Busalphan Tablets Taj Pharma-SMPC

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Rx Busulfan may be useful in selected cases of

essential thrombocythaemia and
Busulfan Tablets USP 2mg Taj myelofibrosis.
Pharma 4.2 Posology and method of
administration
1.NAME OF THE MEDICINAL General

PRODUCT The bioavailability of oral Busulfan shows
Busulfan 2 mg tablets taj pharma large intra-individual variations ranging
from 47% to 103% (mean 80%) in adults
2. QUALITATIVE AND and from 22% to 120% (mean 68%) in
QUANTITATIVE COMPOSITION children (see section 5.2).
Each 2 mg tablet contains 2 mg of the active There are other formulations available
substance busulfan which may be more suitable for paediatric
patients.
Excipient with known effect: lactose
Busulfan tablets are usually given in courses
For the full list of excipients, see section 6.1. or administered continuously. The dose must
be adjusted for the individual patient under
3. PHARMACEUTICAL FORM
close clinical and haematological control.
Film coated tablet Should a patient require an average daily
dose of less than the content of the available
Busulfan 2 mg tablets are white, film-
Busulfan tablets, this can be achieved by
coated, round biconvex tablets engraved
introducing one or more busulfan free days
“GX EF3” on one side and “M” on the
between treatment days. The tablets should
other.
not be divided (see section 6.6).
4. CLINICAL PARTICULARS Obese
4.1 Therapeutic indications Dosing based on body surface area or
Busulfan is indicated as conditioning adjusted ideal body weight should be
treatment prior to haemopoietic progenitor considered in the obese (see section 5.2).
cell transplantation in patients when the
combination of high-dose busulfan and The relevant literature should be consulted
cyclophosphamide is considered the best for full details of treatment schedules.
available option. Conditioning prior to haemopoietic
Busulfan is indicated for the palliative progenitor cell transplantation
treatment of the chronic phase of chronic When bulsulfan is used as a conditioning
myeloid leukaemia. treatment prior to haemopoietic progenitor
Busulfan is effective in producing prolonged cell transplantation, drug level monitoring is
remission in polycythaemia vera, recommended.
particularly in cases with marked Populations
thrombocytosis.
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Adults dose after this point or following depression

of the platelet count to below 100 x 109per
The recommended dose of busulfan in adult
litre is associated with a significant risk of
patients is 1 mg/kg every 6 hours for four
prolonged and possibly irreversible bone
days, starting seven days prior to
marrow aplasia.
transplantation. 60 mg/kg per day of
cyclophosphamide is usually given for two Maintenance in adults
days commencing 24 h after the final dose
Control of the leukaemia may be achieved
of Busulfan (see section 4.4 and 4.5).
for long periods without further Busulfan
Paediatric population treatment; further courses are usually given
when the leucocyte count rises to 50 x
The conventional dosage plan for
109 per litre, or symptoms return.
conditioning before haemopoietic stem cell
transplantation is 30 to 37.5 mg/m2 every 6 Some clinicians prefer to give continuous
hours for 4 days, starting seven days prior to maintenance therapy. Continuous treatment
transplantation. The dosing of is more practical when the duration of
cyclophosphamide is the same as for adults. unmaintained remissions is short.
Chronic myeloid leukaemia The aim is to maintain a leucocyte count of
10 to 15 x 109 per litre and blood counts
Induction in adults
must be performed at least every 4 weeks.
Treatment is usually initiated as soon as the The usual maintenance dosage is on average
condition is diagnosed. The dose is 0.06 0.5 to 2 mg/day, but individual requirements
mg/kg/day, with an initial daily maximum of may be much less. Should a patient require
4 mg, which may be given as a single dose. an average daily dose of less than the
content of one tablet, the maintenance dose
There is individual variation in the response
may be adjusted by introducing one or more
to Busulfan and in a small proportion of
Busulfan free days between treatment days.
patients the bone marrow may be extremely
sensitive (see section 4.4). Note: Lower doses of Busulfan should be
used if it is administered in conjunction with
The blood count must be monitored at least
other cytotoxic agents (see section 4.5 and
weekly during the induction phase and it
4.8).
may be helpful to plot counts on semilog
graph paper. Paediatric population
The dose should be increased only if the Chronic myeloid leukaemia is very rare in
response is inadequate after three weeks. the paediatric age group. Busulfan may be
used to treat Philadelphia chromosome
Treatment should be continued until the total
positive (Ph' positive) disease, but the Ph'
leucocyte count has fallen to between 15 and
negative juvenile variant responds poorly.
25 x 109 per litre (typically 12 to 20 weeks).
Treatment may then be interrupted, Polycythaemia vera
following which a further fall in the
The usual dose is 4 to 6 mg daily, continued
leucocyte count may occur over the next two
for 4 to 6 weeks, with careful monitoring of
weeks. Continued treatment at the induction
the blood count, particularly the platelet immunocompromised hosts. Therefore,

