
cells which turn over rapidly (tumour cells, skin
cells, gastrointestinal cells, bone marrow cells) that
cell death will occur at a faster rate than other cells
with a slower turnover rate (e.g. muscle cells).
Cisplatin exerts its antineoplastic activity when it
has the cis-configuration and without a charge on the
molecule. The trans-configuration is inactive.
7.1.2 Pharmacodynamics
Cisplatin complex moves through cell membranes in an
unionised form and this is achieved in the relatively
high chloride concentration in the plasma.
Intracellularly the concentration of chloride ions is
lower than in the plasma and the chloride ligands on
the cisplatin complex are displaced by water. The
result is the formation of positively charged platinum
complexes that are toxic to cells.
The cisplatin molecule binds to the DNA molecule at the
guanine bases and thus inhibits DNA synthesis, protein
and RNA synthesis (the latter two are inhibited to a
lesser degree).
The drug forms intrastrand and interstrand cross links
in the DNA molecule and appears to correlate well with
the cytotoxicity of the drug. The tumour cells amass
an overburden of mutations which lead eventually to the
cell's death.
Cisplatin also has immunosuppressive, radiosensitizing
and antimicrobial properties.
The exact mechanism of action of cisplatin is not yet
understood but the drug has biochemical properties
similar to those of bifunctional alkylating agents.
(McEvoy, 1992; NDIS, 1985; Gilman et al., 1985;
Prestayko, 1980)
7.2 Toxicity
7.2.1 Human Data
7.2.1.1 Adults
The major toxicity caused during cisplatin
treatment is dose related and cumulative. For
example, renal tubular function impairment can
occur during the second week of therapy and if
higher doses or repeated courses of cisplatin
are given then irreversible renal damage can
occur.
A minimum lethal dose has not been reported in
the literature to date.
Hydration is required during therapy and this
lessens the likelihood of nephrotoxicity and
other toxicities.
With a dose of 100 mg/m2, without hydration,
the problem of nephrotoxicity may become
evident.
Doses of greater than 100 mg/m2 of cisplatin
are likely to cause moderate bone marrow
toxicity in the form of suppression as well as
nephrotoxicity.
7.2.1.2 Children
No data available.
7.2.2 Animal Data
Species Route LD 50 (mg/kg)
Rat IP 12.0
SC 45.0
IV 8.0
Mouse IP 6.0
IV 12.0
Guinea Pig IP 9.7
IP - Intraperitoneal
SC - Subcutaneous
IV - Intravenous(NDIS, 1985)
7.2.3 In-vitro data
No data available.
7.3 Carcinogenicity
Cisplatin is carcinogenic in animals so care must be
exercised in regards to handling cisplatin and wastes
associated with patients receiving cisplatin.
7.4 Teratogenicity
There is positive evidence of human foetal risk, so the
benefits in pregnant women must be weighed against the risk
(Category D in Briggs et al., 1990).
7.5 Mutagenicity
Cisplatin is mutagenic in bacterial cultures and produces
chromosome aberrations in animal cells in tissue culture
(NDIS, 1985).
7.6 Interactions
Aluminium
All aluminium and aluminium alloys in IV sets, needles,
catheters and syringes form a black precipitate of platinum
(with a rapid loss of potency) when cisplatin is given
through these devices.
Nephrotoxic drugs
Cisplatin produces cumulative nephrotoxicity that can be
potentiated by nephrotoxic drugs, e.g. aminoglycosides,
cephalosporins and amphoteracin B, etc.
Aminoglycosides
Concurrent administration of aminoglycosides within 1-2 weeks
of cisplatin therapy has been associated with an increased
risk of nephrotoxicity and renal failure. Therefore
aminoglycosides should be used with extreme care during
treatment.
Other
When in an aqueous solution, cisplatin reacts with a variety
of chemical molecules including bromide and iodide ions,
bisulphite etc.
Metabisulphite, found as a preservative in some parenteral
formulations can rapidly inactivate cisplatin. Therefore
avoid admixture of cisplatin with other agents that may
contain excipients (NDIS, 1985).
