THALIDOMIDE CELGENE 50mg capsules medication leaflet

Thalidomide Celgene 50 mg hard capsules

Each capsule contains 50 mg of thalidomide.

For the full list of excipients, see section 6.1.

Hard capsule.

White opaque capsules marked “Thalidomide Celgene 50 mg”.

Thalidomide Celgene in combination with melphalan and prednisone is indicated as first line treatmentof patients with untreated multiple myeloma, aged ≥ 65 years or ineligible for high dosechemotherapy.

Thalidomide Celgene is prescribed and dispensed according to the Thalidomide Celgene Pregnancy

Prevention Programme (see section 4.4).

Treatment must be initiated and monitored under the supervision of physicians with expertise inmanaging immunomodulatory or chemotherapeutic agents and a full understanding of the risks ofthalidomide therapy and monitoring requirements (see section 4.4).

The recommended dose of thalidomide is 200 mg orally per day.

A maximum number of 12 cycles of 6 weeks (42 days) should be used.

Table 1: Starting doses for thalidomide in combination with melphalan and prednisone

Age ANC* Platelet Count Thalidomidea,b Melphalanc,d,e Prednisonef(years) (/µL) (/µL)≤ 75 ≥ 1,500 AND ≥ 100,000 200 mg daily 0.25 mg/kg daily 2 mg/kg daily≤ 75 < 1,500 but OR < 100,000 but 200 mg daily 0.125 mg/kg daily 2 mg/kg daily≥ 1,000 ≥ 50,000> 75 ≥ 1,500 AND ≥ 100,000 100 mg daily 0.20 mg/kg daily 2 mg/kg daily> 75 < 1,500 but OR < 100,000 but 100 mg daily 0.10 mg/kg daily 2 mg/kg daily≥ 1,000 ≥ 50,000

* ANC: Absolute Neutrophil Counta Thalidomide dosed once daily at bedtime on Days 1 to 42 of each 42-day cycle.b Due to the sedative effect associated with thalidomide, administration at bedtime is known to generally improve tolerability.c Melphalan dosed once daily on Days 1 to 4 of each 42-day cycle.d Melphalan dosing: reduce by 50 % for moderate (creatinine clearance: ≥ 30 but < 50 mL/min) or severe (CrCl: < 30mL/min) renalinsufficiencye Maximum daily melphalan dose: 24 mg (subjects ≤ 75 years old) or 20 mg (subjects > 75 years old).f Prednisone dosed once daily on Days 1 to 4 of each 42-day cycle.

Patients should be monitored for: thromboembolic events, peripheral neuropathy, severe skinreactions, bradycardia, syncope, somnolence, neutropenia and thrombocytopenia (see sections 4.4and 4.8). Dose delay, reduction or discontinuation, dependent upon the NCI CTC (National Cancer

Institute Common Toxicity Criteria) grade, may be necessary.

If less than 12 hours has elapsed since missing a dose, the patient can take the dose. If more than12 hours has elapsed since missing a dose at the normal time, the patient should not take the dose, buttake the next dose at the normal time on the following day.

Thromboprophylaxis should be administered for at least the first 5 months of treatment especially inpatients with additional thrombotic risk factors. Prophylactic antithrombotic medicinal products, suchas low molecular weight heparins or warfarin, should be recommended. The decision to takeantithrombotic prophylactic measures should be made after careful assessment of an individualpatient’s underlying risk factors (see sections 4.4, 4.5 and 4.8).

If the patient experiences any thromboembolic events, treatment must be discontinued and standardanticoagulation therapy started. Once the patient has been stabilised on the anticoagulation treatmentand any complications of the thromboembolic event have been managed, the thalidomide treatmentmay be restarted at the original dose dependent upon a benefit-risk assessment. The patient shouldcontinue anticoagulation therapy during the course of thalidomide treatment.

White blood cell count and differential should be monitored on an ongoing basis, in accordance withoncology guidelines, especially in patients who may be more prone to neutropenia. Dose delay,reduction or discontinuation, dependent upon the NCI CTC grade, may be necessary.

Platelet counts should be monitored on an ongoing basis, in accordance with oncology guidelines.

Dose delay, reduction or discontinuation, dependent upon the NCI CTC grade, may be necessary.

Dose modifications due to peripheral neuropathy are described in Table 2.

Table 2: Recommended dose modifications for thalidomide -related neuropathy in first linetreatment of multiple myeloma

Severity of neuropathy Modification of dose and regimen

Grade 1 (paraesthesia, weakness and/or loss of Continue to monitor the patient with clinicalreflexes) with no loss of function examination. Consider reducing dose if symptomsworsen. However, dose reduction is notnecessarily followed by improvement ofsymptoms.

Grade 2 (interfering with function but not with Reduce dose or interrupt treatment and continueactivities of daily living) to monitor the patient with clinical andneurological examination. If no improvement orcontinued worsening of the neuropathy,discontinue treatment. If the neuropathy resolvesto Grade 1 or better, the treatment may berestarted, if the benefit/risk is favourable.

Grade 3 (interfering with activities of daily Discontinue treatmentliving)

Grade 4 (neuropathy which is disabling) Discontinue treatment

Allergic reactions and severe skin reactions

Thalidomide interruption or discontinuation should be considered for Grade 2-3 skin rash.

Thalidomide must be discontinued for angioedema, anaphylactic reaction, Grade 4 rash, exfoliative orbullous rash, or if Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or drug reactionwith eosinophilia and systemic symptoms (DRESS) is suspected and should not be resumed followingdiscontinuation for these reactions.