count. immunisations with live organism vaccines
are not recommended.
Further courses are given when relapse
occurs; alternatively, maintenance therapy Busulfan should be discontinued if lung
may be given using approximately half the toxicity develops (see section 4.8).
induction dose.
Busulfan should not generally be given in
If the polycythaemia is controlled primarily conjunction with or soon after radiotherapy.
by venesection, short courses of Busulfan
Busulfan is ineffective once blast
may be given solely to control the platelet
transformation has occurred.
count.
If anaesthesia is required in patients with
Myelofibrosis
possible pulmonary toxicity, the
The usual initial dose is 2 to 4 mg daily. concentration of inspired oxygen should be
kept as low as safely as possible and careful
Very careful haematological control is
attention given to post-operative respiratory
required because of the extreme sensitivity
care.
of the bone marrow in this condition.
Hyperuricaemia and/or hyperuricosuria are
Essential thrombocythaemia
not uncommon in patients with chronic
The usual dose is 2 to 4 mg per day. myeloid leukaemia and should be corrected
before starting treatment with Busulfan.
Treatment should be interrupted if the total
During treatment, hyperuricaemia and the
leucocyte count falls below 5 x 109 per litre
risk of uric acid nephropathy should be
or the platelet count below 500 x 109 per
prevented by adequate prophylaxis,
litre.
including adequate hydration and the use of
4.3 Contraindications allopurinol.
Busulfan should not be used in patients
Studies in renally impaired patients have not
whose disease has demonstrated resistance
been conducted, however, as busulfan is
to busulfan.
moderately excreted in the urine, dose
Busulfan should not be given to patients modification is not recommended in these
who have previously suffered a patients. However, caution is recommended.
hypersensitivity reaction to the busulfan or
Busulfan has not been studied in patients
any other component of the preparation.
with hepatic impairment. Since busulfan is
4.4 Special Warnings and precautions for mainly metabolized through the liver,
use caution should be observed when busulfan is
used in patients with pre-existing
Busulfan is an active cytotoxic agent for use impairment of liver function, especially in
only under the direction of physicians those with severe hepatic impairment.
experienced in the administration of such
agents. The medicinal product contains lactose.
Patients with rare hereditary problems of
Immunisation using a live organism vaccine galactose intolerance, the Lapp lactase
has the potential to cause infection in
deficiency or glucose-galactose be at the discretion of the prescribing

