Cyclophosphamide Tablets USP 25mg Taj Pharma

1. NAME OF THE MEDICINAL PRODUCT

Cyclophosphamide Tablets USP 25mg Taj Pharma
Cyclophosphamide Tablets USP 50mg Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

a) Cyclophosphamide Tablets USP 25mg Taj Pharma
Each film tablet contains:
cyclophosphamide monohydrate USP
Equivalent to cyclophosphamide anhydrous 25mg

b) Cyclophosphamide Tablets USP 50mg Taj Pharma
Each film tablet contains:
cyclophosphamide monohydrate USP
Equivalent to cyclophosphamide anhydrous 50mg

2. PHARMACEUTICAL FORM

Coated Tablet.

White round biconvex film sugar-coated tablets.

4. CLINICAL PARTICULARS
   • Therapeutic indications
     Cyclophosphamide Taj Pharma is a cytotoxic drug for the treatment of malignant disease in adults and children. As a single agent, it has successfully produced an objective remission in a wide range of malignant conditions. Cyclophosphamide Taj Pharma is also frequently used in combination with other cytotoxic drugs, radiotherapy or surgery.
   • Posology and method of administration

Cyclophosphamide Taj Pharma Tablets are for oral use.

Cyclophosphamide Taj Pharma should only be used by clinicians experienced in the use of cancer chemotherapy. Cyclophosphamide Taj Pharma should only be administered where there are facilities for regular monitoring of clinical, biochemical and haematological parameters before, during, and after administration and under the direction of a specialist oncology service.

Posology

Dosage must be individualized. Doses and duration of treatment and/or treatment intervals depend on the therapeutic indication, the scheme of a combination therapy, the patient’s general state of health and organ function, and the results of laboratory monitoring (in particular, blood cell monitoring).

The dosage regimen used for most indications is 100 ? 300mg daily as a single or divided dose.

This treatment should be continued until a clear remission or improvement is seen or be interrupted when the extent of leucopenia becomes unacceptable.

In combination with other cytostatics of similar toxicity, a dose reduction or extension of the therapy-free intervals may be necessary.

Activation of Cyclophosphamide Taj Pharma requires hepatic metabolism; therefore, oral and intravenous administrations are preferred.

Use of hematopoiesis stimulating agents (colony-stimulating factors and erythropoiesis stimulating agents) may be considered to reduce the risk of myelosuppressive complications and/or help facilitate the delivery of the intended dosing.

During or immediately after the administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity. Therefore, Cyclophosphamide Taj Pharma should be administered in the morning. See Section 4.4.

Patients with Hepatic Impairment

Severe hepatic impairment may be associated with decreased activation of Cyclophosphamide Taj Pharma. This may alter the effectiveness of Cyclophosphamide Taj Pharma treatment and should be considered when selecting the dose and interpreting response to the dose selected.

Patients with Renal Impairment

In patients with renal impairment, particularly in patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of Cyclophosphamide Taj Pharma and its metabolites. This may result in increased toxicity and should be considered when determining the dosage in such patients.

Cyclophosphamide Taj Pharma and its metabolites are dialyzable, although there may be differences in clearance depending upon the dialysis system being used. In patients requiring dialysis, use of a consistent interval between Cyclophosphamide Taj Pharma administration and dialysis should be considered. See Section 4.4.

Elderly

In elderly patients, monitoring for toxicities and the need for dose adjustment should reflect the higher frequency of decreased hepatic, renal, cardiac, or other organ function, and concomitant diseases or other drug therapy in this population.

Children

No specific information. Children have received Cyclophosphamide Taj Pharma. No adverse reactions specific to this group have been reported.

Method of Administration

Cyclophosphamide Taj Pharma Tablets should be swallowed with sufficient fluid without chewing. The tablets are coated and should not be divided before use.

• Contraindications

Cyclophosphamide Taj Pharma is contra-indicated in patients with:

• hypersensitivity to Cyclophosphamide Taj Pharma or to any of its metabolites.
• acute infections,
• bone-marrow aplasia,
• urinary tract infection
• acute urothelial toxicity from cytotoxic chemotherapy or radiation therapy
• Urinary outflow obstruction.

Cyclophosphamide Taj Pharma should not be used in the management of non-malignant disease, except for immunosuppression in life-threatening situations.