No specific dose adjustments are recommended for the elderly ≤ 75 years of age. For patients> 75 years of age, the thalidomide recommended starting dose is 100 mg per day. The initial dose ofmelphalan is reduced for elderly > 75 years of age considering baseline bone marrow reserve and renalfunction. The melphalan recommended starting dose is 0.1 to 0.2 mg/kg daily according to bonemarrow reserve along with a further 50 % dose reduction for moderate (creatinine clearance: ≥ 30 but< 50 mL/minute) or severe (CrCl: < 30 mL/minute) renal insufficiency. The maximum dailymelphalan dose is 20 mg in patients > 75 years of age (see Table 1).

Thalidomide Celgene has not formally been studied in patients with impaired renal or hepatic function.

No specific dose recommendations for these patient populations are available. Patients with severeorgan impairment should be carefully monitored for adverse reactions.

There is no relevant use of Thalidomide Celgene in the paediatric population in the indication ofmultiple myeloma.

Thalidomide Celgene should be taken as a single dose at bedtime, to reduce the impact of somnolence.

Capsules should not be opened or crushed (see section 6.6).

It is recommended to press only on one end of the capsule to remove it from the blister, therebyreducing the risk of capsule deformation or breakage.

* Hypersensitivity to thalidomide or to any of the excipients listed in section 6.1.

* Women who are pregnant (see section 4.6).

* Women of childbearing potential unless all the conditions of the Pregnancy Prevention

Programme are met (see sections 4.4 and 4.6).

* Male patients unable to follow or comply with the required contraceptive measures (seesection 4.4).

Teratogenic effects

Thalidomide is a powerful human teratogen, inducing a high frequency of severe and life-threatening birth defects. Thalidomide must never be used by women who are pregnant or bywomen who could become pregnant unless all the conditions of the Pregnancy Prevention

Programme are met. The conditions of the Pregnancy Prevention Programme must be fulfilled forall male and female patients.

Criteria for women of non-childbearing potential

A female patient or a female partner of a male patient is considered to have childbearing potentialunless she meets at least one of the following criteria:

* Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year (Amenorrhoea following cancer therapyor during breast-feeding does not rule out childbearing potential).

* Premature ovarian failure confirmed by a specialist gynaecologist.

* Previous bilateral salpingo-oophorectomy, or hysterectomy.

* XY genotype, Turner’s syndrome, uterine agenesis.

For women of childbearing potential, thalidomide is contraindicated unless all of the followingconditions are met:

* She understands the teratogenic risk to the unborn child

* She understands the need for effective contraception, without interruption, at least 4 weeksbefore starting treatment, throughout the entire duration of treatment, and at least 4 weeks afterthe end of treatment

* Even if a woman of childbearing potential has amenorrhea she must follow all the advice oneffective contraception

* She should be capable of complying with effective contraceptive measures

* She is informed and understands the potential consequences of pregnancy and the need torapidly consult her doctor if there is a risk of pregnancy

* She understands the need to commence the treatment as soon as thalidomide is dispensedfollowing a negative pregnancy test

* She understands the need and accepts to undergo pregnancy testing every 4 weeks except in caseof confirmed tubal sterilisation

* She acknowledges that she understands the hazards and necessary precautions associated withthe use of thalidomide.

As thalidomide is found in semen, as a precaution all male patients taking thalidomide must meet thefollowing conditions:

* He understands the teratogenic risk if engaged in sexual activity with a pregnant woman or awoman of childbearing potential.

* He understands the need for the use of a condom if engaged in sexual activity with a pregnantwoman or a woman of childbearing potential not using effective contraception (even if the manhas had a vasectomy), during treatment, during dose interruption and for at least 7 daysfollowing discontinuation of treatment.

* He understands that if his female partner becomes pregnant whilst he is taking thalidomide or 7days after he has stopped taking thalidomide, he should inform his treating physicianimmediately and that it is recommended to refer the female partner to a physician specialised orexperienced in teratology for evaluation and advice.

The prescriber must ensure that:

* The patient complies with the conditions of the Pregnancy Prevention Programme includingconfirmation that she has an adequate level of understanding

* The patient has acknowledged the aforementioned conditions.

Women of childbearing potential must use one effective method of contraception for at least 4 weeksbefore start of treatment, during treatment, and until at least 4 weeks after thalidomide treatment andeven in case of dose interruption unless the patient commits to absolute and continuous abstinenceconfirmed on a monthly basis. If not established on effective contraception, the patient must bereferred preferably to an appropriately trained healthcare professional for contraceptive advice in orderthat contraception can be initiated.

The following can be considered to be examples of effective methods of contraception:

* Implant

* Levonorgestrel-releasing intrauterine system (IUS)

* Medroxyprogesterone acetate depot

* Tubal sterilisation

* Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by twonegative semen analyses

* Ovulation inhibitory progesterone-only pills (i.e. desogestrel)

Because of the increased risk of venous thromboembolism in patients with multiple myeloma (MM),combined oral contraceptive pills are not recommended (see section 4.5). If a patient is currently usingcombined oral contraception, she should switch to one of the effective methods listed above. The riskof venous thromboembolism continues for 4-6 weeks after discontinuing combined oral contraception.

Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/ml must be performed forwomen of childbearing potential as outlined below. This requirement includes women of childbearingpotential who practice absolute and continuous abstinence.