There is a risk of potentiating cisplatin ototoxicity with
the other ototoxic drugs, e.g. aminoglycosides and loop
diuretics.
Studies in animals indicate that the antineoplastic activity
of cisplatin and some other antineoplastic agents can be
potentially synergistic. The agents trialed were bleomycin,
doxorubicin, fluorouracil, methotrexate, vinblastine,
vincristine and etoposide (McEvoy, 1992).
7.7 Main Adverse Effects
Numerous adverse effects during cisplatin therapy have been
reported in the literature.
Renal effects
Nephrotoxicity is dose related and can be severe. Cisplatin
should be administered with adequate intravenous hydration
and diuresis.
Renal toxicity is seen by an increase in serum creatinine,
BUN, serum uric acid and/or a decrease in creatinine
clearance and glomerular filtration rate.
Hypomagnesaemia and other electrolyte disturbances can be
seen during cisplatin therapy which is secondary to
cisplatin-induced renal dysfunction.
Cisplatin increases the excretion of magnesium and calcium
and to a lesser extent potassium, zinc, copper and amino
acids.
The symptoms of hypomagnesaemia include muscle irritability
or cramps, clonus, tremor, carpopedal spasm and/or tetany.
These symptoms can also persist for several months to years
post cisplatin therapy.
Gastrointestinal
Marked nausea and vomiting are seen during cisplatin therapy.
Cisplatin is considered to be amongst the most emetogenic
antineoplastic agents available.
Diarrhoea is also a side effect of cisplatin therapy and
occurs less frequently than nausea and vomiting.
Otic effects
Ototoxicity has occurred in patients receiving cisplatin
therapy and is manifested as tinnitus, with or without loss
of hearing and occasional deafness. Fosfomycin, an
antibacterial antibiotic, appears to protect against
cisplatin-induced ototoxicity. Ototoxicity tends to be more
severe in children than in adults.
Cisplatin has also caused vestibular ototoxicity, i.e.
vertigo or vestibular dysfunction but it is a rare
occurrence. Those patients with pre-existing vestibular
dysfunction are most at risk.
Neurotoxicity
Peripheral neuropathies have been noted during cisplatin
therapy and manifest themselves as paraesthesia of the upper
and lower extremities and other sensory functions.
Peripheral neuropathies generally occur only after prolonged
(4 to 7 months) treatment but their incidence rises if other
neurotoxic agents are used.
Haematological effects
Myelosuppression occurs in about 25 to 30% of patients and
manifests itself as leucopenia, thrombocytopenia and anaemia.
Myelosuppression can be cumulative and severe especially if
the patient has been previously treated with other
antineoplastic agents.
Sensitivity Reactions
Anaphylaxis has occurred during cisplatin therapy and has
occurred after 5 or more doses of the drug. Some of the
manifestations include facial oedema, flushing, wheezing or
respiratory distress, tachycardia and hypotension etc.
These reactions have occurred after intravenous and
intravesical administration.
Cardiovascular effects
Cardiovascular effects are rare but can be debilitating.
Symptoms include bradycardia, left bundle branch block,
congestive heart failure. The vascular toxicities include
myocardial infarction, coronary artery disease, renovascular
lesions, cerebrovascular accidents and Raynaud's phenomenon.
Ocular effects
Optic neuritis, papilloedema and cerebral blindness are rare
occurrences in patients receiving cisplatin therapy.
Hepatic effects
Mild and transient elevations of serum AST (SGOT) and ALT
(SGPT) concentrations are rare in cisplatin therapy.
Local effects
Local phlebitis may occur after intravenous use of cisplatin.
Local pain, oedema and erythema have also occurred following
intra-arterial infusion.
(NDIS, 1985; Gilman et al., 1985; McEvoy, 1992)
8. PHARMACOLOGICAL, TOXICOLOGICAL AND OTHER ANALYSES
8.1 Sample
8.1.1 Collection
8.1.2 Storage
8.1.3 Transport
8.2 Toxicological Analytical Methods
8.2.1 Tests for active ingredient
8.2.2 Tests for biological sample
8.3 Other Laboratory analyses
8.3.1 Biochemical Investigations
8.3.1.1 Blood
The manufacturers recommend serum magnesium,
potassium, calcium, urea and creatinine
concentrations and BUN should be determined
prior to each additional course of therapy.
