Mavenclad (cladribine 10 mg sorbitol 64.04 mg) Dailymed

• Lymphopenia: Monitor lymphocyte counts before, during and after treatment. (5.3)
• Infections: Serious, including life-threatening and fatal infections, have occurred. Screen patients for active and latent infections; delay treatment until infection is fully resolved or controlled. Vaccination of patients seronegative to varicella zoster virus (VZV) is recommended prior to treatment. Vaccination of patients seropositive to VZV with zoster vaccine recombinant, adjuvanted, is recommended prior to or during treatment. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Monitor for infections. (5.4)
• Hematologic toxicity: Monitor complete blood count before, during and after treatment. (5.5)
• Graft-versus-host-disease with blood transfusion: Irradiation of cellular blood components is recommended. (5.6)
• Liver injury: Clinically significant liver injury has occurred. Obtain tests prior to treatment. Discontinue if clinicallysignificant injury is suspected. (5.7)

5.1 Malignancies

Treatment with MAVENCLAD may increase the risk of malignancy. In controlled and extension clinical studies worldwide, malignancies occurred more frequently in MAVENCLAD-treated patients [10 events in 3,754 patient-years (0.27 events per 100 patient-years)], compared to placebo patients [3 events in 2,275 patient-years (0.13 events per 100 patient-years)]. Malignancy cases in MAVENCLAD patients included metastatic pancreatic carcinoma, malignant melanoma (2 cases), ovarian cancer, compared to malignancy cases in placebo patients, all of which were curable by surgical resection [basal cell carcinoma, cervical carcinoma in situ (2 cases)]. The incidence of malignancies in United States MAVENCLAD clinical study patients was higher than the rest of the world [4 events in 189 patient-years (2.21 events per 100 patient-years) compared to 0 events in United States placebo patients]; however, the United States results were based on a limited amount of patient data.

After the completion of 2 treatment courses, do not administer additional MAVENCLAD treatment during the next 2 years [see Dosage and Administration (2.2)]. In clinical studies, patients who received additional MAVENCLAD treatment within 2 years after the first 2 treatment courses had an increased incidence of malignancy [7 events in 790 patient-years (0.91 events per 100 patient-years) calculated from the start of cladribine treatment in Year 3]. The risk of malignancy with reinitiating MAVENCLAD more than 2 years after the completion of 2 treatment courses has not been studied.

MAVENCLAD is contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of the use of MAVENCLAD on an individual patient basis. Follow standard cancer screening guidelines in patients treated with MAVENCLAD.

5.2 Risk of Teratogenicity

MAVENCLAD may cause fetal harm when administered to pregnant women. Malformations and embryolethality occurred in animals [see Use in Specific Populations (8.1)]. Advise women of the potential risk to a fetus during MAVENCLAD dosing and for 6 months after the last dose in each treatment course.

In females of reproductive potential, pregnancy should be excluded before initiation of each treatment course of MAVENCLAD and prevented by the use of effective contraception during MAVENCLAD dosing and for at least 6 months after the last dose of each treatment course. Women who become pregnant during treatment with MAVENCLAD should discontinue treatment [see Use in Specific Populations (8.1, 8.3)]. MAVENCLAD is contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception.

5.3 Lymphopenia

MAVENCLAD causes a dose-dependent reduction in lymphocyte count. In clinical studies, 87% of MAVENCLAD-treated patients experienced lymphopenia. The lowest absolute lymphocyte counts occurred approximately 2 to 3 months after the start of each treatment course and were lower with each additional treatment course. In patients treated with a cumulative dose of MAVENCLAD 3.5 mg per kg over 2 courses as monotherapy, 26% and 1% had nadir absolute lymphocyte counts less than 500 and less than 200 cells per microliter, respectively. At the end of the second treatment course, 2% of clinical study patients had lymphocyte counts less than 500 cells per microliter; median time to recovery to at least 800 cells per microliter was approximately 28 weeks.