Prior to starting treatment

A medically supervised pregnancy test should be performed during the consultation, when thalidomideis prescribed or in the 3 days prior to the visit to the prescriber once the patient had been usingeffective contraception for at least 4 weeks. The test should ensure the patient is not pregnant whenshe starts treatment with thalidomide.

Follow-up and end of treatment

A medically supervised pregnancy test should be repeated every 4 weeks, including 4 weeks after theend of treatment, except in the case of confirmed tubal sterilisation. These pregnancy tests should beperformed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.

As thalidomide is found in semen, as a precaution all male patients must use condoms duringtreatment, during dose interruption and for at least 7 days following discontinuation of treatment iftheir partner is pregnant or is of childbearing potential not using effective contraception.

Male patients should not donate semen or sperm during treatment (including during doseinterruptions) and for at least 7 days following discontinuation of thalidomide.

Prescribing and dispensing restrictions

For women of childbearing potential, prescriptions of thalidomide can be for a maximum duration oftreatment of 4 weeks according to the approved indications dosing regimens (see section 4.2) andcontinuation of treatment requires a new prescription. Ideally, pregnancy testing, issuing a prescriptionand dispensing should occur on the same day. Dispensing of thalidomide should occur within amaximum of 7 days of the prescription.

For all other patients, prescriptions of thalidomide can be for a maximum duration of treatment of12 weeks and continuation of treatment requires a new prescription.

Additional precautions

Patients should be instructed never to give this medicinal product to another person and to return anyunused capsules to their pharmacist at the end of treatment.

Patients should not donate blood during treatment (including during dose interruptions) and for at least7 days following discontinuation of thalidomide.

Healthcare professionals and caregivers should wear disposable gloves when handling the blister orcapsule. Women who are pregnant or suspect they may be pregnant should not handle the blister orcapsule (see section 6.6).

In order to assist patients in avoiding foetal exposure to thalidomide, the Marketing Authorisation

Holder will provide educational material to healthcare professionals to reinforce the warnings aboutthe teratogenicity of thalidomide, to provide advice on contraception before treatment is started andprovides guidance on the need for pregnancy testing.

The prescriber must inform male and female patients about the expected teratogenic risk and the strictpregnancy prevention measures as specified in the Pregnancy Prevention Programme and providepatients with appropriate educational brochure for patients, patient card and/or equivalent tool inaccordance to the national implemented patient card system. A national controlled distribution systemhas been implemented in collaboration with each National Competent Authority. The controlleddistribution system includes the use of a patient card and/or equivalent tool for prescribing and/ordispensing controls, and the collecting of detailed data relating to the indication in order to monitorclosely the off-label use within the national territory. Ideally, pregnancy testing, issuing a prescriptionand dispensing should occur on the same day. Dispensing of thalidomide to women of childbearingpotential should occur within 7 days of the prescription and following a medically supervised negativepregnancy test result.

Amenorrhea

The use of thalidomide could be associated with menstrual disorders including amenorrhea.

Amenorrhea during thalidomide therapy should be assumed to result from pregnancy, until it ismedically confirmed that the patient is not pregnant. A clear mechanism by which thalidomide caninduce amenorrhea is not elucidated. The reported events occurred in young (premenopausal) women(median age 36 years) receiving thalidomide for non-multiple myeloma indications, had an onsetwithin 6 months of initiating treatment and reversed upon discontinuation of thalidomide. Indocumented case reports with hormone evaluation, the event of amenorrhoea was associated withdecreased estradiol levels and elevated FSH/LH levels. When provided, antiovary antibodies werenegative and prolactin level was within the normal range.

Myocardial infarction (MI) has been reported in patients receiving thalidomide, particularly in thosewith known risk factors. Patients with known risk factors for MI, including prior thrombosis, shouldbe closely monitored and action should be taken to try to minimise all modifiable risk factors(e.g. smoking, hypertension, and hyperlipidaemia).

Venous and arterial thromboembolic events

Patients treated with thalidomide have an increased risk of venous thromboembolism (such as deepvein thrombosis and pulmonary embolism) and arterial thromboembolism (such as myocardialinfarction and cerebrovascular event) (see section 4.8). The risk appears to be greatest during the first5 months of therapy. Thromboprophylaxis and dosing/anticoagulation therapy recommendations areprovided in section 4.2.

Previous history of thromboembolic events or concomitant administration of erythropoietic agents orother agents such as hormone replacement therapy, may also increase thromboembolic risk in thesepatients. Therefore, these agents should be used with caution in multiple myeloma patients receivingthalidomide with prednisone and melphalan. Particularly, a haemoglobin concentration above 12g/dlshould lead to discontinuation of erythropoietic agents. Action should be taken to try to minimize allmodifiable risk factors (e.g. smoking, hypertension and hyperlipidaemia).

Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism.

Patients should be instructed to seek medical care if they develop symptoms such as shortness ofbreath, chest pain, arm or leg swelling.

Thyroid disorders

Cases of hypothyroidism have been reported. Optimal control of co-morbid conditions influencingthyroid function is recommended before start of treatment. Baseline and ongoing monitoring ofthyroid function is recommended.

Peripheral neuropathy is a very common, potentially severe, adverse reaction to treatment withthalidomide that may result in irreversible damage (see section 4.8). In a phase 3 study, the mediantime to first neuropathy event was 42.3 weeks.