Peripheral blood counts should also be
monitored at least weekly in patients using
therapeutic doses of cisplatin. Liver function
tests should also be performed regularly.
8.3.1.2 Urine
The manufacturers recommend creatinine
clearance be determined prior to beginning
cisplatin therapy.
8.3.1.3 Other
Visual and auditory tests should be performed
throughout treatment with cisplatin.
8.3.2 Arterial Blood Gas Analysis
8.3.3 Haematological or Haemostasiological Investigations
Peripheral blood counts should be monitored at least
weekly (as recommended by the manufacturers) during
cisplatin therapy. Cisplatin has the potential to
cause myelosuppression and the blood counts will give
an indication of how severely the condition has
progressed.
8.3.4 Other Relevant Biomedical Analyses
ECG and other cardiac monitoring devices should be
employed to enable electrolyte and cardiac disturbances
to be recognised.
8.4 Interpretation
Cisplatin induces nephrotoxicity with hypomagnesaemia,
hypocalcaemia and hypokalaemia as manifestations. By
interpreting blood and urine electrolyte concentrations the
degree of toxicity can be determined.
Auditory tests can give an indication of the ototoxicity
caused by cisplatin and doses should be postponed or reduced
as indicated.
Peripheral blood counts indicate the degree of
myelosuppression and carcinoma treatment should not continue
if these counts are not within the normal ranges (McEvoy,
1992; Gilman et al., 1985; NDIS, 1985).
9. CLINICAL EFFECTS
9.1 Acute Poisoning
9.1.1 Ingestion
Cisplatin is not effective when administered orally.
This route would not be a likely source of poisoning
(Gilman et al., 1985).
9.1.2 Inhalation
No data available.
9.1.3 Skin Exposure
Dermal contact absorption can occur during
administration to either the operator or the patient
receiving the drug.
Local necrosis following cisplatin extravasation has
been reported.
Also a pruritic erythematous macular rash and non
infectious pyoderma have been reported in the
literature.
(NDIS, 1985; Gilman et al., 1985; McEvoy, 1992;
Reynolds, 1989)
9.1.4 Eye Contact
Necrosis is a possible effect when cisplatin is given
by the intravenous route.
Cisplatin can cause papilloedema and retrobular
neuritis following systemic administration.
9.1.5 Parenteral Exposure
Intravenous, intraperitoneal and intra-arterial routes
have all been used in cisplatin therapy and it is by
these routes that poisoning is most likely to occur.
Adequate pretreatment and post treatment hydration
(with intravenous fluids and diuresis) and maintenance
of adequate urinary output must be ensured throughout
cisplatin therapy to help minimise renal complications.
The hypothesis is that this regimen dilutes the
cisplatin metabolite concentrations in the kidney and
lessens the incidence of toxicity to the cells.
Renal toxicity is manifested by an increase in serum
creatinine, BUN, serum uric acid and/or a decrease in
creatinine clearance and glomerular filtration rate.
The renal impairment is a direct result of cisplatin
induced renal tubular damage leading ultimately to
renal failure.
Disturbances have been seen in serum electrolytes due
principally to cisplatin induced renal tubular
dysfunction. Patients subsequently develop
hypomagnesaemia, hypocalcaemia and hypokalaemia and to
a lesser extent hypophosphatemia and hyponatremia.
Cisplatin produces marked nausea and vomiting in almost
all patients to the extent that some patients
experience anticipatory nausea and vomiting. Diarrhoea
has also occurred but with less frequency than nausea
and vomiting.
Ototoxicity develops in various degrees on cisplatin
therapy. In larger and prolonged dosing with cisplatin
the ototoxicity can be irreversible. Although this is
not a life threatening event, it can be severe enough
for patients to refuse further antineoplastic therapy.
The haematological effects of cisplatin are usually
moderate and reversible.
Myelosuppression is a common problem seen as
leucopenia, thrombocytopenia and anaemia and if severe
enough can cause the death of the patient.