Additive hematological adverse reactions may be expected if MAVENCLAD is administered prior to or concomitantly with other drugs that affect the hematological profile [see Drug Interactions (7.3)]. The incidence of lymphopenia less than 500 cells per microliter was higher in patients who had used drugs to treat relapsing forms of MS prior to study entry (32.1%), compared to those with no prior use of these drugs (23.8%).

Obtain complete blood count (CBC) with differential including lymphocyte count prior to, during, and after treatment with MAVENCLAD. See Dosage and Administration (2.1, 2.5) and Warnings and Precautions (5.4) for timing of CBC measurements and additional instructions based on the patient's lymphocyte counts and clinical status (e.g., infections).

5.4 Infections

Serious, including life-threatening or fatal, bacterial, viral, parasitic, and fungal infections have been reported in patients receiving MAVENCLAD. MAVENCLAD reduces the body's immune defense, and an increased risk of infections has been observed in patients receiving MAVENCLAD.

Infections occurred in 49% of MAVENCLAD-treated patients compared to 44% of placebo patients in clinical studies; serious or severe infections occurred in 2.4% of MAVENCLAD-treated patients and 2.0% of placebo-treated patients. The most frequent serious infections in MAVENCLAD-treated patients included herpes zoster and pyelonephritis (see Herpes Virus Infections). Fungal infections were observed, including cases of coccidioidomycosis.

In the postmarketing setting, serious infections have been reported, including nocardiosis, varicella zoster, histoplasmosis, cryptococcosis, and toxoplasmosis. The majority of patients with these infections who had an available absolute lymphocyte count at the time of the event had concurrent lymphopenia, consistent with the mechanism of action of MAVENCLAD [see Warnings and Precautions (5.3)].

HIV infection, active tuberculosis, and active hepatitis must be excluded before initiation of each treatment course of MAVENCLAD [see Contraindications (4)].

Delay initiation of MAVENCLAD in patients with an acute infection until the infection is fully resolved or controlled.

Initiation of MAVENCLAD in patients currently receiving immunosuppressive or myelosuppressive therapy is not recommended [see Drug Interactions (7.1)]. Concomitant use of MAVENCLAD with these therapies could increase the risk of immunosuppression.

Tuberculosis

Three of 1,976 (0.2%) cladribine-treated patients in the clinical program developed tuberculosis. All three cases occurred in regions where tuberculosis is endemic. One case of tuberculosis was fatal, and two cases resolved with treatment.

Perform tuberculosis screening prior to initiation of the first and second treatment course of MAVENCLAD. Latent tuberculosis infections may be activated with use of MAVENCLAD. In patients with tuberculosis infection, delay initiation of MAVENCLAD until the infection has been adequately treated.

Hepatitis

One clinical study patient died from fulminant hepatitis B infection. Perform screening for hepatitis B and C prior to initiation of the first and second treatment course of MAVENCLAD. Latent hepatitis infections may be activated with use of MAVENCLAD. Patients who are carriers of hepatitis B or C virus may be at risk of irreversible liver damage caused by virus reactivation. In patients with hepatitis infection, delay initiation of MAVENCLAD until the infection has been adequately treated.

Herpes Virus Infections

In controlled clinical studies, 6% of MAVENCLAD-treated patients developed a herpes viral infection compared to 2% of placebo patients. The most frequent types of herpes viral infections were herpes zoster infections (2.0% vs. 0.2%) and oral herpes (2.6% vs. 1.2%). Serious herpes zoster infections occurred in 0.2% of MAVENCLAD-treated patients.

Vaccination of patients who are seronegative for varicella zoster virus is recommended prior to initiation of MAVENCLAD. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD. Vaccination with zoster vaccine recombinant, adjuvanted is recommended for patients who are seropositive to VZV, either prior to or during MAVENCLAD treatment, including when their lymphocyte counts are less than or equal to 500 cells per microliter.

The incidence of herpes zoster was higher during the period of absolute lymphocyte count less than 500 cells per microliter, compared to the time when the patients were not experiencing this degree of lymphopenia. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter.