Cyclophosphamide Taj Pharma is contra-indicated during pregnancy. See section 4.4 and 4.6.

• Special Warnings and precautions for use

WARNINGS

Anaphylactic Reactions, Cross-sensitivity with Other Alkylating Agents

Anaphylactic reactions including those with fatal outcomes have been reported in association with Cyclophosphamide Taj Pharma.

Possible cross-sensitivity with other alkylating agents has been reported.

Myelosuppression, Immunosuppression, Infections

Treatment with Cyclophosphamide Taj Pharma may cause myelosuppression and significant suppression of immune responses.

Cyclophosphamide Taj Pharma-induced myelosuppression can cause leukopenia, neutropenia, thrombocytopenia (associated with a higher risk of bleeding events), and anaemia.

Severe immunosuppression has lead to serious, sometimes fatal, infections. Sepsis and septic shock have also been reported. Infections reported with Cyclophosphamide Taj Pharma include pneumonias, as well as other bacterial, fungal, viral, protozoal, and parasitic infections.

Latent infections can be reactivated. Reactivation has been reported for various bacterial, fungal, viral, protozoal, and parasitic infections.

Infections must be treated appropriately.

Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician.

In case of neutropenic fever, antibiotics and/or antimycotics must be given.

Cyclophosphamide Taj Pharma should be used with caution, if at all, in patients with severe impairment of bone marrow function and in patients with severe immunosuppression.

Unless essential, Cyclophosphamide Taj Pharma should not be administered to patients with a leukocyte count below 2500 cells/microlitre (cells/ mm3 and/or a platelet count below 50,000 cells/microlitre (cells/mm3).

Cyclophosphamide Taj Pharma treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection.

In principle, the fall in the peripheral blood cell and thrombocyte count and the time taken to recover may increase with increasing doses of Cyclophosphamide Taj Pharma.

The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. The bone marrow recovers relatively quickly, and the levels of peripheral blood cell counts normalize, as a rule, after approximately 20 days.

Severe myelosuppression must be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy.

Close haematological monitoring is required for all patients during treatment.

Urinary Tract and Renal Toxicity

Hemorrhagic cystitis, pyelitis, ureteritis, and haematuria have been reported with Cyclophosphamide Taj Pharma therapy. Bladder ulceration/necrosis, fibrosis/contracture and secondary cancer may develop.

Urotoxicity may mandate interruption of treatment.

Cystectomy may become necessary due to fibrosis, bleeding, or secondary malignancy.

Cases of urotoxicity with fatal outcomes have been reported.

Urotoxicity can occur with short-term and long-term use of Cyclophosphamide Taj Pharma. Hemorrhagic cystitis after single doses of Cyclophosphamide Taj Pharma has been reported.

Past or concomitant radiation or busulfan treatment may increase the risk for Cyclophosphamide Taj Pharma-induced hemorrhagic cystitis.

Cystitis is, in general, initially abacterial. Secondary bacterial colonization may follow.

Before starting treatment, it is necessary to exclude or correct any urinary tract obstructions. See Section 4.3.

Urinary sediment should be checked regularly for the presence of erythrocytes and other signs of uro/nephrotoxicity.

Cyclophosphamide Taj Pharma should be used with caution, if at all, in patients with active urinary tract infections.

Adequate treatment with mesna and/or strong hydration to force dieresis can markedly reduce the frequency and severity of bladder toxicity. It is important to ensure that patients empty the bladder at regular intervals.

Hematuria usually resolves in a few days after Cyclophosphamide Taj Pharma treatment is stopped, but it may persist.

It is usually necessary to discontinue Cyclophosphamide Taj Pharma therapy in instances of severe hemorrhagic cystitis.

Cyclophosphamide Taj Pharma has also been associated with nephrotoxicity, including renal tubular necrosis.

Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone) have been reported in association with Cyclophosphamide Taj Pharma administration. Fatal outcomes have been reported.

Cardiotoxicity, Use in Patients with Cardiac Disease

Myocarditis and myopericarditis, which may be accompanied by significant pericardial effusion and cardiac tamponade, have been reported with Cyclophosphamide Taj Pharma therapy and have led to severe, sometimes fatal congestive heart failure.