Myelosuppression can be cumulative so care must be
exercised during cisplatin therapy so that the
patient's blood counts can return to normal levels
before the next dose of cisplatin is due.
Anaphylactoid reactions can occur when cisplatin is
given and the manufacturer recommends that if they
occur, cisplatin administration should be stopped
immediately.
Cardiovascular effects are rare but include
bradycardia, left bundle branch block and congestive
heart failure.
Hepatic enzyme concentrations in the sera become
elevated including AST (SGOT) and ALT (SGPT).
9.1.6 Other
No data available.
9.2 Chronic poisoning
9.2.1 Ingestion
No data available.
9.2.2 Inhalation
No data available.
9.2.3 Skin data
No data available.
9.2.4 Eye Contact
No data available.
9.2.5 Parenteral Exposure
Renal toxicity is cumulative and seen usually after
several courses of cisplatin therapy. Disturbances in
electrolytes can be a long term manifestation due to
cisplatin induced renal tubular dysfunction.
Ototoxicity develops and is cumulative especially after
repeated high doses of cisplatin or when other ototoxic
drugs are given concurrently. Although this is not
life threatening it can be irreversible.
Haematological effects of cisplatin are cumulative
especially if the blood forming cells are not allowed
to recover after the course of treatment. Vigorous
treatments to prevent infections during the period of
myelosuppression will be required if the patient is to
survive.
9.2.6 Other
No data available.
9.3 Course, prognosis and cause of death
When an overdose of cisplatin is given the adverse effects
are not seen until days after the initial event, although
nausea and vomiting may occur initially.
The effects of myelosuppression can be seen starting about
one week after the overdose event. During this time patients
would require, if needed, adequate antibiotic therapy to
prevent infections.
The effects of nephrotoxicity can be seen immediately post
overdose and acute renal failure can be experienced days
later. The electrolytes to be monitored include magnesium,
potassium and calcium, all of which are involved in the
normal cell's functioning. Renal failure can lead, if not
treated, to the death of the patient.
The causes of death from an overdose of cisplatin include
myelosuppression, renal failure and tetany.
9.4 Systemic description of clinical effects
9.4.1 Cardiovascular
Acute
Cardiovascular effects are rare events during cisplatin
therapy. They can include bradycardia, left bundle
branch block and ST-T-wave changes with congestive hear
failure. Postural hypotension associated with
neurotoxicity has also occurred.
Vascular toxicities have also occurred including
myocardial infarction, coronary artery disease,
renovascular lesions, cerebrovascular accidents or
cerebral arteritis and Raynaud's phenomenon. The
mechanism for the vascular toxicity has been proposed
as damage to the endothelial cells.
ECG changes secondary to electrolyte disturbances also
occur.
Chronic
No data available.
9.4.2 Respiratory
Acute
Hyperpnoea and acute respiratory failure have been
reported (Fassoulaki & Pavlov, 1989).
Chronic
No data available.
9.4.3 Neurological
9.4.3.1 Central Nervous System (CNS)
Acute
Decreased hearing, "thick" speech, impairment
of taste and numbness of hands was experienced
by a 36-year-old man who received 480 mg/m2 of
cisplatin. Eighteen months later, he was no
longer dysarthric and he could taste normally
(Schiller 1989).
Gait disturbances, loss or reduction of deep
tendon reflexes and seizures have also been
reported.
Disorientation, paranoia and agitation can be
attributed to cisplatin therapy (Reynolds
1989).
Chronic
No data available.
9.4.3.2 Peripheral Nervous System
Acute
Sensory function loss, with loss of
proprioception and vibratory sense in a
stocking-glove distribution and motor function
loss leading to ataxia have been seen with
cisplatin dosing (Reynolds, 1989; Dorr & Fritz,
1982).
Chronic
No data available.
9.4.3.3 Autonomic Nervous System
Acute
No data available.
Chronic
No data available.
9.4.3.4 Skeletal and smooth muscle
Acute
Tetany secondary to electrolyte imbalance has
been reported (Reynolds, 1989).
Chronic
No data available.