Patients with lymphocyte counts below 500 cells per microliter should be monitored for signs and symptoms suggestive of infections, including herpes infections. If such signs and symptoms occur, initiate treatment as clinically indicated. Consider interruption or delay of MAVENCLAD until resolution of the infection.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

No case of PML has been reported in clinical studies of cladribine in patients with multiple sclerosis. In patients treated with parenteral cladribine for oncologic indications, cases of PML have been reported in the postmarketing setting.

Obtain a baseline (within 3 months) magnetic resonance imaging (MRI) before initiating the first treatment course of MAVENCLAD. At the first sign or symptom suggestive of PML, withhold MAVENCLAD and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms.

Vaccinations

Administer all immunizations (except as noted for VZV) according to immunization guidelines prior to starting MAVENCLAD. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD, because of a risk of active vaccine infection (see Herpes Virus Infections). Avoid vaccination with live-attenuated or live vaccines during and after MAVENCLAD treatment while the patient's white blood cell counts are not within normal limits.

5.5 Hematologic Toxicity

In addition to lymphopenia [see Warnings and Precautions (5.3)], decreases in other blood cells and hematological parameters have been reported with MAVENCLAD in clinical studies. Mild to moderate decreases in neutrophil counts (cell count between 1,000 cells per microliter and < lower limit of normal (LLN)) were observed in 27% of MAVENCLAD-treated patients, compared to 13% of placebo patients whereas severe decreases in neutrophil counts (cell count below 1,000 cells per microliter) were observed in 3.6% of MAVENCLAD-treated patients, compared to 2.8% of placebo patients. Decreases in hemoglobin levels, in general mild to moderate (hemoglobin 8.0 g per dL to < LLN), were observed in 26% of MAVENCLAD-treated patients, compared to 19% of placebo patients. Decreases in platelet counts were generally mild (cell count 75,000 cells per microliter to < LLN) and were observed in 11% of MAVENCLAD- treated patients, compared to 4% of placebo patients.

In clinical studies at dosages similar to or higher than the approved MAVENCLAD dosage, serious cases of thrombocytopenia, neutropenia, and pancytopenia (some with documented bone marrow hypoplasia) requiring transfusion and granulocyte-colony stimulating factor treatment have been reported [see Warnings and Precautions (5.6) for information regarding graft-versus- host disease with blood transfusion].

Obtain complete blood count (CBC) with differential prior to, during, and after treatment with MAVENCLAD [see Dosage and Administration (2.1, 2.5)].

5.6 Graft-Versus-Host Disease With Blood Transfusion

Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of nonirradiated blood in patients treated with cladribine for non-MS treatment indications.

In patients who require blood transfusion, irradiation of cellular blood components is recommended prior to administration to decrease the risk of transfusion-related graft-versus-host disease. Consultation with a hematologist is advised.

5.7 Liver Injury

Mavenclad can cause liver injury. In clinical studies, 0.3% of MAVENCLAD-treated patients had liver injury (serious or causing treatment discontinuation) considered related to treatment, compared to 0 placebo patients. Onset ranged from a few weeks to several months after initiation of treatment with MAVENCLAD. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 20-fold the upper limit of normal, were observed. These abnormalities resolved upon treatment discontinuation.

Clinically significant and life-threatening liver injury has been reported in patients treated with MAVENCLAD in the postmarketing setting. Patients with pre-existing liver disease and patients taking other hepatotoxic drugs may be at increased risk for developing liver injury when taking MAVENCLAD. Most reported cases of liver injury associated with MAVENCLAD occurred approximately 30 days after initiation (i.e., course 1, cycle 1) of treatment.

MAVENCLAD is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh score greater than 6) [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to each treatment cycle and course [see Dosage and Administration (2.1)]. If a patient develops clinical signs, including unexplained liver enzyme elevations, or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with MAVENCLAD, as appropriate.