Histopathologic examination has primarily shown hemorrhagic myocarditis. Haemopericardium has occurred secondary to hemorrhagic myocarditis and myocardial necrosis.

Acute cardiac toxicity has been reported with a single dose of less than 2mg/kg Cyclophosphamide Taj Pharma.

Following exposure to treatment regimens that included Cyclophosphamide Taj Pharma, supraventricular arrhythmias (including atrial fibrillation and flutter) as well as ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia) have been reported in patients with and without other signs of cardiotoxicity.

The risk of Cyclophosphamide Taj Pharma cardiotoxicity may be increased for example, following high doses of Cyclophosphamide Taj Pharma, in patients with advanced age, and in patients with previous radiation treatment of the cardiac region and/or previous or concomitant treatment with other cardiotoxic agents. See Section 4.5.

Particular caution is necessary in patients with risk factors for cardiotoxicity and in patients with pre-existing cardiac disease.

Pulmonary Toxicity

Pneumonitis and pulmonary fibrosis have been reported during and following treatment with Cyclophosphamide Taj Pharma. Pulmonary veno-occlusive disease and other forms of pulmonary toxicity have also been reported.

Pulmonary toxicity leading to respiratory failure has been reported.

While the incidence of Cyclophosphamide Taj Pharma-associated pulmonary toxicity is low, prognosis for affected patients is poor.

Late onset of pneumonitis (greater than 6 months after start of Cyclophosphamide Taj Pharma) appears to be associated with a particularly high mortality. Pneumonitis may develop even years after treatment with Cyclophosphamide Taj Pharma.

Acute pulmonary toxicity has been reported after a single Cyclophosphamide Taj Pharma dose.

Secondary Malignancies

As with all cytotoxic therapy, treatment with Cyclophosphamide Taj Pharma involves the risk of secondary tumours and their precursors as late sequelae.

The risk of urinary tract cancer as well as the risk of myelodysplastic alterations, partly progressing to acute leukemias, is increased. Other malignancies reported after use of Cyclophosphamide Taj Pharma or regimens with Cyclophosphamide Taj Pharma include lymphoma, thyroid cancer, and sarcomas.

In some cases, the second malignancy developed several years after Cyclophosphamide Taj Pharma treatment had been discontinued. Malignancy has also been reported after?in utero?exposure.

Veno-occlusive Liver Disease

Veno-occlusive liver disease (VOLD) has been reported in patients receiving Cyclophosphamide Taj Pharma.

A cytoreductive regimen in preparation for bone marrow transplantation that consists of Cyclophosphamide Taj Pharma in combination with whole-body irradiation, busulfan, or other agents has been identified (see Section 4.5) as a major risk factor for the development of VOLD. After cytoreductive therapy, the clinical syndrome typically develops 1 to 2 weeks after transplantation and is characterized by sudden weight gain, painful hepatomegaly, ascites, and hyperbilirubinemia/jaundice.

However, VOLD has also been reported to develop gradually in patients receiving long-term low-dose immunosuppressive doses of Cyclophosphamide Taj Pharma.

As a complication of VOLD, hepatorenal syndrome and multiorgan failure may develop. Fatal outcome of Cyclophosphamide Taj Pharma-associated VOLD has been reported.

Risk factors predisposing a patient to the development of VOLD with high-dose cytoreductive therapy include:

• preexisting disturbances of hepatic function,
• previous radiation therapy of the abdomen, and a
• low performance score.

Genotoxicity

Cyclophosphamide Taj Pharma is genotoxic and mutagenic, both in somatic and in male and female germ cells. Therefore, women should not become pregnant and men should not father a child during therapy with Cyclophosphamide Taj Pharma.

Both women and men should wait at least 6 to 12 months after stopping Cyclophosphamide Taj Pharma before attempting to conceive or father a child.

Animal data indicate that exposure of oocytes during follicular development may result in a decreased rate of implantations and viable pregnancies, and in an increased risk of malformations. This effect should be considered in case of intended fertilization or pregnancy after discontinuation of Cyclophosphamide Taj Pharma therapy. The exact duration of follicular development in humans is not known, but may be longer than 12 months.

Sexually active women and men should use effective methods of contraception during these periods of time.

Fertility, see section 4.6.

Impairment of Wound Healing

Cyclophosphamide Taj Pharma may interfere with normal wound healing.