9.4.4 Gastrointestinal
Acute
Cisplatin is a potent emetogenic and induces marked
nausea and vomiting in almost all patients.
The nausea and vomiting appears to be mediated via a
central mechanism and usually commences 1 to 6 hours
post administration of cisplatin and continues for up
to 24 hours or longer. The nausea and anorexia can
persist for up to 5 to 10 days in some patients.
Cisplatin can also cause diarrhoea.
A metallic taste has also been reported in some
patients.
Chronic
No data available.
9.4.5 Hepatic
Acute
Serum AST (SGOT) and ALT (SGPT), bilirubin, alkaline
phosphatase concentrations can become elevated during
cisplatin therapy and it appears to be mild and
transient.
Reversible liver toxicity has occurred (McEvoy, 1992;
Dorr & Fritz, 1982).
Chronic
No data available.
9.4.6 Urinary
9.4.6.1 Renal
Acute
Nephrotoxicity is dose related, can be severe
and is most often reversible. It is manifested
by renal tubular damage resulting in an
elevation of the BUN, serum creatinine, serum
uric acid and/or a decrease in creatinine
clearance and glomerular filtration rate.
The peak detrimental effect on renal function
usually occurs between the 10th and 20th days
after treatment. Patients concomitantly
receiving other nephrotoxic agents, eg
aminoglycosides, have been shown to be at a
greater risk of developing renal failure (Dorr
& Fritz, 1982).
Hypomagnesaemia, hypocalcaemia, hypokalaemia
have all been experienced during therapy.
Hyperuricemia has also occurred but secondary
to impaired tubular transport of uric acid.
This increase in uric acid is seen with the
increased tumour breakdown during therapy.
Chronic
No data available.
9.4.6.2 Others
No data available.
9.4.7 Endocrine and Reproductive Systems
Acute
Gynaecomastia is a rare occurrence following
combination chemotherapy including cisplatin.
Transient or permanent sterility has also been noted
(McEvoy, 1992).
Chronic
No data available.
9.4.8 Dermatological
Pruritic erythematous macular rashes have been reported
as well as non infectious pyoderma (McEvoy, 1992).
9.4.9 Eye, Ear, Nose, Throat: Local effects
Acute
Papilloedema, cerebral blindness and optic neuritis
have occurred during combination therapy with cisplatin
and other antineoplastic agents but it is a rare
occurrence.
Improvement and/or total recovery usually occurs when
cisplatin is discontinued but children and patients
with abnormal pre-treatment audiograms are most at risk
and sometimes severe impairment may not be reversible
(McEvoy, 1992; NDIS, 1985).
Tinnitus and the decreased ability to hear normal
conversations are observed during cisplatin therapy.
Ototoxicity is seen more frequently in patients with
pre-existing hearing impairment, concomitant
administration of other ototoxic substances, eg
aminoglycosides, and with higher doses of cisplatin.
Tinnitus is usually transient and can persist from
several hours to up to a week post therapy with
cisplatin.
Hearing loss is usually bilateral and normally occurs
at 4000 to 8000 Hz, progressing with time to lower
frequencies. The auditory damage appears to be due to
degenerative changes in cochlear hair cells (McEvoy,
1992).
Chronic
No data available.
9.4.10 Haematological
Acute
Myelosuppression, which is manifested by leucopenia,
thrombocytopenia and anaemia has been noted in about
25 to 30% of patients receiving cisplatin therapy.
Myelosuppression may be cumulative and more severe in
those patients previously treated with antineoplastic
agents, radiotherapy/cisplatin or already
immunocompromised.
Leucopenia and thrombocytopenia are dose related and
become more pronounced when the dose of cisplatin is
greater than 50 mg/m2. Leucocyte and platelet nadirs
generally occur 18 to 23 days (range of 7.2 to 45
days) following a single dose of cisplatin, with
levels returning to pre-treatment levels in most
patients within 39 days (range 13 to 62 days).
Subsequent courses of cisplatin should not be
instituted until platelets are present at levels
greater than 100,000/mm3 and white cells greater than
4000/mm3.
