Announcement of the China Food and Drug Administration on Revising the Instructions for Clodronate Disodium Preparations

According to the results of the adverse drug reaction assessment, in order to further ensure the safety of the public use of drugs, the State Drug Administration has decided to uniformly revise the contents of the instructions for clodronate disodium preparations
.
The relevant matters are hereby announced as follows: 1.
The marketing authorization holders of the above-mentioned drugs shall comply with the relevant provisions of the "Administrative Measures for Drug Registration" and in accordance with the requirements for the revision of the instructions for clodronate disodium preparations (see attachment), on February 21, 2022 A few days ago, it was reported to the Drug Evaluation Center of the State Drug Administration or the provincial drug supervision and administration department for the record
.
If the revised content involves the label of a drug, it shall be revised together; the instructions and other content of the label shall be consistent with the original approved content
.
Drugs produced on the date of filing shall not continue to use the original drug instructions
.
The holder of the drug marketing authorization shall replace the instructions and labels of the drugs that have been shipped out of the factory within 9 months after filing
.
2.
The drug marketing license holder shall conduct in-depth research on the mechanism of new adverse reactions, take effective measures to conduct publicity and training on drug use and safety issues, and instruct physicians and pharmacists to use drugs rationally
.
3.
Clinicians and pharmacists should carefully read the revised contents of the above-mentioned drug inserts, and when choosing medications, they should conduct a sufficient benefit/risk analysis based on the newly revised inserts
.
4.
The patient should read the drug insert carefully before taking the medicine.
If using prescription drugs, they should strictly follow the doctor's advice
.
5.
The provincial drug supervision and administration department shall supervise and urge the drug marketing license holders of the above-mentioned drugs in the administrative area to do the corresponding manual revision and label and manual replacement work as required, and severely investigate and punish violations of laws and regulations in accordance with the law
.
Special announcement
.
Attachment: Requirements for the revision of the instructions for clodronate disodium preparations National Food and Drug Administration November 22, 2021 Annex: Requirements for the revision of the instructions for clodronate disodium preparations The following information should be included to monitor the following adverse reactions/events of clodronate disodium preparations after marketing: 1.
Digestive system: nausea, vomiting, abdominal pain, abdominal distension, diarrhea
.
2.
Systemic reactions: fever, chills, chest discomfort, pain, fatigue
.
3.
Skin and subcutaneous tissue: rash, itching
.
4.
Nervous system: dizziness, decreased sensation
.
5.
Respiratory system: difficulty breathing, suffocation
.
6.
Musculoskeletal and connective tissue: myalgia, bone pain, back pain, osteonecrosis of the jaw and atypical femoral fractures are very rare after long-term extensive use
.
7.
Metabolism and nutrition: hypocalcemia
.
(2) [Precautions] The following should be included: 1.
Sufficient fluid intake must be maintained during clodronate treatment.
This is especially important when patients with hypercalcemia or impaired renal function are treated with clodronate
.
Patients with renal failure should be cautious when using clodronate.
Patients with moderate and severe renal failure are advised to reduce the daily dose of clodronate
.
2.
Among cancer patients receiving intravenous or oral bisphosphonate treatment regimens, there have been reports of osteonecrosis of the jaw, usually related to oral treatment procedures and/or local infections (including osteomyelitis)
.
Many of these patients also receive chemotherapy and corticosteroid therapy
.
In patients with risk factors (such as cancer, chemotherapy, radiotherapy, corticosteroid treatment, poor dental hygiene), preventive dental examinations should be performed before bisphosphonate treatment, and bisphosphonate treatment in these patients Invasive dental procedures should be avoided
.
(3) [Drug interactions] The following should be included: 1.
Simultaneous use with other bisphosphonates is prohibited
.
2.
Clodronate and divalent cations can form insoluble complexes
.
Therefore, this product should not be taken at the same time with foods or drugs containing calcium or other divalent cations (such as antacids or iron preparations)
.
3.
Clodronate is used in combination with non-steroidal anti-inflammatory drugs (NSAIDs), the most common is diclofenac, which has been reported to cause renal insufficiency
.
4.
Due to the increased risk of hypocalcemia, special care should be taken when using clodronate and aminoglycosides at the same time
.