5.8 Hypersensitivity

In clinical studies, 11% of MAVENCLAD-treated patients had hypersensitivity reactions, compared to 7% of placebo patients. Hypersensitivity reactions that were serious and/or led to discontinuation of MAVENCLAD (e.g., dermatitis, pruritis) occurred in 0.5% of 13 MAVENCLAD-treated patients, compared to 0.1% of placebo patients. One patient had a serious hypersensitivity reaction with rash, mucous membrane ulceration, throat swelling, vertigo, diplopia, and headache after the first dose of MAVENCLAD.

If a hypersensitivity reaction is suspected, discontinue MAVENCLAD therapy. Do not use MAVENCLAD in patients with a history of hypersensitivity to cladribine [see Contraindications (4)].

5.9 Cardiac Failure

In clinical studies, one MAVENCLAD-treated patient experienced life-threatening acute cardiac failure with myocarditis, which improved after approximately one week. Cases of cardiac failure have also been reported with parenteral cladribine used for treatment indications other than multiple sclerosis.

Instruct patients to seek medical advice if they experience symptoms of cardiac failure (e.g., shortness of breath, rapid or irregular heartbeat, swelling).

6 Adverse Reactions

The following serious adverse reactions and potential risks are discussed, or discussed in greater detail, in other sections of the labeling:

• Malignancies [see Warnings and Precautions (5.1)]
• Risk of Teratogenicity [see Warnings and Precautions (5.2)]
• Lymphopenia [see Warnings and Precautions (5.3)]
• Infections [see Warnings and Precautions (5.4)]
• Hematologic Toxicity [see Warnings and Precautions (5.5)]
• Graft-Versus-Host Disease With Blood Transfusion [see Warnings and Precautions(5.6)]
• Liver Injury [see Warnings and Precautions (5.7)]
• Hypersensitivity [see Warnings and Precautions (5.8)]
• Cardiac Failure [see Warnings and Precautions (5.9)]

Most common adverse reactions (incidence > 20%) are upper respiratory tract infection, headache, and lymphopenia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono at 1-800-283-8088 ext. 5563 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

In the clinical trial program of cladribine in MS, 1,976 patients received cladribine for a total of 9,509 patient years. The mean time on study including follow-up was approximately 4.8 years, and approximately 24% of cladribine-treated patients had approximately 8 years of time on study including follow-up. Of these, 923 patients aged 18 to 66 years received MAVENCLAD as monotherapy at a cumulative dose of 3.5 mg per kg.

Table 2 shows adverse reactions in Study 1 [see Clinical Studies (14)] with an incidence of at least 5% for MAVENCLAD and higher than placebo. The most common (> 20%) adverse reactions reported in Study 1 are upper respiratory tract infection, headache, and lymphopenia.

Table 2 Adverse Reactions in Study 1 with an Incidence of at Least 5% for MAVENCLAD and Higher than Placebo

	MAVENCLAD(N=440)%	Placebo(N=435)%
Upper respiratory tract infection	38	32
Headache	25	19
Lymphopenia	24	2
Nausea	10	9
Back pain	8	6
Arthralgia and arthritis	7	5
Insomnia	6	4
Bronchitis	5	3
Hypertension	5	3
Fever	5	3
Depression	5	3

Hypersensitivity

In clinical studies, 11% of MAVENCLAD patients had hypersensitivity adverse reactions, compared to 7% of placebo patients [see Warnings and Precautions (5.8)].

Alopecia

Alopecia occurred in 3% of MAVENCLAD-treated patients compared to 1% of placebo patients.

Myelodysplastic Syndrome

Cases of myelodysplastic syndrome have been reported in patients that had received parenteral cladribine at a higher dosage than that approved for MAVENCLAD. These cases occurred several years after treatment.

Herpes Meningoencephalitis

Fatal herpes meningoencephalitis occurred in one MAVENCLAD-treated patient, at a higher dosage and longer duration of therapy than the approved MAVENCLAD dosage and in combination with interferon beta-1a treatment.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)

SJS and TEN are identified risks of parenteral cladribine for the treatment of oncologic indications.