malabsorption should not take this medicine. physician and should be based on a
risk/benefit assessment.
Conventional dose Treatment
A reduced incidence of hepatic veno-
Patients who are concurrently treated with
occlusive disease and other regimen-related
the conventional dose of busulfan and
toxicities have been observed in patients
itraconazole or metronidazole should be
treated with high-dose Busulfan and
closely monitored for signs of busulfan
cyclophosphamide when the first dose of
toxicity. At concomitant use of these agents
cyclophosphamide has been delayed for >
with busulfan weekly blood counts are
24 hours after the last dose of Busulfan.
recommended (see section 4.5).
Safe Handling of Busulfan Tablets
Monitoring
See section 6.6
Careful attention must be paid to monitoring
the blood counts throughout treatment to Busulfan is genotoxic in non-clinical studies
avoid the possibility of excessive (see section 5.3).
myelosuppression and the risk of
Mutagenicity
irreversible bone marrow aplasia (see
section 4.8). Various chromosome aberrations have been
noted in cells from patients receiving
Hepatic veno-occlusive disease is a major
busulfan.
complication that can occur during treatment
with Busulfan. Patients who have received Carcinogenicity
prior radiation therapy, for three or more
On the basis of human studies, Busulfan was
cycles of chemotherapy, or prior progenitor
considered by the International Agency for
cell transplant may be at an increased risk of
Research on cancer to show sufficient
developing hepatic veno-occlusive disease
evidence for carcinogenicity. The World
(see section 4.8).
Health Association has concluded that there
High-dose Treatment (used for Haemopoetic is a causal relationship between Busulfan
Stem Cell Transplantation) exposure and cancer.
If high-dose Busulfan is prescribed, patients Widespread epithelial dysplasia has been
should be given prophylactic anticonvulsant observed in patients treated with long-term
therapy, preferably with a benzodiazepine Busulfan, with some of the changes
rather than phenytoin. resembling precancerous lesions.
Concomitant administration of itraconazole A number of malignant tumours have been
or metronidazole with high-dose busulfan reported in patients who have received
has been reported to be associated with an Busulfan treatment.
increased risk of busulfan toxicity (see
The evidence is growing that Busulfan, in
section 4.5). Co-administration of
common with other alkylating agents, is
metronidazole and high-dose busulfan is not
leukaemogenic. In a controlled prospective
recommended. Co-administration of
study in which 2 years' Busulfan treatment
itraconazole with high-dose busulfan should
was given as an adjuvant to surgery for lung
cancer, long-term follow-up showed an itraconazole or metronidazole is reported to

increased incidence of acute leukaemia be associated with an increased risk of
compared with the placebo-treated group. busulfan toxicity (see section 4.4).
The incidence of solid tumours was not
A reduced incidence of hepatic veno-
increased.
occlusive disease and other regimen-related
Although acute leukaemia is probably part toxicities have been observed in patients
of the natural history of polycythaemia vera, treated with high-dose Busulfan and
prolonged alkylating agent therapy may cyclophosphamide when the first dose of
increase the incidence. cyclophosphamide has been delayed for >
24 hours after the last dose of busulfan.
Very careful consideration should be given
to the use of busulfan for the treatment of Paracetamol is described to decrease
polycythaemia vera and essential glutathione levels in blood and tissues, and
thrombocythaemia in view of the drug's may therefore decrease busulfan clearance
carcinogenic potential. The use of busulfan when used in combination.
for these indications should be avoided in
4.6 Fertility, Pregnancy and lactation
younger or asymptomatic patients. If the
drug is considered necessary treatment Fertility
courses should be kept as short as possible.
Busulfan can lead to suppression of ovarian
4.5 Interaction with other medicinal function and amenorrhoea in women and
products and other forms of interaction suppression of spermatogenesis in men (see
section 4.8 and 5.3).
Vaccinations with live organism vaccines
are not recommended in Pregnancy
immunocompromised individuals (see
As with all cytotoxic chemotherapy,
section 4.4).
adequate contraceptive precautions should
The effects of other cytotoxics producing be advised when either partner is receiving
pulmonary toxicity may be additive. Busulfan.
The administration of phenytoin to patients The use of Busulfan should be avoided
receiving high-dose Busulfan may result in a during pregnancy whenever possible. In
decrease in the myeloblative effect. animal studies (see section 5.3) it has the
potential for teratogenic effects, whilst
In patients receiving high-dose busulfan it
exposure during the latter half of pregnancy
has been reported that co-administration of
resulted in impairment of fertility in
itraconazole decreases clearance of busulfan
offspring. In every individual case the
by approximately 20 % with corresponding
expected benefit of treatment to the mother
increases in plasma busulfan levels. In
must be weighed against the possible risk to
combination with metronidazole (1200 mg,
the foetus.
given as 400 mg three times daily) busulfan
values are increased in approximately 80% A few cases of congenital abnormalities, not
(see section 4.4). Fluconazole had no effect necessarily attributable to busulfan, have
on busulfan clearance. Consequently, high- been reported and third trimester exposure
dose Busulfan in combination with may be associated with impaired intra-
uterine growth. However, there have also Neoplasms Common Leukaemia