If the patient experiences peripheral neuropathy, follow the dose and schedule modification instructionprovided in section 4.2.

Careful monitoring of patients for symptoms of neuropathy is recommended. Symptoms includeparaesthesia, dysaesthesia, discomfort, abnormal co-ordination or weakness.

It is recommended that clinical and neurological examinations are performed in patients prior tostarting thalidomide therapy, and that routine monitoring is carried out regularly during treatment.

Medicinal products known to be associated with neuropathy should be used with caution in patientsreceiving thalidomide (see section 4.5).

Thalidomide may also potentially aggravate existing neuropathy and should therefore not be used inpatients with clinical signs or symptoms of peripheral neuropathy unless the clinical benefits outweighthe risks.

Syncope, bradycardia and atrioventricular block

Patients should be monitored for syncope, bradycardia and atrioventricular block; dose reduction ordiscontinuation may be required.

Cases of pulmonary hypertension, some fatal, have been reported in patients treated with thalidomide.

Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior toinitiating and during thalidomide therapy.

The incidence of neutropenia grade 3 or 4 reported as adverse reactions was higher in multiplemyeloma patients receiving MPT (Melphalan, Prednisone, Thalidomide) than in those receiving MP(Melphalan, Prednisone): 42.7 % versus 29.5 % respectively (study IFM 99-06). Adverse reactionsfrom post-marketing experience such as febrile neutropenia and pancytopenia were reported withthalidomide. Patients should be monitored and dose delay, reduction or discontinuation may berequired (see section 4.2).

Thrombocytopenia, including grade 3 or 4 adverse reactions, has been reported in multiple myelomapatients receiving MPT. Patients should be monitored and dose delay, reduction or discontinuationmay be required (see section 4.2). Patients and physicians are advised to be observant for signs andsymptoms of bleeding including petechiae, epistaxis and gastrointestinal haemorrhage, especially incase of concomitant medicinal product prone to inducing bleeding (see sections 4.5 and 4.8).

Hepatic disorders

Hepatic disorders, mainly abnormal liver test results, were reported. No specific pattern was identifiedbetween hepatocellular and cholestatic abnormalities, with some cases having a mixed presentation.

The majority of the reactions occurred within the first 2 months of therapy and resolved spontaneouslywithout treatment after thalidomide discontinuation. Patients should be monitored for liver function,particularly in case of pre-existing liver disorder or concomitant use of medicinal product susceptibleto induce liver dysfunction (see section 4.8).

Allergic reactions and severe skin reactions

Cases of allergic reactions including angioedema, anaphylactic reaction and severe cutaneousreactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drugreaction with eosinophilia and systemic symptoms (DRESS) have been reported with the use of

Thalidomide. Patients should be advised of the signs and symptoms of these reactions by theirprescribers and should be told to seek medical attention immediately if they develop these symptoms.

Thalidomide interruption or discontinuation should be considered for Grade 2-3 skin rash.

Thalidomide must be discontinued for angioedema, anaphylactic reaction, Grade 4 rash, exfoliative orbullous rash, or if SJS, TEN or DRESS is suspected, and should not be resumed followingdiscontinuation for these reactions. (see sections 4.2 and 4.8).

Somnolence

It is very common that thalidomide causes somnolence. Patients should be instructed to avoidsituations where somnolence may be a problem and to seek medical advice before taking othermedicinal products known to cause somnolence. Patients should be monitored and dose reduction maybe required.

Patients should be advised as to the possible impairment of mental and/or physical abilities requiredfor the performance of hazardous tasks (see section 4.7).

The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment.

These patients should be monitored closely and appropriate precautions taken.

Patients should be monitored for severe infections including sepsis and septic shock.

Cases of viral reactivation have been reported in patients receiving thalidomide, including seriouscases of herpes zoster or hepatitis B virus (HBV) reactivation.

Some of the cases of herpes zoster reactivation resulted in disseminated herpes zoster, requiring atemporary hold of the treatment with thalidomide and adequate antiviral treatment.

Some of the cases of HBV reactivation progressed to acute hepatic failure and resulted indiscontinuation of thalidomide. Hepatitis B virus status should be established before initiatingtreatment with thalidomide. For patients who test positive for HBV infection, consultation with aphysician with expertise in the treatment of hepatitis B is recommended.

Previously infected patients should be closely monitored for signs and symptoms of viral reactivation,including active HBV infection, throughout therapy.

Cases of progressive multifocal leukoencephalopathy, including fatal cases, have been reported withthalidomide. PML was reported several months to several years after starting the treatment withthalidomide. Cases have generally been reported in patients taking concomitant dexamethasone orprior treatment with other immunosuppressive chemotherapy. Physicians should monitor patients atregular intervals and should consider PML in the differential diagnosis in patients with new orworsening neurological symptoms, cognitive or behavioural signs or symptoms. Patients should alsobe advised to inform their partner or caregivers about their treatment, since they may notice symptomsthat the patient is not aware of.

The evaluation for PML should be based on neurological examination, magnetic resonance imaging ofthe brain, and cerebrospinal fluid analysis for JC virus (JCV) DNA by polymerase chain reaction(PCR) or a brain biopsy with testing for JCV. A negative JCV PCR does not exclude PML. Additionalfollow-up and evaluation may be warranted if no alternative diagnosis can be established.

If PML is suspected, further dosing must be suspended until PML has been excluded. If PML isconfirmed, thalidomide must be permanently discontinued.

Acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS)

A statistically significant increase of AML and MDS was observed in one clinical study in patientswith previously untreated MM receiving the combination of melphalan, prednisone, and thalidomide(MPT). The risk increased over time and was about 2 % after two years and about 4 % after threeyears. An increased incidence of second primary malignancies (SPM) has also been observed inpatients with newly diagnosed MM receiving lenalidomide. Among invasive SPMs, cases of

MDS/AML were observed in patients receiving lenalidomide in combination with melphalan orimmediately following high dose melphalan and autologous stem cell transplantation.

The benefit achieved with thalidomide and the risk of AML and MDS must be taken into accountbefore initiating treatment with thalidomide in combination with melphalan and prednisone.

Physicians should carefully evaluate patients before and during treatment using standard cancerscreening and institute treatment as indicated.

Studies conducted in healthy subjects and patients with multiple myeloma suggest that thalidomide isnot influenced to any significant extent by renal or hepatic function (see section 5.2). However, thishas not formally been studied in patients with impaired renal or hepatic function; therefore patientswith severe renal or hepatic impairment should be carefully monitored for any adverse events.

Thalidomide is a poor substrate for cytochrome P450 isoenzymes and therefore clinically importantinteractions with medicinal products that are inhibitors and/or inducers of this enzyme system areunlikely. Non-enzymatic hydrolysis of thalidomide, being the primary clearance mechanism, suggeststhat the potential for drug-drug interactions with thalidomide is low.

Increase of sedative effects of other medicinal products

Thalidomide has sedative properties, thus may enhance the sedation induced by anxiolytics, hypnotics,antipsychotics, H1 antihistamines, opiate derivatives, barbiturates and alcohol. Caution should be usedwhen thalidomide is given in combination with medicinal products that cause drowsiness.

Bradycardic effect

Due to thalidomide’s potential to induce bradycardia, caution should be exercised with medicinalproducts having the same pharmacodynamic effect such as active substances known to induce torsadede pointes, beta blockers or anticholinesterase agents.

Medicinal products known to cause peripheral neuropathy

Medicinal products known to be associated with peripheral neuropathy (e.g. vincristine andbortezomib) should be used with caution in patients receiving thalidomide.

Thalidomide does not interact with hormonal contraceptives. In 10 healthy women, thepharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a singledose containing 1.0 mg of norethindrone acetate and 0.75 mg of ethinyl estradiol were studied. Theresults were similar with and without co-administration of thalidomide 200 mg/day to steady-statelevels. However, combined hormonal contraceptives are not recommended due to the increased risk ofvenous thromboembolic disease.

Multiple dose administration of 200 mg thalidomide q.d. for 4 days had no effect on the internationalnormalized ratio (INR) in healthy volunteers. However, due to the increased risk of thrombosis incancer patients, and a potentially accelerated metabolism of warfarin with corticosteroids, closemonitoring of INR values is advised during thalidomide-prednisone combination treatment as well asduring the first weeks after ending these treatments.

Thalidomide does not interact with digoxin. In 18 healthy male volunteers, multiple doseadministration of 200 mg thalidomide had no apparent effect on the single dose pharmacokinetics ofdigoxin. In addition, single dose administration of 0.5 mg digoxin had no apparent effect onthalidomide pharmacokinetics. It is not known whether the effect will be different in multiplemyeloma patients.

Women of childbearing potential must use one effective method of contraception for at least 4 weeksbefore start of treatment, during treatment including during dose interruptions, and until at least4 weeks after thalidomide treatment (see section 4.4). If pregnancy occurs in a woman treated withthalidomide, treatment must be stopped immediately and the patient should be referred to a physicianspecialised or experienced in teratology for evaluation and advice.

As thalidomide is found in semen, as a precaution all male patients must use condoms duringtreatment, during dose interruption and for at least 7 days following discontinuation of treatment whenhaving sexual intercourse with a pregnant woman or with a woman of childbearing potential who isnot using effective contraception. This applies even if the man has had a vasectomy.

If pregnancy occurs in a partner of a male patient taking thalidomide, the female partner should bereferred to a physician specialised or experienced in teratology for evaluation and advice.

Thalidomide is contraindicated during pregnancy and in women of childbearing potential unless all theconditions of the Pregnancy Prevention Programme are met (see section 4.3)

Thalidomide is a powerful human teratogen, inducing a high frequency (about 30 %) of severe andlive-threatening birth defects such as: ectromelia (amelia, phocomelia, hemimelia) of the upper and/orlower extremities, microtia with abnormality of the external acoustic meatus (blind or absent), middleand internal ear lesions (less frequent), ocular lesions (anophthalmia, microphthalmia), congenitalheart disease, renal abnormalities. Other less frequent abnormalities have also been described.

It is unknown whether thalidomide is excreted in human breast milk. Animal studies have shownexcretion of thalidomide in breast milk. Therefore breast-feeding should be discontinued duringtreatment with thalidomide.

A study in rabbits demonstrated no effect on fertility indices in males or females although testiculardegeneration was observed in males.

Thalidomide Celgene as per the recommended posology has minor or moderate influence on theability to drive and use machines.

Thalidomide may cause fatigue (very common), dizziness (very common), somnolence (verycommon) and blurred vision (common) (see section 4.8). Patients should be instructed not to drivecars, use machines or perform hazardous tasks while being treated with thalidomide if they feel tired,dizzy, sleepy or have blurred vison.

