(1) Stomatitis

Stomatitis is observed in over half of the cases of persons taking sirolimus. Most cases are mild, but the following actions should be continued as preventive measures before the onset of stomatitis.

1. Oral cleansing, moisturizing, and anti-inflammatory analgesia through gargling three or more times a day
2. Oral care through brushing or other means

Mouthwash containing Azunol® may be used for gargling.

If stomatitis develops despite these preventive measures, it may be treated using acetaminophen or non-steroidal anti-inflammatory drugs, narcotic analgesics, adrenal cortex hormones, and other drugs, as well as gargling with a local anesthetic, depending on the degree of pain. Although few cases are serious, discontinuing or reducing the dosage of sirolimus should be considered if pain reduces food ingestion.

(2) Acneiform rash

Acne-like red papules and pustules appear on the head, face, precordium, lower abdomen, thighs, etc., at the location of pores. The rash resembles acne but unlike acne, may not be accompanied by bacterial infection. Depending on the symptoms, antibiotics and topical steroids are used as treatments.

(3) Dyslipidemia

As mTOR, which is suppressed by sirolimus, is involved in cell metabolism, oral administration of sirolimus may result in a variety of metabolic abnormalities. The most common of these is dyslipidemia (hypercholesteremia). As treatment, serum lipid testing is performed regularly, and dietary therapy and statin or other drug therapy are performed. If these treatments do not yield improvements, discontinuing or reducing the dosage of sirolimus should be considered.
In an MLSTS trial, six subjects had been under the oral administration of statins for hyperlipidemia prior to taking sirolimus. At the end of the trial, 15 subjects were taking statins. Improvement in hyperlipidaemia due to oral treatment was observed in 13 of the 15 subjects. By contrast, of the 57 subjects who did not exhibit hyperlipidemia prior to taking sirolimus, 20 did not exhibit hyperlipidemia at the end of treatment (with seven subjects leaving the study midway). Summarizing the outcome, hyperlipidemia was observed in about four out of six subjects taking sirolimus. Three out of four subjects who contracted hyperlipidemia were treated with dietary therapy; in the remaining one out of four, hyperlipidemia was treated with oral drug (statin) therapy.

(4) Interstitial lung disease

Subjects with LAM often exhibit decreased respiratory function. As Japanese people are more likely to develop drug-induced interstitial lung disease than Westerners, this sirolimus side effect is a disorder that requires particular attention. Subjective symptoms include dry coughing (coughing without sputum), dyspnea, and fever; however, in some cases, only abnormalities in chest X-rays and CT photographs have been observed, with no subjective symptoms. Before beginning the oral administration of sirolimus, it is necessary to perform a chest CT examination and confirm the absence of symptoms, such as coughing, dyspnea, and fever. After the oral administration of sirolimus, chest CT scans should be performed regularly. If changes in respiratory symptoms are observed, changes in the chest CT scans should be confirmed. If new shadows (particularly interstitial shadows) are observed in chest X-ray or CT scans, it is important to identify the interstitial lung disease and take early action.

In an MLSTS trial, interstitial lung disease was observed in three patients, thought to be due to sirolimus. While the period from the oral administration of sirolimus to the onset of interstitial lung disease varied from 1.5 months to 11 months, chest CT scans showed new ground-glass opacity shadows in all three cases. However, all three subjects recovered following the discontinuation of sirolimus and treatments that included steroids.

(5) Infectious diseases

Due to its immunosuppressive action, sirolimus can cause the onset of infection, particularly opportunistic infection caused by attenuated pathogens. There have also been cases reported of individuals who were not affected by LAM but in whom the hepatitis B virus was activated while under the oral administration of sirolimus, resulting in serious liver damage. Accordingly, screening should be performed for HBs antigen in all cases before the start of treatment. If past incidence of hepatitis B virus is suspected as a result, measures should be taken in accordance with the Guidelines for Measures against Hepatitis B Caused by Immunosuppression/Chemotherapy.

Side effects not widely reported

mTOR, which is suppressed by sirolimus, plays a role in cellular growth and proliferation. As a result, sirolimus has effects on skeletal muscle, the liver, the pancreas, adipose tissue, and other organs of the body. In an MLSTS trial, weight loss was observed in 33 out of 63 subjects. However, the degree of loss was slight, and no subject exhibited a decrease in appetite. In addition, 24 months after the oral administration of sirolimus, systolic blood pressure increased by 9.6 mmHg and diastolic blood pressure increased by 5.9 mmHg on average. Of the subjects, five were diagnosed with hypertension and began treatment with oral hypotensive drugs.