Anaemia (decrease of greater than 2 g percent
haemoglobin) occurs in a significant number of
patients but usually after several courses of
treatment.
The anaemia is of the normochromic - normocytic type
and frequently returns to normal on cessation of
therapy. Transfusions may be indicated in severe cases
of anaemia.
Cisplatin has been shown to sensitise red blood cells
and sometimes results in a direct Coombs positive
haemolytic anaemia. It has been suggested that
anaemia caused by cisplatin may have resulted from a
drug induced decrease in erythropoietin or erythroid
stem cells. There is also some evidence that both
haemolysis and decreased erythropoiesis may contribute
to the anaemia (Dorr & Fritz, 1982; McEvoy, 1992;
NDIS, 1985; Reynolds, 1989).
Chronic
Myelosuppression and anaemia have been reported to be
cumulative especially if courses of cisplatin are
given more frequently than every 3 to 4 weeks. This
interval allows the bone marrow suppression to reverse
(Dorr & Fritz, 1982; NDIS, 1985; McEvoy, 1992).
9.4.11 Immunological
Acute
Anaphylactoid reactions have occurred during therapy
with cisplatin. Those patients with a history atopy
are particularly at risk. The reaction is
characterised by facial oedema, wheezing, tachycardia,
hypotension and skin rash of urticarial nonspecific
maculopapular type. These all can occur within a few
minutes of administration.
The anaphylactoid reactions usually occur after about
5 doses of cisplatin. The mechanism of action is not
yet known but the reactions appear to be immune
mediated in some patients (McEvoy, 1992; NDIS, 1985;
Dorr & Fritz, 1982).
Chronic
Anaphylactoid reactions would occur after repeated
courses of cisplatin especially in those patients with
a history of atopy.
9.4.12 Metabolic
9.4.12.1 Acid Base disturbances
Acute
A 59-year-old female experienced hypocapnia
with the with the resultant acid-base
disturbances during an overdose of cisplatin.
It was postulated that the cisplatin crossed
the blood-brain barrier and had a direct
effect on the respiratory centre (Fassoulaki
& Pavlov, 1989).
Chronic
No data available.
9.4.12.2 Fluid and Electrolyte Disturbances
Acute
Cisplatin can cause severe electrolyte
disturbances, principally hypomagnesaemia,
hypocalcaemia and hypokalaemia.
Hypophosphatemia and hyponatremia have also
occurred but to a lesser degree.
The disturbance in electrolytes is a direct
result of cisplatin induced renal tubular
dysfunction.
Cisplatin causes marked excretion of calcium
and magnesium as well as potassium, zinc,
copper and amino acids. The mechanism is not
known but it may be a specific drug-induced
membrane or transport system defect.
Hypomagnesaemia and hypocalcaemia can occur
during cisplatin therapy or within 3 to 4
weeks post administration. The severity of
hypomagnesaemia increases with each
subsequent course of cisplatin.
Children are particularly sensitive to
cisplatin and tend to develop hypomagnesaemia
more readily than adults. The effects of
hypomagnesaemia and hypocalcaemia include
muscle irritability or cramps, clonus,
tremor, carpopedal spasm and/or tetany.
Hyperuricemia may occur in patients
principally as a result of cisplatin induced
nephrotoxicity.
Hyperuricemia is more pronounced when doses
of cisplatin exceed 50 mg/m2 and peak serum
concentrations of uric acid generally occur
3 - 5 days after the administration of the
drug (McEvoy, 1992; NDIS, 1985; Reynolds,
1989).
Chronic
Hypomagnesaemia has persisted for several
months to years after cisplatin therapy has
been discontinued, and in some patients the
effect has lasted longer than three years
(McEvoy, 1992).
9.4.12.3 Other
Acute
Other adverse effects associated with
cisplatin therapy include alopecia, myalgia,
pyrexia, and gingival platinum line.
Cisplatin has also been associated with the
occurrence of the Syndrome of Inappropriate
Antidiuretic Hormone Secretion (SIADH).
9.4.13 Allergic Reactions
See Section 9.4.11
9.4.14 Other Clinical Effects
No data available.