Most patients taking thalidomide can be expected to experience adverse reactions.

The most commonly observed adverse reactions associated with the use of thalidomide in combinationwith melphalan and prednisone are: neutropenia, leukopenia, constipation, somnolence, paraesthesia,peripheral neuropathy, anaemia, lymphopenia, thrombocytopenia, dizziness, dysaesthesia, tremor andperipheral oedema.

In addition to the adverse reactions outlined above, thalidomide in combination with dexamethasone inother clinical studies led to the very common adverse reaction of fatigue; common adverse reactions oftransient ischaemic event, syncope, vertigo, hypotension, mood altered, anxiety, blurred vision, nauseaand dyspepsia; and uncommon adverse reactions of cerebrovascular accident, diverticular perforation,peritonitis, orthostatic hypotension and bronchitis.

The most clinically important adverse reactions associated with the use of thalidomide in combinationwith melphalan and prednisone or dexamethasone include: deep vein thrombosis and pulmonaryembolism, peripheral neuropathy, severe skin reactions including Stevens-Johnson syndrome, toxicepidermal necrolysis and drug reaction with eosinophilia and systemic symptoms, syncope,bradycardia, and dizziness (see sections 4.2, pct. 4.4 and 4.5).

Table 3 contains only the adverse reactions for which a causal relationship with medicinal producttreatment could reasonably be established observed in the pivotal study and from post-marketingexperience. Frequencies given are based on the observations during a pivotal comparative clinicalstudy investigating the effect of thalidomide in combination with melphalan and prednisone inpreviously untreated multiple myeloma patients.

Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon(≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000) and not known (cannot beestimated from the available data). Within each frequency grouping, adverse reactions are presented inorder of decreasing seriousness.

Table 3: Adverse drug reactions (ADRs) reported in pivotal clinical study with thalidomide incombination with melphalan and prednisone and from post marketing use

System Organ Class Frequency Adverse reaction

Common Pneumonia

Infections and infestations Severe infections (e.g. fatal sepsis including septic

Not Known shock)†, Viral infections, including herpes zosterand hepatitis B virus reactivation†

Neoplasms benign, Common Acute myeloid leukaemia*,^malignant and unspecified Uncommon Myelodysplastic syndrome*,^(incl cysts and polyps) Not Known Tumour lysis syndrome†

Very Common Neutropenia, Leukopenia, Anaemia,

Blood and lymphatic Lymphopenia, Thrombocytopeniasystem disorders Common Febrile neutropenia†, Pancytopenia†

Immune System Disorders Not Known Allergic reactions (hypersensitivity, angioedema,anaphylactic reaction, urticaria) †

Endocrine Disorders Not Known Hypothyroidism†

Psychiatric disorders Common Confusional state, Depression

Very Common Peripheral neuropathy*, Tremor, Dizziness,

Paraesthesia, Dysaesthesia, Somnolence

Nervous system disorders Common Convulsions†, Abnormal coordination

Not Known (PRES)*,†, Worsening of Parkinson’s diseasesymptoms†

Ear and labyrinthdisorders Common Hearing impaired or deafness†

Common Cardiac failure, Bradycardia

Cardiac disorders † †

Uncommon Myocardial infarction , Atrial fibrillation ,

Atrioventricular block†

Vascular disorders Common Deep vein thrombosis*

Common Pulmonary embolism*, Interstitial lung disease,

Respiratory, thoracic and Bronchopneumopathy, Dyspneamediastinal disorders Not Known Pulmonary hypertension†

System Organ Class Frequency Adverse reaction

Very Common Constipation

Common Vomiting, Dry mouth

Gastrointestinal disorders Uncommon Intestinal obstruction†

Not Known Gastrointestinal perforation†, Pancreatitis†,

Gastrointestinal haemorrhage†

Hepatobiliary disorders Not Known Hepatic disorders†

Common Toxic skin eruption, Rash, Dry skin,†

Skin and subcutaneous Stevens-Johnson syndrome* , Toxic epidermaltissue disorders Not Known necrolysis*,†, Drug reaction with eosinophilia andsystemic symptoms*,†, Leukocytoclasticvasculitis†

Renal and urinarydisorders Common Renal failure†

Reproductive System and Not Known Sexual dysfunction†, Menstrual disorders

Breast Disorders including amenorrhea†

General disorders and Very Common Peripheral oedemaadministration siteconditions Common Pyrexia, Asthenia, Malaise

* see section 4.8 description of selected adverse reactions† identified from post marketing data^ Acute myeloid leukaemia and Myelodysplastic syndrome were reported in one clinical study in patients with previously untreated MMreceiving the combination of melphalan, prednisone and thalidomide (MPT)

Adverse reactions for haematological disorders are provided compared to the comparator arm, as thecomparator has a significant effect on these disorders (Table 4).

Table 4: Comparison of haematological disorders for the melphalan, prednisone (MP) andmelphalan, prednisone, thalidomide (MPT) combinations in study IFM 99-06 (see section 5.1)n (% of patients)

MP (n=193) MPT (n=124)

Grades 3 and 4*

Neutropenia 57 (29.5) 53 (42.7)

Leukopenia 32 (16.6) 32 (25.8)

Anaemia 28 (14.5) 17 (13.7)

Lymphopenia 14 (7.3) 15 (12.1)

Thrombocytopenia 19 (9.8) 14 (11.3)

* WHO Criteria

Additional adverse reactions from post-marketing experience with thalidomide and not seen in thepivotal study include febrile neutropenia and pancytopenia.