(Note: If the other contents of the instructions are inconsistent with the above revision requirements, they should be revised together
.
) 2.
Clodronate disodium injection (1) [Adverse reactions] should include the following content.
The following adverse reactions/events of sodium preparations: 1.
Digestive system: nausea, vomiting, abdominal pain, abdominal distension, diarrhea
.
2.
Systemic reactions: fever, chills, chest discomfort, pain, fatigue
.
3.
Skin and subcutaneous tissue: rash, itching
.
4.
Nervous system: dizziness, decreased sensation
.
5.
Respiratory system: difficulty breathing, suffocation
.
6.
Musculoskeletal and connective tissue: myalgia, bone pain, back pain, osteonecrosis of the jaw and atypical femoral fractures are very rare after long-term extensive use
.
7.
Metabolism and nutrition: hypocalcemia
.
(2) [Precautions] The following should be included: 1.
During clodronate treatment, adequate fluid intake must be maintained, intravenous infusion of clodronate and patients with hypercalcemia or renal impairment should use clodronate This is especially important during treatment
.
Patients with renal failure should be cautious when applying clodronate.
It is recommended to reduce the infusion dose of clodronate according to renal function.

.
2.
The intravenous dose of clodronate may cause severe renal damage when the dose is significantly higher than the recommended dose, especially when the infusion rate is too fast
.
3.
Among cancer patients receiving intravenous or oral bisphosphonate treatment regimens, there have been reports of osteonecrosis of the jaw, usually related to oral treatment procedures and/or local infections (including osteomyelitis)
.
Many of these patients also receive chemotherapy and corticosteroid therapy
.
In patients with risk factors (such as cancer, chemotherapy, radiotherapy, corticosteroid treatment, poor dental hygiene), preventive dental examinations should be performed before bisphosphonate treatment, and bisphosphonate treatment in these patients Invasive dental procedures should be avoided
.
(3) [Drug interactions] The following should be included: 1.
Simultaneous use with other bisphosphonates is prohibited
.
2.
Clodronate and divalent cations can form insoluble complexes
.
Therefore, this product should not be used intravenously with solutions containing divalent cations (such as Ringer's solution)
.
3.
Clodronate disodium is used in combination with non-steroidal anti-inflammatory drugs (NSAIDs), the most common is diclofenac, which has been reported to cause renal insufficiency
.
4.
Due to the increased risk of hypocalcemia, special care should be taken when using clodronate and aminoglycoside antibiotics at the same time
.
(Note: If the other contents of the instructions are inconsistent with the above-mentioned revision requirements, they should be revised together
.
) 3.
Clodronate disodium for injection (1) [Adverse reactions] should include the following contents.
The following adverse reactions/events of sodium preparations: 1.
Digestive system: nausea, vomiting, abdominal pain, abdominal distension, diarrhea
.
2.
Systemic reactions: fever, chills, chest discomfort, pain, fatigue
.
3.
Skin and subcutaneous tissue: rash, itching
.
4.
Nervous system: dizziness, decreased sensation
.
5.
Respiratory system: difficulty breathing, suffocation
.
6.
Musculoskeletal and connective tissue: myalgia, bone pain, back pain, osteonecrosis of the jaw and atypical femoral fractures are very rare after long-term extensive use
.
(2) [Precautions] The following should be included: 1.
During clodronate treatment, adequate fluid intake must be maintained, intravenous infusion of clodronate and patients with hypercalcemia or renal impairment should use clodronate This is especially important during treatment
.
2.
Among cancer patients receiving intravenous or oral bisphosphonate treatment regimens, there have been reports of osteonecrosis of the jaw, usually related to oral treatment procedures and/or local infections (including osteomyelitis)
.
Many of these patients also receive chemotherapy and corticosteroid therapy
.
In patients with risk factors (such as cancer, chemotherapy, radiotherapy, corticosteroid treatment, poor dental hygiene), preventive dental examinations should be performed before bisphosphonate treatment, and bisphosphonate treatment in these patients Invasive dental procedures should be avoided
.
(Note: If the other contents of the manual are inconsistent with the above revision requirements, they should be revised together
.
)