been many reported cases of apparently benign, secondary to
normal children born after exposure to malignant and oncology
Busulfan in utero, even during the first unspecified chemotherapy (see
trimester. (including section 4.4)
Breastfeeding cysts and
polyps)
It is not known whether Busulfan or its Blood and Very Dose-related bone
metabolites are excreted in human breast lymphatic common marrow failure,
milk. Mothers receiving Busulfan should not system manifesting as
breast-feed their infants. disorders * leukopenia and
4.7 Effects on ability to drive and use particularly
machines thrombocytopenia
Rare Aplastic anaemia
There are no data on the effect of Busulfan Nervous Rare At high-dose:
on driving performance or the ability to system convulsion (see
operate machinery. A detrimental effect on disorders section 4.4 and
these activities cannot be predicted from the 4.5)
pharmacology of the drug.
Very rare Myasthenia gravis
4.8 Undesirable Effects Eye disorders Rare Lens disorder and
cataract (which
For this product there is no modern clinical
may be bilateral)
documentation which can be used as support
corneal thinning
for determining the frequency of undesirable
(reported after
effects. Undesirable effects may vary in
bone marrow
their incidence depending on the dose
transplantation
received and also when given in
preceded by high-
combination with other therapeutic agents.
dose Busulfan
The following convention has been utilised treatment)
for the classification of frequency: Very Cardiac Common At high-dose:
common (≥ 1/10), common (≥ 1/100 and < disorders cardiac tamponade
1/10), uncommon (≥ 1/1000 and < 1/100), in patients with
rare (≥ 1/10,000 and < 1/1000), very rare (< thalassaemia
1/10,000) and not known (frequency cannot
Respiratory, Very At high-dose:
be estimated from the available data).
thoracic and common idiopathic
The following table of adverse reactions mediastinal pneumonia
originated from the use of busulfan, or disorders * syndrome
busulfan in combination with other Common Interstitial lung
therapeutic agents. disease following
long term
System organ Frequency Side effects
conventional dose
class
use including
Gastrointestin Very At high-dose: urticaria,
al disorders common nausea, vomiting, erythema
diarrhoea, mouth multiforme,
ulceration erythema
nodosum,
Rare At conventional
porphyrianon-
dose: nausea,
acute, rash, dry
vomiting,
skin and fragility
diarrhoea, mouth
of the skin with
ulceration, which
complete
may possibly be
anhydrosis
ameliorated by
cheilosis,
using divided
Sjögren's
doses. Dry mouth
syndrome. An
Not Tooth hypoplasia increased
known radiation skin
Hepatobiliary Very At-high-dose: injury in patients
disorders * commonhyperbilirubinaem receiving
ia, jaundice, radiotherapy soon
venoocclusive after high-dose
liver disease (see Busulfan
section 4.4 and Renal and Common At high-dose: in
4.5) and biliary urinary combination with
fibrosis with disorders cyclophosphamide
hepatic atrophy cystitis
and necrosis haemorrhagic
Rare Jaundice and Reproductive Very Ovarian disorder
abnormal hepatic system and common and amenorrhoea
function, at breast with menopausal
conventional dose. disorders * symptoms in pre-
Biliary fibrosis menopausal
Skin and Common Alopecia at high- patients at high-
subcutaneous dose. Skin dose; severe and
tissue hyperpigmentatio persistent ovarian
disorders * n (see also failure, including
General disorders failure to achieve
and administration puberty after
site conditions) administration to
Rare Alopecia at young girls and
conventional dose, pre-adolescents at
skin reactions high-dose. Male
infertility,
azoospermia and subclinical lung injury caused by busulfan.