The risk of intra-uterine death or severe birth defects, primarily phocomelia, is extremely high.

Thalidomide must not be used at any time during pregnancy (see sections 4.4 and 4.6).

Venous and arterial thromboembolic events

An increased risk of venous thromboembolism (such as deep vein thrombosis and pulmonaryembolism) and arterial thromboembolism (such as myocardial infarction and cerebrovascular event)has been reported in patients treated with thalidomide (see section 4.4).

Peripheral neuropathy is a very common, potentially severe, adverse reaction of treatment withthalidomide that may result in irreversible damage (see section 4.4). Peripheral neuropathy generallyoccurs following chronic use over a period of months. However, reports following relatively short-term use also exist. Incidence of neuropathy events leading to discontinuation, dose reduction orinterruption increases with cumulative dose and duration of therapy. Symptoms may occur some timeafter thalidomide treatment has been stopped and may resolve slowly or not at all.

Posterior reversible encephalopathy syndrome (PRES)/ Reversible posterior leukoencephalopathysyndrome (RPLS)

Cases of PRES/RPLS have been reported. Signs and symptoms included visual disturbance, headache,seizures and altered mental status, with or without associated hypertension. A diagnosis of

PRES/RPLS requires confirmation by brain imaging. The majority of the reported cases hadrecognized risk factors for PRES/RPLS, including hypertension, renal impairment and concomitantuse of high dose corticosteroids and/or chemotherapy.

Acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS)

AML and MDS were reported in one clinical study in patients with previously untreated multiplemyeloma receiving the combination of melphalan, prednisone, and thalidomide (see section 4.4).

Allergic reactions and severe skin reactions

Cases of allergic reactions including angioedema, anaphylactic reaction and severe cutaneousreactions including Stevens-Johnson syndrome, TEN and DRESS have been reported with the use ofthalidomide therapy. If angioedema, anaphylactic reaction, Stevens-Johnson syndrome, TEN or

DRESS is suspected, use of thalidomide should not be resumed (see section 4.2 and 4.4).

The adverse reaction profile reported in patients > 75 years of age treated with thalidomide 100 mgonce daily was similar to the adverse reaction profile observed in patients ≤ 75 years of age treatedwith thalidomide 200 mg once daily (see Table 3). However, patients with age > 75 years arepotentially at risk for a higher frequency of serious adverse reactions.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Eighteen cases of overdose have been reported in the literature concerning doses up to 14.4 grams. Inthirteen of these cases, patients took thalidomide alone; amounts ranged from 350 mg to 4000 mg.

These patients either exhibited no symptoms or exhibited symptoms of drowsiness, irritability,“sickness,” and/or headache. In one 2-year-old child who took 700 mg, there was an abnormal plantarresponse in addition to drowsiness and irritability. No fatalities have been reported and all overdosepatients recovered without sequelae. There is no specific antidote for a thalidomide overdose. In theevent of an overdose, the patient’s vital signs should be monitored and appropriate supportive caregiven to maintain blood pressure and respiratory status.

Pharmacotherapeutic group: immunosuppressants, other immunosuppressants, ATC code: L04AX02.

Thalidomide has a chiral centre and is used clinically as a racemate of (+)-(R)- and(-)-(S)-thalidomide. The spectrum of activity of thalidomide is not fully characterised.

Thalidomide shows immunomodulatory, anti-inflammatory and potential anti-neoplastic activities.

Data from in vitro studies and clinical trials suggest that the immunomodulatory, anti-inflammatoryand anti-neoplastic effects of thalidomide may be related to suppression of excessive tumour necrosisfactor-alpha (TNF-α) production, down-modulation of selected cell surface adhesion moleculesinvolved in leukocyte migration and anti-angiogenic activity. Thalidomide is also a non-barbituratecentrally active hypnotic sedative. It has no antibacterial effects.

Results from IFM 99-06, a Phase 3, randomised, open label, parallel group, multicentre study havedemonstrated a survival advantage when thalidomide is used in combination with melphalan andprednisone for 12 cycles of 6 weeks in the treatment of newly diagnosed multiple myeloma patients. Inthis study the age range of patients was 65-75 years, with 41 % (183/447) of patients 70 years old orolder. The median dose of thalidomide was 217 mg and > 40 % of patients received 9 cycles.

Melphalan and prednisone were dosed at 0.25 mg/kg/day and 2 mg/kg/day respectively on days 1 to 4of each 6 weeks cycle.

Further to the per protocol analysis, an update was conducted for the IFM 99-06 study providing anadditional 15 months follow-up data. The median overall survival (OS) was 51.6 ± 4.5 and33.2 ± 3.2 months in the MPT and MP groups, respectively (97.5 % CI 0.42 to 0.84). This 18 monthdifference was statistically significant with a hazard ratio of reduction of risk of death in the MPT armof 0.59, 97.5 % confidence interval of 0.42-0.84 and p-value of < 0.001 (see Figure 1).

Figure 1: Overall survival according to treatment0.80.6

Proportion0.4

Treatment O/N + Survival timemedian ± se (month)0.2 MP 128/196 33.2 ± 3.2

MP - T 62/125 51.6 ± 4.50 12 24 36 48 60 72 84

Time from randomization ( month )

The European Medicines Agency has waived the obligation to submit the results of studies withthalidomide in all subsets of the paediatric population in multiple myeloma (see section 4.2 forinformation on paediatric use).