Seizures

In clinical studies, serious events of seizure occurred in 0.3% of MAVENCLAD-treated patients compared to 0 placebo patients. Serious events included generalized tonic-clonic seizures and status epilepticus. It is unknown whether these events were related to the effects of multiple sclerosis alone, to MAVENCLAD, or to a combination of both.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of MAVENCLAD. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections and Infestations: nocardiosis, varicella zoster, histoplasmosis, cryptococcosis, and toxoplasmosis [see Warnings and Precautions (5.4)]

Hepatobiliary Disorders: liver injury [see Warnings and Precautions (5.7)]

7 Drug Interactions

Table 3 Drug Interactions with MAVENCLAD

7.1 Immunomodulatory, Immunosuppressive, or Myelosuppressive Drugs
Clinical Impact	Concomitant use of MAVENCLAD with immunomodulatory, immunosuppressive, or myelosuppressive drugs may increase the risk of adverse reactions because of the additive effects on the immune system [see Warnings and Precautions (5.4)].
Prevention or Management	Concomitant use with myelosuppressive or other immunosuppressive drugs is not recommended. Acute short-term therapy with corticosteroids can be administered.In patients who have previously been treated with immunomodulatory or immunosuppressive drugs, consider potential additive effect, the mode of action, and duration of effect of the other drugs prior to initiation of MAVENCLAD.
7.2 Interferon-Beta
Clinical Impact	Concomitant use of MAVENCLAD with interferon-beta did not change the exposure of cladribine to a clinically significant effect; however, lymphopenia risk may be increased [see Warnings and Precautions (5.3)].
Prevention or Management	Concomitant use is not recommended.
7.3 Hematotoxic Drugs
Clinical Impact	Concomitant use of MAVENCLAD with hematotoxic drugs may increase the risk of adverse reactions because of the additive hematological effects [see Warnings and Precautions (5.5)].
Prevention or Management	Monitor hematological parameters.
7.4 Antiviral and Antiretroviral Drugs
Clinical Impact	Compounds that require intracellular phosphorylation to become active (e.g., lamivudine, zalcitabine, ribavirin, stavudine, and zidovudine) could interfere with the intracellular phosphorylation and activity of cladribine.
Prevention or Management	Avoid concomitant use.
7.5 Potent ENT, CNT and BCRP Transporter Inhibitors
Clinical Impact	Cladribine is a substrate of breast cancer resistance protein (BCRP), equilibrative nucleoside (ENT1), and concentrative nucleoside (CNT3) transport proteins. The bioavailability, intracellular distribution, and renal elimination of cladribine may be altered by potent ENT1, CNT3, and BCRP transporter inhibitors.
Prevention or Management	Avoid co-administration of potent ENT1, CNT3, or BCRP transporter inhibitors (e.g., ritonavir, eltrombopag, curcumin, cyclosporine, dilazep, nifedipine, nimodipine, cilostazol, sulindac, dipyridamole, or reserpine) during the 4 to 5 day MAVENCLAD treatment cycles. If this is not possible, consider selection of alternative concomitant drugs with no or minimal ENT1, CNT3, or BCRP transporter inhibiting properties. If this is not possible, dose reduction to the minimum mandatory dose of drugs containing these compounds, separation in the timing of administration, and careful patient monitoring is recommended.
7.6 Potent BCRP and P-gp Transporter Inducers
Clinical Impact	Possible decrease in cladribine exposure if potent BCRP or P-gp transporter inducers are co-administered.
Prevention or Management	Consider a possible decrease in cladribine efficacy if potent BCRP (e.g., corticosteroids) or P-gp (e.g., rifampicin, St. John's Wort) transporter inducers are co-administered.