testicular atrophy Once pulmonary toxicity is established the
in male patients prognosis is poor despite busulfan
receiving withdrawal and there is little evidence that
Busulfan corticosteroids are helpful.
Uncommo Ovarian disorder Idiopathic pneumonia syndrome is a non-
n and amenorrhoea infectious diffuse pneumonia which usually
with menopausal occurs within three months of high-dose
symptoms in pre- Busulfan conditioning prior to allogeneic or
menopausal autologous haemopoietic transplant. Diffuse
patients at alveolar haemorrhage may also be detected
conventional dose. in some cases after broncholavage. Chest X-
In very rare cases, rays or CT scans show diffuse or non-
recovery of specific focal infiltrates and biopsy shows
ovarian function interstitial pneumonitis and diffuse alveolar
has been reported damage and sometimes fibrosis.
with continuing
treatment Interstitial pneumonitis may occur following
conventional dose use and lead to
Very rare Gynaecomastia pulmonary fibrosis. This usually occurs after
General Rare Dysplasia prolonged treatment over a number of years.
disorders and The onset is usually insidious but may also
administratio be acute. Histological features include
n site atypical changes of the alveolar and
conditions * bronchiolar epithelium and the presence of
* Description of selected adverse events giant cells with large hyperchromatic nuclei.
The lung pathology may be complicated by
Blood and lymphatic system disorders superimposed infections. Pulmonary
Aplastic anaemia (sometimes irreversible) ossification and dystrophic calcification
has been reported rarely, typically following have also been reported.
long-term conventional doses and also high Hepatobiliary disorders
doses of Busulfan.
Busulfan is not generally considered to be
Respiratory, thoracic and mediastinal significantly hepatotoxic at normal
disorders therapeutic doses. However, retrospective
Pulmonary toxicity after either high or review of postmortem reports of patients
conventional dose treatment typically who had been treated with low-dose
presents with non-specific non-productive busulfan for at least two years for chronic
cough, dyspnoea and hypoxia with evidence myeloid leukaemia showed evidence of
of abnormal pulmonary physiology. Other centrilobular sinusoidal fibrosis.
cytotoxic agents may cause additive lung Skin and subcutaneous tissue disorders
toxicity (see section 4.5). It is possible that
subsequent radiotherapy can augment
Hyperpigmentation occurs, particularly system common

in those with a dark complexion. It is often disorders
most marked on the neck, upper trunk, Metabolism Very Hyperglycaemia,
nipples, abdomen and palmar creases. This and nutrition common hypocalcaemia,
may also occur as part of a clinical disorders hypokalaemia,
syndrome (see General disorders and hypomagnesaemi
administration site conditions). a,
Reproductive system and breast disorders hypophosphatae
mia
Studies of busulfan treatment in animals
have shown reproductive toxicity (see Common Hyponatraemia
section 5.3). Psychiatric Very Anxiety,
disorders common depression,
General disorders and administration site insomnia
conditions
Common Confusional state
Clinical syndrome (weakness, severe
Uncommo Delirium,
fatigue, anorexia, weight loss, nausea and
n nervousness,
vomiting and hyperpigmentation of the skin)
hallucination,
resembling adrenal insufficiency (Addison's
agitation
disease) but without biochemical evidence
of adrenal suppression, mucous membrane Nervous Very Headache,
hyperpigmentation or hair loss (see Skin and system common dizziness
subcutaneous tissue disorders) has been seen disorders Uncommo Encephalopathy,
in a few cases following prolonged Busulfan n cerebral
therapy. The syndrome has sometimes haemorrhage
resolved when busulfan has been withdrawn. Cardiac Very Tachycardia
Many histological and cytological changes disorders common
have been observed in patients treated with Common Arrhythmia, atrial
busulfan, including widespread dysplasia fibrillation,
affecting uterine cervical, bronchial and cardiomegaly,
other epithelia. Most reports relate to long- pericarditis
term treatment but transient epithelial Uncommo Ventricular
abnormalities have been observed following n extrasystoles,
short-term, high-dose treatment. bradycardia
The following table of adverse reactions Vascular Very Hypertension,
originated from the intravenous use of disorders common hypotension,
busulfan in combination with thrombosis,
cyclophosphamide or melphalan. vasodilation
System organ Frequency Side effects Uncommo Femoral artery
class n thrombosis,
capillary leak
Immune Very Hypersensitivity syndrome
Respiratory, Common Hyperventilation,