Absorption of thalidomide is slow after oral administration. The maximum plasma concentrations arereached 1-5 hours after administration. Co-administration of food delayed absorption but did not alterthe overall extent of absorption.

The plasma protein binding of the (+)-(R) and (-)-(S) enantiomers was found to be 55 % and 65 %respectively. Thalidomide is present in the semen of male patients at levels similar to plasmaconcentrations (see section 4.4). The distribution of thalidomide is not influenced by age, gender, renalfunction and blood chemistry variables, to any significant level.

Thalidomide is metabolised almost exclusively by non-enzymatic hydrolysis. In plasma, unchangedthalidomide represents 80 % of the circulatory components. Unchanged thalidomide was a minorcomponent (< 3 % of the dose) in urine. In addition to thalidomide, hydrolytic products

N-(o-carboxybenzoyl) glutarimide and phthaloyl isoglutamine formed via non-enzymatic processesare also present in plasma and in majority in urine. Oxidative metabolism does not contributesignificantly to the overall metabolism of thalidomide. There is minimal cytochrome P450 catalysedhepatic metabolism of thalidomide. There are in vitro data indicating that prednisone may give rise toenzyme induction which could reduce the systemic exposure of concomitantly used medicinalproducts. The in vivo relevance of these findings is unknown.

The mean elimination half-life of thalidomide in plasma following single oral doses between 50 mgand 400 mg was 5.5 to 7.3 hours. Following a single oral dose of 400 mg of radio-labelledthalidomide, the total mean recovery was 93.6 % of the administered dose by day 8. The majority ofthe radioactive dose was excreted within 48 hour following dose administration. The major route ofexcretion was via the urine (> 90 %) while faecal excretion was minor.

There is a linear relationship between body weight and estimated thalidomide clearance; in multiplemyeloma patients with body weight from 47-133 kg, thalidomide clearance ranged fromapproximately 6-12 L/h, representing an increase in thalidomide clearance of 0.621 L/h per 10 kg bodyweight increase.

Total systemic exposure (AUC) is proportional to dose at single-dose conditions. No time dependencyof the pharmacokinetics has been observed.

The extent of thalidomide metabolism by the liver cytochrome P450 system is minimal and intactthalidomide is not excreted by the kidney. Measures of renal function (CrCl) and liver function (bloodchemistry) indicate minimal effect of kidney and liver function on the pharmacokinetics ofthalidomide. As such the metabolism of thalidomide is not expected to be affected by hepatic or renaldysfunction. Data from patients with end-stage renal disease suggest no impact of kidney function onthalidomide pharmacokinetics.

In the male dog, after one year of dosing, reversible bile plugs in canaliculi were observed atexposures greater than 1.9-fold the human exposure.

Decreased platelet counts were noted in the mouse and rat studies. The latter appears to be related tothalidomide and occurred at exposures greater than 2.4-fold the human exposure. This decrease did notresult in clinical signs.

In a one-year dog study, enlarged and/or blue discoloration of mammary glands and prolonged estruswere observed in females at exposures equal to 1.8 or greater than 3.6-fold the human exposure,respectively. The relevance to humans is unknown.

The effect of thalidomide on thyroid function was assessed in both rats and dogs. No effects wereobserved in dogs; however in rats, there was an apparent dose-dependent decrease in total and free T4that was more consistent in the female.

No mutagenic or genotoxic effect has been revealed when thalidomide was assayed in a standardbattery of genotoxicity tests. No evidence of carcinogenicity was observed at exposures approximately15, 13 and 39 times the estimated clinical AUC at the recommended starting dose in mice, male ratsand female rats respectively.

Animal studies have demonstrated differences in species susceptibility to the teratogenic effects ofthalidomide. In humans, thalidomide is a proven teratogen.

A study in rabbits demonstrated no effect on fertility indices in males or females although testiculardegeneration was observed in males.

A peri- and postnatal toxicity study performed in rabbits with thalidomide administered at doses up to500 mg/kg/day resulted in abortions, increased stillbirths and decreased pup viability during lactation.

Pups from mothers treated with thalidomide had increased abortions, reduced body weight gain,alterations in learning and memory, decreased fertility, and reduced pregnancy index.

Starch, pregelatinised

Magnesium stearate

Gelatin

Titanium dioxide (E171)

Shellac

Black iron oxide (E172)

Not applicable.

5 years

This medicinal product does not require any special storage conditions.

PVC/PCTFE/aluminium blister containing 14 capsules.

Pack sizes: 28 capsules (two blisters) in a wallet card.

Capsules should not be opened or crushed. If powder from thalidomide makes contact with the skin,the skin should be washed immediately and thoroughly with soap and water. If thalidomide makescontact with the mucous membranes, they should be thoroughly flushed with water.

Healthcare professionals and caregivers should wear disposable gloves when handling the blister orcapsule. Gloves should then be removed carefully to prevent skin exposure, placed in a sealable plasticpolyethylene bag and disposed of in accordance with local requirements. Hands should then be washedthoroughly with soap and water. Women who are pregnant or suspect they may be pregnant should nothandle the blister or capsule (see section 4.4).

All unused capsules should be returned to the pharmacist at the end of treatment.

Celgene Europe B.V.

Winthontlaan 6 N3526 KV Utrecht

Netherlands

EU/1/08/443/001

Date of first authorisation: 16 April 2008

Date of latest renewal: 08 February 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.