PRECAUTIONS

Alopecia

Alopecia has been reported and may occur more commonly with increasing doses.

Alopecia may progress to baldness.

The hair can be expected to grow back after treatment with the drug or even during continued drug treatment, though it may be different in texture or colour.

Nausea and Vomiting

Administration of Cyclophosphamide Taj Pharma may cause nausea and vomiting.

Current guidelines on the use of antiemetics for prevention and amelioration of nausea and vomiting should be considered.

Alcohol consumption may increase Cyclophosphamide Taj Pharma-induced vomiting and nausea.

Stomatitis

Administration of Cyclophosphamide Taj Pharma may cause stomatitis (oral mucositis).

Current guidelines on measures for prevention and amelioration of stomatitis should be considered.

Paravenous Administration

The cytostatic effect of Cyclophosphamide Taj Pharma occurs after its activation, which takes place mainly in the liver. Therefore, the risk of tissue injury from accidental paravenous administration is low.

In case of accidental paravenous administration of Cyclophosphamide Taj Pharma, the infusion should be stopped immediately, the extravascular Cyclophosphamide Taj Pharma solution should be aspirated with the cannula in place, and other measures should be instituted as appropriate.

Use in Patients with Renal Impairment

In patients with renal impairment, particularly in patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of Cyclophosphamide Taj Pharma and its metabolites. This may result in increased toxicity and should be considered when determining the dosage in such patients. See Section 4.2.

Use in Patients with Hepatic Impairment

Severe hepatic impairment may be associated with decreased activation of Cyclophosphamide Taj Pharma. This may alter the effectiveness of Cyclophosphamide Taj Pharma treatment and should be considered when selecting the dose and interpreting response to the dose selected.

Use in Adrenalectomized Patients

Patients with adrenal insufficiency may require an increase in corticoid substitution dose when exposed to stress from toxicity due to cytostatics, including Cyclophosphamide Taj Pharma.

• Interaction with other medicinal products and other forms of interaction

Planned coadministration or sequential administration of other substances or treatments that could increase the likelihood or severity of toxic effects (by means of pharmacodynamic or pharmacokinetic interactions) requires careful individual assessment of the expected benefit and the risks.

Patients receiving such combinations must be monitored closely for signs of toxicity to permit timely intervention. Patients being treated with Cyclophosphamide Taj Pharma and agents that reduce its activation should be monitored for a potential reduction of therapeutic effectiveness and the need for dose adjustment.

Interactions Affecting the Pharmacokinetics of Cyclophosphamide Taj Pharma and its Metabolites

• Reduced activation of Cyclophosphamide Taj Pharma may alter the effectiveness of Cyclophosphamide Taj Pharma treatment. Substances that delay activation of Cyclophosphamide Taj Pharma include:
• Aprepitant
• Bupropion
• Busulfan: Cyclophosphamide Taj Pharma clearance has been reported to be reduced and half-life prolonged in patients who receive high-dose Cyclophosphamide Taj Pharma less than 24 hours after high-dose busulfan.
• Ciprofloxacin: When given prior to the treatment with Cyclophosphamide Taj Pharma (used for conditioning prior to bone marrow transplantation), ciprofloxacin has been reported to result in a relapse of the underlying disease.
• Chloramphenicol
• Fluconazole
• Itraconazole
• Prasugrel
• Sulfonamides
• Thiotepa: A strong inhibition of Cyclophosphamide Taj Pharma bioactivation by thiotepa in high-dose chemotherapy regimens has been reported when thiotepa was administered 1 hour prior to Cyclophosphamide Taj Pharma.
• An increase of the concentration of cytotoxic metabolites may occur with:
• Allopurinol
• Chloral hydrate
• Cimetidine
• Disulfiram
• Glyceraldehyde
• Inducers of human hepatic and extrahepatic microsomal enzymes (e.g., cytochrome P450 enzymes): The potential for hepatic and extrahepatic microsomal enzyme induction must be considered in case of prior or concomitant treatment with substances known to induce an increased activity of such enzymes such as rifampin, phenobarbital, carbamazepine, phenytoin, St. John’s wort, and corticosteroids.
• Protease inhibitors: Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving Cyclophosphamide Taj Pharma, doxorubicin, and etoposide (CDE) than use of an NNRTI-based regimen.
• Ondansetron

There have been reports of a pharmacokinetic interaction between ondansetron and high-dose Cyclophosphamide Taj Pharma resulting in decreased Cyclophosphamide Taj Pharma AUC.