thoracic and respiratory
mediastinal failure, asthma, Reporting of suspected adverse reactions
disorders atelectasis, Reporting suspected adverse reactions after
pleural effusion authorisation of the medicinal product is
Gastrointestin Very Abdominal pain, important. It allows continued monitoring of
al disorders common dyspepsia, the benefit/risk balance of the medicinal
ascites, product. Healthcare professionals are asked
constipation, to report any suspected adverse reactions via
anorectal the Yellow Card Scheme at
discomfort www.mhra.gov.uk/yellowcard or search for
Common Haematemesis, MHRA Yellow Card in the Google Play or
ileus, Apple App Store
oesophagitis 4.9 Overdose
Uncommo Gastrointestinal Symptoms and signs
n haemorrhage
The acute dose-limiting toxicity of Busulfan
Hepatobiliary Very Hepatomegaly in man is myelosuppression (see section
disorders common 4.8).
Musculoskelet Very Myalgia, back The main effect of chronic overdose is bone
al and common pain, arthralgia marrow depression and pancytopenia.
connective
tissue Treatment
disorders
There is no known antidote to Busulfan.
Renal and Very Dysuria, oliguria Haemoialysis should be considered in the
urinary common management of overdose as there is one
disorders Common Haematuria, report of successful haemodialysis of
moderate renal Busulfan.
insufficiency
Appropriate supportive treatment should be
General Very Chills, pyrexia, given during the period of haematological
disorders and common chest pain, toxicity.
administration oedema, general
site conditions oedema, pain 5. PHARMACOLOGICAL
Investigations Very Weight increased, PROPERTIES
common abnormal breath 5.1 Pharmacodynamic properties
sounds, blood
creatinine Busulfan (1,4-butanediol
increased dimethanesulfonate) is a bifunctional
Common Blood urea alkylating agent. Binding to DNA is
increased, believed to play a role in its mode of action
decreased and di-guanyl derivaties have been isolated
ejection fraction
but interstrand crosslinking has not been nanograms.h/ml (range 2484 to 21090) and
conclusively demonstrated. 1047 nanograms/ml (range 295 to 2558)
respectively when measured by HPLC and
The basis for the uniquely selective effect of
6135 nanograms.h/ml (range 3978 to 12304)
busulfan on granulocytopoiesis is not fully
and 1980 nanograms/ml (range 894 to 3800)
understood. Although not curative, Busulfan
respectively using gas chromatography.
is very effective in reducing the total
granulocyte mass, relieving the symptoms of Distribution
disease and improving the clinical state of
Busulfan is reported to have a volume of
the patient. Busulfan has been shown to be
distribution of 0.64 ± 0.12 L/kg in adults.
superior to splenic irradiation when judged
by survival times and maintenance of Busulfan given in high-doses has recently
haemoglobin levels and is as effective in been shown to enter the cerebrospinal fluid
controlling spleen size. (CSF) in concentrations comparable to those
found in plasma, with a mean CSF:plasma
ration of 1.3:1. The saliva:plasma
5.2 Pharmacokinetic properties
distribution of Busulfan was 1.1:1.
Absorption
The level of busulfan bound reversibly to
The bioavailability of oral Busulfan shows plasma proteins has been variably reported
large intra-individual variations ranging to be insignificant or approximately 55 %.
from 47 % to 103 % (mean 80 %) in adults. Irreversible binding of drug to blood cells
and plasma proteins has been reported to be
The area under the curve (AUC) and peak
47 % and 32 %, respectively.
plasma concentrations (Cmax) of Busulfan
have been shown to be linearly dose Biotransformation
dependent. Following administration of a
Busulfan metabolism involves a reaction
single 2 mg oral dose of Busulfan, the AUC
with glutathione, which occurs via the liver
and Cmax of Busulfan were 125 ± 17
and is mediated by glutathione-S-
nanograms.h/ml and 28 ± 5 nanograms/ml
transferase.
respectively.
The urinary metabolites of busulfan have
A lag time between Busulfan administration
been identified as 3-hydroxysulpholane,
and detection in the plasma of up to 2 h has
tetrahydrothiophene 1-oxide and sulpholane,
been reported.
in patients treated with high-dose Busulfan.
High-dose Treatment Very little busulfan is excreted unchanged in
the urine.
Drug was assayed either using gas liquid
chromatography with electron capture Elimination
detection or by high-performance liquid
Busulfan has a mean elimination half life of
chromatography (HPLC).
between 2.3 and 2.8 h. Adult patients have
Following oral administration of high-dose demonstrated a clearance of busulfan of 2.4
Busulfan (1 mg/kg every 6 h for 4 days), to 2.6 ml/min/kg. The elimination half life
AUC and Cmax in adults are highly variable of busulfan has been reported to decrease
but have been reported to be 8260
upon repeat dosing suggesting that busulfan In vivo cytogenetic studies in rodents have
potentially increases its own metabolism. shown an increased incidence of
chromosome aberrations in both germ cells
Very little (1 to 2 %) busulfan is excreted
and somatic cells after Busulfan treatment.
unchanged in the urine.
Carcinogenicity
Special Patient Populations
There is limited evidence from preclinical
Paediatric population
studies that Busulfan is carcinogenic in
The bioavailability of oral busulfan shows animals (see section 4.4).
large intra-individual variation ranging from
Teratogenicity
22 % to 120 % (mean 68 %) in children.
There is evidence form animal studies that
Plasma clearance is reported to be 2 to 4
busulfan produces foetal abnormalities and
times higher in children than in adults when
adverse effects on off-spring, including
receiving 1 mg/kg every 6 h for 4 days.
defects of the musculo-skeletal system,
Dosing children according to body surface
reduced body weight and size, impairment
area has been shown to give AUC and
of gonad development and effects on
Cmax values similar to those seen in adults.
fertility.
The area under the curve has been shown to
be half that of adults in children under the Fertility
age of 15 years and a quarter of that of
Busulfan interferes with spermatogenesis in
adults in children under 3 years of age.
experimental animals. Limited studies in
Busulfan is reported to have a volume of female animals indicate busulfan has a
distribution of 1.15 ± 0.52 L/kg in children. marked and irreversible effect on fertility
through oocyte depletion.
When busulfan is administered at a dose of 1
mg/kg every 6 h for 4 days, the CSF:plasma 6. PHARMACEUTICAL
ratio has been shown to be 1.02:1. However, PARTICULARS
when administered at a dose of 37.5
mg/m2 every 6 h for 4 days the ratio was 6.1 List of excipients
1.39:1. Tablet core:
Obese Patients Lactose, anhydrous, Pregelatinised starch
Obesity has been reported to increase Magnesium stearate.
busulfan clearance. Dosing based on body
surface area or adjusted ideal bodyweight Tablet coating:
should be considered in the obese. Hypromellose, Titanium dioxide, Triacetin
5.3 Preclinical safety data 6.2 Incompatibilities
Busulfan has been shown to be mutagenic in Not applicable
various experimental systems, including
bacteria, fungi, Drosophila and cultured 6.3 Shelf life
mouse lymphoma cells.
3 years.
6.4 Special precautions for storage
Do not store above 25°C

