Einzelstoffe

Latensin® Kapseln schwach, stark

1 Kps. schwach, stark enth.: Keime des Bacillus cereus M.U. 345a (= DSM 5194) 8,7 µg/17,4 µg (als Lyophilisat).

Latensin®

Umstimmungsmittel.

Treatment must be initiated and administered under the supervision of a physician qualified and experienced in the use of chemotherapeutic agents.

Monotherapy

Recommended dosage

The recommended starting dose of bortezomib is 1.3 mg/m² body surface area twice weekly for two weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of VELCADE.

It is recommended that patients with a confirmed complete response receive 2 additional cycles of VELCADE beyond a confirmation. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of VELCADE therapy.

Currently there are limited data concerning retreatment with VELCADE.

Recommended dosage adjustments during treatment and re-initiation of treatment

VELCADE treatment must be withheld at the onset of any Grade 3 non-haematological or any Grade 4 haematological toxicities, excluding neuropathy as discussed below (see also section 4.4). Once the symptoms of the toxicity have resolved, VELCADE treatment may be re-initiated at a 25% reduced dose (1.3 mg/m² reduced to 1.0 mg/m²; 1.0 mg/m² reduced to 0.7 mg/m²). If the toxicity is not resolved or if it recurs at the lowest dose, discontinuation of VELCADE must be considered unless the benefit of treatment clearly outweighs the risk.

Patients who experience VELCADE related neuropathic pain and/or peripheral neuropathy are to be managed as presented in Table 1. Patients with pre-existing severe neuropathy may be treated with VELCADE only after careful risk/benefit assessment.

Table 1: Recommended* dose modifications for VELCADE related neuropathy.

*Based on dose modifications in phase II & III multiple myeloma studies and post-marketing experience.

Latensin® Injektion, mittel, stark
Zus.: 1 ml Inj. mittel/stark enth.: Keime des Bacillus cereus M.U. 345a (= DSM 5194) ca. 20 Mill./200 Mill.
Weit. Bestandteile: isotonische Natriumchloridlsg.

Hypersensitivity to bortezomib, boron or to any of the excipients.

Severe hepatic impairment.

Acute diffuse infiltrative pulmonary and pericardial disease

Gastrointestinal

Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common with VELCADE treatment. Cases of ileus have been reported, therefore patients who experience constipation should be closely monitored.

Haematological

VELCADE treatment is very commonly associated with haematological toxicities (thrombocytopenia, neutropenia and anaemia). The most common haematologic toxicity is transient thrombocytopenia. Platelets were lowest at Day 11 of each cycle of VELCADE treatment. There was no evidence of cumulative thrombocytopenia, including in the phase II extension study. The mean platelet count nadir measured was approximately 40% of baseline. In patients with advanced myeloma the severity of thrombocytopenia was related to pre-treatment platelet count: for baseline platelet counts <75,000/μl, 90% of 21 patients had a count 25,000/μl during the study, including 14% <10,000/μl; in contrast, with a baseline platelet count>75,000/μl, only 14% of 309 patients had a count 25×10⁹/l during the study. Platelet counts should be monitored prior to each dose of VELCADE. Therapy should be held when the platelet count is <25,000/μl and re-initiated at a reduced dose after resolution. Potential benefit of the treatment should be carefully weighed against the risks, particularly in case of moderate to severe thrombocytopenia and risk factors for bleeding.

Therefore, complete blood counts (CBC) including platelet counts should be frequently monitored throughout treatment with VELCADE.

Peripheral Neuropathy

Treatment with VELCADE is very commonly associated with peripheral neuropathy, which is predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported. The incidence of peripheral neuropathy increases early in the treatment and has been observed to peak during cycle 5.

It is recommended that patients be carefully monitored for symptoms of neuropathy such as a burning sensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy should undergo neurological evaluation and may require the dose and schedule of VELCADE to be modified. Neuropathy has been managed with supportive care and other therapies. Improvement in, or resolution of, peripheral neuropathy was reported in 51% of patients with Grade 2 peripheral neuropathy in the single agent phase III multiple myeloma study and 71% of patients with grade 3 or 4 peripheral neuropathy or peripheral neuropathy leading to discontinuation of treatment in phase II studies, respectively.

In addition to peripheral neuropathy, there may be a contribution of autonomic neuropathy to some adverse reactions such as postural hypotension and severe constipation with ileus. Information on autonomic neuropathy and its contribution to these undesirable effects is limited.

Seizures

Seizures have been uncommonly reported in patients without previous history of seizures or epilepsy. Special care is required when treating patients with any risk factors for seizures.