Pharmacodynamic Interactions and Interactions of Unknown Mechanism Affecting the Use of Cyclophosphamide Taj Pharma

Combined or sequential use of Cyclophosphamide Taj Pharma and other agents with similar toxicities can cause combined (increased) toxic effects.

• Increased hematotoxicity and/or immunosuppression may result from a combined effect of Cyclophosphamide Taj Pharma and, for example
• ACE inhibitors: ACE inhibitors can cause leukopenia.
• Natalizumab
• Paclitaxel: Increased hematotoxicity has been reported when Cyclophosphamide Taj Pharma was administered after paclitaxel infusion.
• Thiazide diuretics
• Zidovudine
• Clozapine
• Increased cardiotoxicity may result from a combined effect of Cyclophosphamide Taj Pharma and, for example
• Anthracyclines
• Cytarabine
• Pentostatin
• Radiation therapy of the cardiac region
• Trastuzumab
• Increased pulmonary toxicity may result from a combined effect of Cyclophosphamide Taj Pharma and, for example
• Amiodarone
• G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor): Reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes Cyclophosphamide Taj Pharma and G-CSF or GMCSF.
• Increased nephrotoxicity may result from a combined effect of Cyclophosphamide Taj Pharma and, for example
• Amphotericin B
• Indomethacin: Acute water intoxication has been reported with concomitant use of indomethacin.
• Increase in other toxicities
• Azathioprine: Increased risk of hepatotoxicity (liver necrosis)
• Busulfan: Increased incidence of hepatic veno-occlusive disease and mucositis has been reported.
• Protease inhibitors: Increased incidence of mucositis.

Other interactions

• Alcohol

A reduced antitumor activity was observed in tumor-bearing animals during ethanol (alcohol) consumption and concomitant oral low-dose Cyclophosphamide Taj Pharma medication.

In some patients, alcohol may increase Cyclophosphamide Taj Pharma-induced vomiting and nausea.

• Etanercept

In patients with Wegener’s granulomatosis, the addition of etanercept to standard treatment, including Cyclophosphamide Taj Pharma, was associated with a higher incidence of non-cutaneous solid malignancies.

• Metronidazole

Acute encephalopathy has been reported in a patient receiving Cyclophosphamide Taj Pharma and metronidazole. Causal association is unclear.

In an animal study, the combination of Cyclophosphamide Taj Pharma with metronidazole was associated with increased Cyclophosphamide Taj Pharma toxicity.

• Tamoxifen

Concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications.

Interactions Affecting the Pharmacokinetics and/or Actions of Other Drugs

• Bupropion

Cyclophosphamide Taj Pharma metabolism by CYP2B6 may inhibit bupropion metabolism.

• Coumarins

Both increased and decreased warfarin effect have been reported in patients receiving warfarin and Cyclophosphamide Taj Pharma.

• Cyclosporine

Lower serum concentrations of cyclosporine have been observed in patients receiving a combination of Cyclophosphamide Taj Pharma and cyclosporine than in patients receiving only cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease.

• Depolarizing muscle relaxants

Cyclophosphamide Taj Pharma treatment causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine). If a patient has been treated with Cyclophosphamide Taj Pharma within 10 days of general anesthesia, the anesthesiologist should be alerted.

• Digoxin, ?-acetyldigoxin

Cytotoxic treatment has been reported to impair intestinal absorption of digoxin and ?-acetyldigoxin tablets.

• Vaccines

The immunosuppressive effects of Cyclophosphamide Taj Pharma can be expected to reduce the response to vaccination. Use of live vaccines may lead to vaccine-induced infection.

• Verapamil

Cytotoxic treatment has been reported to impair intestinal absorption of orally administered verapamil

• Fertility, Pregnancy and lactation

Pregnancy

Cyclophosphamide Taj Pharma is contraindicated in pregnancy (see section 4.3). Cyclophosphamide Taj Pharma crosses the placental barrier. Treatment with Cyclophosphamide Taj Pharma has a genotoxic effect and may cause foetal damage when administered to pregnant women. Both women and men should wait at least 6 to 12 months after stopping Cyclophosphamide Taj Pharma before attempting to conceive or father a child.