6.5 Nature and contents of container
Busulfan Tablets are packed in Bottle.
Pack Size of: 7, 14, 28, 30, 50, 90, 100 or
200 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and
other handling
Safe handling of Busulfan tablets
The tablets should not be divided and
provided the outer coating is intact, there is
no risk in handling Busulfan tablets.
Handlers of Busulfan tablets should follow
guidelines for the handling of cytotoxic
drugs.
Disposal
Busulfan tablets surplus to requirements
should be destroyed in a manner appropriate
for the destruction of dangerous substances.
7. MANUFACTURER:
Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210
(INDIA)

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Bus ulfan Ta blets USP 2 mg Taj Phar ma: U ses, Side E ffe cts, Intera ctions, Picture s, Warni

Rx Busulfan may be useful in selected cases of

1.NAME OF THE MEDICINAL General

Adults dose after this point or following depression

the blood count, particularly the platelet immunocompromised hosts. Therefore,

deficiency or glucose-galactose be at the discretion of the prescribing

cancer, long-term follow-up showed an itraconazole or metronidazole is reported to

uterine growth. However, there have also Neoplasms Common Leukaemia

azoospermia and subclinical lung injury caused by busulfan.

Hyperpigmentation occurs, particularly system common

Respiratory, Common Hyperventilation,

Do not store above 25°C

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