• Immunosuppressive drugs: Consider overlapping effects on immune system, when used sequentially. Concomitant use not recommended. (7.1)
• Hematotoxic drugs: Monitor patients for additive effects on the hematological profile. (7.3)
• Antiviral and antiretroviral drugs: Avoid concomitant use. (7.4)
• BCRP or ENT/CNT inhibitors: May alter bioavailability of cladribine. Avoid concomitant use. (7.5)

8 Use In Specific Populations

8.1 Pregnancy

Risk Summary

MAVENCLAD is contraindicated in pregnant women and in females and males of reproductive potential who do not plan to use effective contraception. There are no adequate data on the developmental risk associated with use of MAVENCLAD in pregnant women. Cladribine was embryolethal when administered to pregnant mice and produced malformations in mice and rabbits [see Data]. The observed developmental effects are consistent with the effects of cladribine on DNA [see Contraindications (4) and Warnings and Precautions (5.2)].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

There is a pregnancy safety study that monitors the pregnancy and infant outcomes following exposure to cladribine. Physicians and patients are encouraged to report pregnancies of women with multiple sclerosis exposed to oral cladribine during pregnancy or within 6 months before conception as well as pregnancies fathered by men with multiple sclerosis who had taken oral cladribine within 6 months before conception by calling EMD Serono's Adverse Event reporting line at 1-800-283-8088 ext. 5563 or by faxing 1-781-681-2961.

Data

Animal Data

When cladribine was administered intravenously (0, 0.5, 1.5, or 3 mg/kg/day) to pregnant mice during the period of organogenesis, fetal growth retardation and malformations (including exencephaly and cleft palate) and embryofetal death were observed at the highest dose tested. An increase in skeletal variations was observed at all but the lowest dose tested. There was no evidence of maternal toxicity.

When cladribine was administered intravenously (0, 0.3, 1, and 3 mg/kg/day) to pregnant rabbits during the period of organogenesis, fetal growth retardation and a high incidence of craniofacial and limb malformations were observed at the highest dose tested, in the absence of maternal toxicity.

When cladribine was administered intravenously (0, 0.5, 1.5, or 3.0 mg/kg/day) to mice throughout pregnancy and lactation, skeletal anomalies and embryolethality were observed at all but the lowest dose tested.

8.2 Lactation

Risk Summary

MAVENCLAD is contraindicated in breastfeeding women because of the potential for serious adverse reactions in breastfed infants [see Contraindications (4) and Warnings and Precautions (5)]. Advise women not to breastfeed during dosing with MAVENCLAD and for 10 days after the last dose.

There are no data on the presence of cladribine in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

In females of reproductive potential, pregnancy should be excluded before the initiation of each treatment course of MAVENCLAD [see Use in Specific Populations (8.1)].

Contraception

Females

Females of reproductive potential should prevent pregnancy by use of effective contraception during MAVENCLAD dosing and for at least 6 months after the last dose in each treatment course. Women who become pregnant during MAVENCLAD therapy should discontinue treatment [see Warnings and Precautions (5.2)].

Males

As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected. Therefore, male patients of reproductive potential should take precautions to prevent pregnancy of their partner during MAVENCLAD dosing and for at least 6 months after the last dose in each treatment course [see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness in pediatric patients (below 18 years of age) have not been established. Use of MAVENCLAD is not recommended in pediatric patients because of the risk of malignancies [see Warnings and Precautions (5.1)].

8.5 Geriatric Use

Clinical studies with MAVENCLAD did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution is recommended when MAVENCLAD is used in elderly patients, taking into account the potential greater frequency of decreased hepatic, renal, or cardiac function, concomitant diseases, and other drug therapy.

8.6 Patients with Renal Impairment

The concentration of cladribine is predicted to increase in patients with renal impairment [see Clinical Pharmacology (12.3)]. No dosage adjustment is recommended in patients with mild renal impairment (creatinine clearance 60 to 89 mL per minute). MAVENCLAD is not recommended in patients with moderate to severe renal impairment (creatinine clearance below 60 mL per minute) [see Clinical Pharmacology (12.3)].

8.7 Patients with Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of cladribine is unknown [see Clinical Pharmacology (12.3)]. No dosage adjustment is recommended in patients with mild hepatic impairment. MAVENCLAD is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh score greater than 6) [see Warnings and Precautions (5.7), Clinical Pharmacology (12.3)].