• Malformations have been reported in children born to mothers treated with Cyclophosphamide Taj Pharma during the first trimester of pregnancy. However, there are also reports of children without malformations born to women exposed during the first trimester.
• Exposure to Cyclophosphamide Taj Pharma in utero may cause miscarriage, foetal growth retardation, and foetotoxic effects manifesting in the newborn, including leukopenia, anaemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis.
• Animal data suggest that an increased risk of failed pregnancy and malformations may persist after discontinuation of Cyclophosphamide Taj Pharma as long as oocytes/follicles exist that were exposed to Cyclophosphamide Taj Pharma during any of their maturation phases. See Section 4.4, Genotoxicity.
• If Cyclophosphamide Taj Pharma is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment (see Section 4.4, Genotoxicity), the patient should be apprised of the potential hazard to a foetus.

Breastfeeding

Cyclophosphamide Taj Pharma is passed into the breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhoea have been reported in children breast fed by women treated with Cyclophosphamide Taj Pharma. Women must not breastfeed during treatment with Cyclophosphamide Taj Pharma.

Fertility

Cyclophosphamide Taj Pharma interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes.

Development of sterility appears to depend on the dose of Cyclophosphamide Taj Pharma, duration of therapy, and the state of gonadal function at the time of treatment.

Cyclophosphamide Taj Pharma-induced sterility may be irreversible in some patients.

Sexually active women and men should use effective methods of contraception during these periods of time.

• Female patients

Amenorrhea, transient or permanent, associated with decreased oestrogen and increased gonadotrophin secretion develops in a significant proportion of women treated with Cyclophosphamide Taj Pharma.

For older women, in particular, amenorrhea may be permanent.

Oligomenorrhea has also been reported in association with Cyclophosphamide Taj Pharma treatment.

Girls treated with Cyclophosphamide Taj Pharma during prepubescence generally develop secondary sexual characteristics normally and have regular menses.

Girls treated with Cyclophosphamide Taj Pharma during prepubescence subsequently have conceived.

Girls treated with Cyclophosphamide Taj Pharma who have retained ovarian function after completing treatment are at increased risk of developing premature menopause (cessation of menses before age of 40 years).

• Male patients

Men treated with Cyclophosphamide Taj Pharma may develop oligospermia or azoospermia, which are normally associated with increased gonadotrophin but normal testosterone secretion.

Sexual potency and libido generally are unimpaired in these patients.

Boys treated with Cyclophosphamide Taj Pharma during prepubescence may develop secondary sexual characteristics normally, but may have oligospermia or azoospermia.

Some degree of testicular atrophy may occur.

Cyclophosphamide Taj Pharma-induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.

• Effects on ability to drive and use machine

Patients undergoing treatment with Cyclophosphamide Taj Pharma may experience undesirable effects (including, e.g., dizziness, blurred vision, visual impairment) which could affect the ability to drive or use machines. The decision to drive or operate machinery should be made on an individual basis.

• Undesirable Effects
  
  ADR frequency is based upon the following scale: Very Common (?1/10); Common (?1/100 – <1/10), Uncommon (?1/1,000 – <1/100), Rare (?1/10,000 – <1/1,000), Very Rare (<1/10,000), Unknown (adverse reactions reported in the post-marketing experience)