9.4.15 Special risks
Pregnancy
There is positive evidence of human foetal risks but
the benefits from use in pregnant women may be
acceptable despite the risk (Category D1 "A Reference
Guide to Foetal and Neonatal Risk in Pregnancy &
Lactation", Briggs et al., 1990).
Pregnancy is a relative contraindication in the use of
cisplatin because of its mutagenic effects on
bacterial cell cultures. It also causes chromosome
aberrations in animal cells in tissue culture (NDIS,
1985).
Breastfeeding
Breastfeeding is not recommended during cisplatin
therapy due to potential risk to the infant (Briggs et
al., 1990).
Enzyme Deficiencies
No data available.
10. MANAGEMENT
10.1 General Principles
Treatment is supportive and symptomatic. Patients should be
monitored for at least 3 to 4 weeks in case of delayed
toxicity.
The anticipated complications would be nephrotoxic,
ototoxic, neurotoxic and haematotoxic.
There is no specific antidote to use in cisplatin toxicity.
Hydration with 3 to 6 L intravenous fluids/day and
intravenous mannitol, which increases the urinary volume and
thus decrease the effective urinary concentration of
platinum and its metabolites, is recommended.
Monitor vital signs. Renal and hepatic function, ECG,
haematological, otic and neurological functions should also
be monitored. Serum electrolyte concentrations and fluid
requirements should be monitored and corrected if required.
The manufacturers recommend that serum magnesium, potassium,
calcium and creatinine concentrations, creatinine clearance
and BUN be determined prior to and during therapy.
The peripheral blood counts should be monitored as the
haematological effects can be slow in developing and
monitoring should be continued 3 to 4 weeks post incident.
Although not a life threatening problem, ototoxicity can be
cumulative and persistent. Auditory function tests should
be performed regularly.
10.2 Relevant laboratory analyses and other investigations
10.2.1 Sample Collection
No data available.
10.2.2 Biomedical analysis
Monitor electrolytes including magnesium, potassium,
calcium, phosphate and creatinine levels.
Monitor liver function tests.
Monitor peripheral blood counts.
Monitor cardiac functions.
10.2.3 Toxicological analysis
No data available.
10.2.4 Other Investigations
Auditory function tests can be performed to give an
indication of ototoxicity.
10.3 Life Supportive procedures and symptomatic treatment
Cisplatin causes myelosuppression to some degree in all
patients. In the overdosed patient the haemopoietic system
should be supported. Therapy would include packed cells and
other blood products. In immuno-compromised patients anti-
infective prophylaxis may be indicated.
Correction of the electrolyte imbalances to prevent serious
secondary effects should be monitored.
Correction of the nausea and vomiting episodes to avoid
gastro-oesophageal mechanical tears and electrolyte
imbalances.
10.4 Decontamination
Wash all cisplatin-contaminated areas with copious amounts
of water or irrigation fluids. The irrigation should last
for at least 15 minutes when eye exposure is suspected.
Oral ingestion of cisplatin has not yet been reported but if
this occurs then emesis, gastric lavage and activated
charcoal should be instigated.
If cisplatin is spilled, wipe up spillage with disposable
sponges which should be incinerated. Any remainder may be
inactivated with sodium tetraborate 2% stabilised with 0.2%
sodium hydroxide (this solution is stable for one week).
10.5 Elimination
Adequate hydration with 3 to 6 litres of intravenous fluids
should be given when cisplatin is administered, together
with mannitol and diuretics (e.g. frusemide). This
maintains adequate urine output as well as having cisplatin
diluted in the urine.
Haemodialysis has been tried but because cisplatin rapidly
becomes protein bound it is of little value.
10.6 Antidote
10.6.1 Adults
To date there is no antidote available for cisplatin
overdose.
10.6.2 Children
To date there is no antidote available for cisplatin
overdose.
10.7 Management discussion
Extreme caution should be taken by persons handling
biological fluids and wastes of treated patients (either in
normal therapy or in overdose cases).
If the plasma proteins to which cisplatin has become bound
could be removed (e.g. plasma exchange) then this may be an
effective method of reducing the cisplatin burden.