Hypotension

VELCADE treatment is commonly associated with orthostatic/postural hypotension. Most undesirable effects are mild to moderate in nature and are observed throughout treatment. Patients developing orthostatic hypotension on VELCADE did not have evidence of orthostatic hypotension prior to treatment with VELCADE. Most patients required treatment for their orthostatic hypotension. A minority of patients with orthostatic hypotension experienced syncopal events. Orthostatic/postural hypotension was not acutely related to bolus infusion of VELCADE. The mechanism of this event is unknown although a component may be due to autonomic neuropathy. Autonomic neuropathy may be related to bortezomib or bortezomib may aggravate an underlying condition such as diabetic or amyloidotic neuropathy. Caution is advised when treating patients with a history of syncope receiving medicinal products known to be associated with hypotension; or who are dehydrated due to recurrent diarrhoea or vomiting. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medicinal products, rehydration or administration of mineralocorticosteroids and/or sympathomimetics. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, light-headedness or fainting spells.

Heart failure

Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported during bortezomib treatment. In a single agent phase III randomized, comparative study the incidence of heart failure in the VELCADE group was similar to that in the dexamethasone group. Fluid retention may be a predisposing factor for signs and symptoms of heart failure. Patients with risk factors for or existing heart disease should be closely monitored.

ECG Investigations

There have been isolated cases of QT-interval prolongation in clinical studies, causality has not been established.

Pulmonary Disorders

There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown aetiology such as pneumonitis, interstitial pneumonia, lung infiltration, and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. A pretreatment chest radiograph is recommended to determine if any additional diagnostic measures are necessary and to serve as a baseline for potential post-treatment pulmonary changes.

In the event of new or worsening pulmonary symptoms (e.g. cough, dyspnoea), a prompt diagnostic evaluation should be performed and patients treated appropriately. The benefit/risk ratio should be considered prior to continuing VELCADE therapy.

In a clinical trial, two patients given high-dose cytarabine (2 g/m² per day) by continuous infusion over 24 hours with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. Therefore, this specific regimen with concomitant administration with high-dose cytarabine (2g/m² per day) by continuous infusion over 24 hours is not recommended.

Renal Impairment

Renal complications are frequent in patients with multiple myeloma. Such patients should be monitored closely.

Hepatic Impairment

Patients with hepatic impairment should be treated with extreme caution and a dose reduction should be considered.

Hepatic Reactions

Rare cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include increases in liver enzymes, hyperbilirubinaemia, and hepatitis. Such changes may be reversible upon discontinuation of bortezomib.

Tumour lysis syndrome

Because bortezomib is a cytotoxic agent and can rapidly kill malignant plasma cells, the complications of tumour lysis syndrome may occur. 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.

Amyloidosis

The impact of proteasome inhibition by bortezomib on disorders associated with protein accumulation such as amyloidosis is unknown. Caution is advised in these patients.

Precautions with certain concomitant medicinal products

Patients should be closely monitored when given bortezomib in combination with potent CYP3A4inhibitors. Caution should be exercised when bortezomib is combined with CYP3A4- or CYP2C19 substrates.

Normal liver function should be confirmed and caution should be exercised in patients receiving oral hypoglycemics.

Potentially immunocomplex-mediated reactions

Potentially immunocomplex-mediated reactions, such as serum-sickness –type reaction, polyarthritis with rash and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should be discontinued if serious reactions occur.

In vitro studies indicate that bortezomib is a weak inhibitor of the cytochrome P450 (CYP) isozymes 1A2, 2C9, 2C19, 2D6 and 3A4. Based on the limited contribution (7%) of CYP2D6 to the metabolism of bortezomib, the CYP2D6 poor metabolizer phenotype is not expected to affect the overall disposition of bortezomib.

A drug-drug interaction study based on data from 12 patients, assessing the effect of ketoconazole, a potent CYP3A4-inhibitor, showed a bortezomib AUC mean increase of 35% (CI_90% [1.032 to 1.772]). Therefore patients should be closely monitored when given bortezomib in combination with potent CYP3A4-inhibitors (e.g. ketoconazole, ritonavir).

In a drug-drug interaction study based on data from 17 patients, assessing the effect of omeprazole, a potent CYP2C19-inhibitor, there was no significant effect on the pharmacokinetics of bortezomib.

Patients should be closely monitored when given bortezomib in combination with CYP2C19-inhibitors (e.g. fluoxetine).

In the absence of drug-drug interaction studies investigating the effect of CYP3A4-inducers on the PK of bortezomib, patients should be closely monitored when given bortezomib in combination with potent CYP3A4-inducers (e.g. rifampicin).

A drug-drug interaction study assessing the effect of melphalan-prednisone on VELCADE showed a 17% increase in mean bortezomib AUC based on data from 21 patients. This is not considered clinically relevant.

During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetics.

The following undesirable effects were considered to have at least a possible or probable causal relationship to VELCADE by the investigators during the conduct of 5 non-comparative Phase II studies and 1 comparative phase III trial VELCADE vs dexamethasone in 663 patients with relapsed or refractory multiple myeloma, of whom 331 received VELCADE as single agent. The safety database comprises data from patients with multiple myeloma or B-cell lymphocytic leukemia (CLL). Patients were treated with VELCADE as a single agent, or in combination with dexamethasone.

Adverse drug reactions are listed below by system organ class and frequency. Frequencies are defined as: 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), not known (cannot be estimated from the available data) including isolated reports.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Sanum-Kehlbeck

26 March 2009