System Organ Class	Preferred term	Frequency
Infections and infestations	Infections1 Pneumonia2 Sepsis1 Septic shock	Common Uncommon Uncommon Not Known
Neoplasms benign, malignant and unspecified (incl cycts and polyps)	Acute leukemia3 Myelodysplastic syndrome Secondary tumours Bladder cancer Tumour lysis syndrome	Rare Rare Rare Rare Not known
Blood and lymphatic system disorders	Myelosuppression?4 Haemolytic uraemic syndrome Disseminated intravascular coagulation (DIC ) Lymphopenia	Very common Very common Very rare Not known
Immune system disorders	Immunosuppression Anaphylactic/Anaphylactoid reaction Hypersensitivity reaction	Very common Very rare Uncommon
Endocrine disorders	SIADH	Rare
Metabolism and nutrition disorders	Anorexia Dehydration Hyponatraemia Fluid retention Blood glucose changes (increase or decrease)	Uncommon Rare Very rare Very rare Not known
Psychiatric disorders	Confusion	Very rare
Nervous system disorders	Dizziness Convulsion Neurotoxicity5 Encephalopathy	Rare Very rare Unknown Unknown
Eye disorders	Conjunctivitis Eye Oedema Visual impairment Lacrimation increased	Very Rare Very Rare Rare Not known
Ear and labyrinth disorders	Deafness Tinnitus	Not known Not known
Cardiac disorders	Ventricular fibrillation Ventricular tachycardia Cardiogenic shock Pericardial effusion Myocardial infarction Cardiac failure Cardiomyopathy Myocarditis Pericarditis Electrocardiogram QT prolonged Arrhythmias6	Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known
Vascular disorders	Flushing Pulmonary embolism Venous thrombosis Vasculitis Peripheral ischaemia	Uncommon Not known Not known Not known Not known
Respiratory, thoracic and mediastinal disorders	Pulmonary veno-occlusive disease Acute respiratory distress syndrome (ARDS) Interstitial Lung Diseases7 Pulmonary hypertension Pulmonary oedema Bronchospasm Dyspnea Hypoxia Cough Nasal congestion Rhinorrhea Oropharyngeal pain	Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known
Gastrointestinal disorders	Enterocolitis haemorrhagic Acute pancreatitis Mucosal ulceration Stomatitis Diarrhoea Vomiting Constipation Nausea Gastrointestinal Haemorrhage Colitis Enteritis Cecitis Abdominal pain Parotid gland inflammation	Very rare Very rare Very rare Very rare Very rare Very rare Very rare Very rare Unknown Unknown Unknown Unknown Unknown Unknown
Hepatobiliary disorders	Hepatic function abnormal Veno-occlusive disorder Hepatitis Cholestasis Hepatotoxicity8	Common Not known Not known Not known Not known
Skin and subcutaneous tissue disorders	Alopecia Rash Dermatitis Discoloration of the palms, fingernails, soles Toxic epidermal necrolysis Stevens Johnson syndrome Erythema multiforme Palmar-plantar erythrodysaesthesia Radiation recall dermatitis Erythema in irradiated area Pruritus (including inflammatory itching) Erythema Urticaria Blisters Facial swelling Hyperhidrosis	Very common Rare Rare Rare Very rare Very rare Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known
Musculoskeletal and connective tissue disorders	Rhabdomyolysis Scleroderma Muscle spasms Myalgia Arthralgia	Not known Not known Not known Not known Not known
Renal and urinary disorders	Cystitis Microhematuria Haemorrhagic cystitis Macrohematuria Suburethral bleeding Oedema of the bladder wall Interstitial inflammation, fibrosis, and sclerosis of bladder Renal failure Blood creatinine increased Renal tubular necrosis Renal tubular disorder Nephropathy toxic Hemorrhagic ureteritis Cystitis ulcerative Bladder contracture Nephrogenic diabetes insipidus Atypical urinary bladder epithelial cells Blood urea nitrogen increased	Very common Very common Common Common Very rare Very rare Very rare Very rare Very rare Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown
Pregnancy, puerperium and perinatal conditions	Premature labour	Not known
Reproductive system and breast disorders	Impairment of spermatogenesis Ovulation disorder Amenorrhoea9 Azoospermia9 Oligospermia9 Infertility Ovarian Failure Oligomenorrhoea, Testicular atrophy Blood oestrogen decreased Blood gonadotrophin increased	Common Uncommon Rare Rare Rare Unknown Unknown Unknown Unknown Unknown Unknown
Congenital, familial and genetic disorders	Intra-uterine death Fetal malformation Fetal growth retardation Fetal toxicity (including myelosuppression/gastroenteritis)	Not known Not known Not known Not known
General disorders and administration site conditions	Fever Asthenia Mucosal inflammation Chest pain Headache Injection/infusion site reactions10 Multiorgan failure Oedema Influenza-like illness General physical deterioration	Very common Common Common Rare Very Rare Not known Not known Not known Not known Not known
Investigations	Blood lactate hydrogenase increased C-reactive protein increased	Not known Not known

 

^?