11. ILLUSTRATIVE CASES
11.1 Case reports from the Literature
Case 1
Fassoulaki & Pavlov (1989) - a 59-year-old patient with
advanced ovarian carcinoma was given in error 150 mg of
cisplatin for three consecutive days instead of 50 mg/day
for three days (a total dose of 450 mg was given within
three days). On day four following the cisplatin
overdosage the patient developed numbness of the upper and
lower limbs, headache and hyperpnoea. Electrocardiogram,
central venous pressure, direct arterial blood pressure and
urine output were monitored continuously. The patient
became unconscious and was thus intubated and ventilated
mechanically. The K+ and PO4- renal losses were
significant and K+ daily replacement reached 18 g/day.
Myelosuppression developed and in treatment received 26
units of platelets and 9 units of blood. The patient's
recovery was complete except for a hearing impairment.
Case 2
Schiller et al. - A 36-year-old white male developed
testicular choriocarcinoma for which he was to receive
cisplatin. On the third cycle he inadvertently received a
continuous infusion of 40 mg/m2 every eight hours for 4
days (198 mg/day = 480 mg/m2) instead of 40 mg/m2 /day
divided into three equal eight-hour infusions.
Complications included myelosuppression, neurotoxicity,
ototoxicity and nephrotoxicity. Treatment included broad-
spectrum antibiotics when the patient became febrile,
intensive parenteral hydration, mannitol diuresis and
administering the drug in hypertonic saline. The patient
recovered from the event but had residual ototoxicity.
Case 3
A 59-year-old woman with metastatic adenocarcinoma was
given hydroxyurea and cisplatin every three weeks. Four
days after the third case of treatment the patient
developed confusion and then status epilepticus. The
total cumulative dose of cisplatin was 225 mg/m2. She
remained unconscious for 36 hours despite treatment. On
the fifth day she regained consciousness but had reduced
visual acuity of 6/60 bilaterally. The visual acuity slowly
improved and was normal by the tenth day (Clin Alert,
1991a).
Case 4
A 26-year-old man with an abdominal mass and two pulmonary
nodules was given cisplatin, etoposide and bleomycin in
conventional doses. After the third cycle of the regimen,
the patient noted a transitory speech disorder and weakness
of the left arm on discharge from hospital. He was
readmitted to hospital with motor aphasia, left hemiparesis
and right-sided Jackson seizures. An occlusion of the
right middle cerebral artery was suspected and confirmed.
A thrombectomy was performed but the patient deteriorated
and died from uncontrollable cerebral oedema (Clin Alert,
1991b).
11.2 Internally extracted data on cases
No data available.
11.3 Internal Cases
To be added by the centre
12. ADDITIONAL INFORMATION
12.1 Availability of Antidotes
There is no recommended antidote available for cisplatin
overdose. To be added by the centre.
12.2 Specific Preventative Measures
No data available.
12.3 Other
No data available.
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14. AUTHOR(S), REVIEWER(S), DATE(S), COMPLETE ADDRESS(ES)
Author Ms A.E.F. Kaye
Tasmanian Poison Information Centre
Royal Hobart Hospital
GPO Box 1061L
Hobart 7001
Tasmania
Australia
Tel: 61-02-388465
Fax: 61-02-312043
Date April 1992
Reviewer Dr K. Hartigan-Go
Department of Pharmacology
University of the Philippines Medical School
Pedro Gil Street
Manila
Philippines
Date July 1992
Peer London, United Kingdom, September 1992,
review (Drs Caitens, Critchley, Kaye, Maramba, Ombega,
Panganiban)
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Fischer DS & Knobf MT (1989) The Cancer chemotherapy handbook 3rd
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Gosselin RE, Smith RP & Hodge HC (1984) Clinical toxicology of
commercial products. 5th ed., Baltimore, MD, Williams and Wilkins.
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Edition, Drug Intelligence Publications Inc.
Mollman JE (1990) Cisplatin Neurotoxicity. The New England Journal
of Medicine, 322 ( 2):
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Trissel LA (1990) Handbook on injectable drugs, 6th ed. Bethesda,
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