¹?including other bacterial, fungal, viral, protozoal, parasitic, reactivation of latent infections, including viral hepatitis, tuberculosis, JC virus with progressive multifocal leucoencephalopathy (including fatal outcomes), Pneumocystis jiroveci, herpes zoster, Strongyloides

²?including fatal outcomes

³?including acute myeloid leukemia, acute promyelocytic leukemia

⁴?manifested as Bone marrow failure, Pancytopenia, Neutropaenia, Agranulocytosis, Granulocytopenia,Thrombocytopaenia (complicated by bleeding), Leukopenia, Anaemia

⁵?manifested as reversible posterior leukoencephalopathy syndrome, myelopathy, peripheral neuropathy, polyneuropathy,neuralgia, dysesthesia, hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia,parosmia.

⁶?manifested as Atrial fibrillation,Supraventricular arrhythmia ,Ventricular arrhythmia, Bradycardia, Tachycardia,Palpitation

⁷?manifested by pulmonary fibrosis, obliterative bronchiolitis, organizing pneumonia, alveolitis allergic, pneumonitis

^8?Hepatic failure, Hepatic encephalopathy, Ascites, Hepatomegaly, Jaundice, Blood bilirubin increased, Hepatic enzymes increased (ASAT, ALAT, ALP, gamma-GT)

⁹?persistent

¹⁰?manifested by thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythema.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

• Overdose

Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno-occlusive hepatic disease, and stomatitis. See Section 4.4.

Patients who received an overdose should be closely monitored for the development of toxicities, and haematotoxicity in particular.

No specific antidote for Cyclophosphamide Taj Pharma is known.

Cyclophophamide and its metabolites are dialysable. Consider haemodialysis in cases of severe overdose presenting early, particularly in patients with renal impairment

Overdosage should be managed with supportive measures, including appropriate, state-of-the-art treatment for any concurrent infection, myelosuppression, or other toxicity, should it occur.

Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with Cyclophosphamide Taj Pharma overdose.

5. PHARMACOLOGICAL PROPERTIES
   • Pharmacodynamic properties

Cyclophosphamide Taj Pharma has been demonstrated to have a cytostatic effect in many tumour types. The active metabolites of Cyclophosphamide Taj Pharma are alkylating agents which transfer alkyl groups to DNA during the process of cell division, thus preventing normal synthesis of DNA.

?

• Pharmacokinetic properties

Cyclophosphamide Taj Pharma is well absorbed following an oral dose with a mean half-life of 4-8 hours for both oral and parenteral administration.

It is an inactive pro drug with alkylating metabolites produced by hepatic metabolism, reaching peak levels 4-6 hours after an iv injection. Hepatic enzymes may be induced. The parent compound binds poorly to plasma protein but the active metabolites are significantly protein-bound. The drug is widely distributed and crosses the blood-brain barrier, the placental barrier and is found in ascites. The metabolites are excreted renally.

• Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to the information already stated in other sections of the Summary of Product Characteristics.

6. PHARMACEUTICAL PARTICULARS
   • List of excipients

Tablet: Maize starch, lactose monohydrate, calcium hydrogen phosphate dihydrate, talc, magnesium stearate, gelatine, glycerol (85%).

Coating: Sucrose, titanium dioxide, calcium carbonate, talc, macrogol 35000, silica colloidal anhydrous, povidone, sodium carboxymethylcellulose, polysorbate 20, montan glycol wax.

• Incompatibilities

Not applicable.

• Shelf life

36 months.

• Special precautions for storage

Do not store above 25?C.

Store in original container.

• Nature and contents of packs look like container

White round biconvex film sugar coated tablets.

10 tablets in a PVC/aluminium blister strip and 10 blister strips in a box

• Special precautions for disposal and other handling

Cyclophosphamide Taj Pharma is a cytotoxic agent. The handling of Cyclophosphamide Taj Pharma should always be in accordance with current guidelines on safe handling of cytotoxic agents.

The coating of the tablets prevents direct contact of persons handling the tablets with the active substance. To prevent inadvertent exposure of third persons to the active substance, the tablets should not be divided or crushed.

The tablets should not be handled by women who are pregnant or who are breast feeding.

7. Manufactured by:
TAJ PHARMACEUTICALS LIMITED
At SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).